ARBITER 6-HALTS: HDL Raising With Niacin Superior to Ezetimibe

Monday, November 30, 2009

by Michael O'Riordan

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November 18, 2009 — Adding extended-release niacin (Niaspan, Abbott) to statin therapy results in a significant regression of atherosclerosis as measured by carotid intima-media thickness (IMT), whereas the addition of ezetimibe (Zetia, Merck/Schering-Plough) to statin therapy did not, according to an eagerly anticipated study [1].

The results, from the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6: HDL and LDL Treatment Strategies in Atherosclerosis (ARBITER 6-HALTS) study, were presented at the American Heart Association 2009 Scientific Sessions and published simultaneously online in the New England Journal of Medicine.

"The proper framework of the ARBITER 6-HALTS study is to compare the effectiveness of two drugs," lead investigator Dr Allen Taylor (Medstar Research Institute, Washington, DC) told heartwire . "In this regard, the data are clear--niacin is clearly superior to ezetimibe. That's good news for patients, and it's also good news for doctors who need to know how different drugs compare against one another so they can practice evidence-based medicine."

Dr James Stein (University of Wisconsin, Madison), who was not part of the ARBITER 6-HALTS trial, told heartwire that while the study tells clinicians little, if anything, about ezetimibe, the results are good news for niacin.

"If you practice evidence-based medicine in 2009, after high-dose statin therapy, niacin is your number-two drug," he said. "The amount of evidence available for niacin, although it's less than for high-dose statins, dwarfs the evidence available for any of the prevention interventions that we currently have available. It certainly dwarfs the evidence available for ezetimibe and fibrates, and we really think that niacin should be the number-two drug for all patients who are taking a statin and that doctors should rarely be using ezetimibe these days."

Dr Steven Nissen (Cleveland Clinic, OH), also commenting on the results for heartwire , called ARBITER 6-HALTS a classic "comparative-effectiveness" study and said there have been calls in the US legislature for such trials for the past few years.

"Now, here it is," he said. "Niacin is a 50-year-old drug, and you can buy it over the counter at your local pharmacy. When you have an inexpensive therapy like this--there are issues about being able to tolerate high-dose niacin, but if you get patients to tolerate it--niacin looks to be a better strategy."

Significant Difference in IMT

The results of the ARBITER 6-HALTS study have been keenly awaited, but not because clinicians questioned the efficacy of niacin. Previous studies have shown that niacin, alone or in combination with other drugs, including simvastatin, was associated with plaque stabilization or a modest regression of atherosclerosis.

Instead, the ARBITER 6-HALTS study was anticipated because investigators compared two distinct lipid-modifying strategies in patients who had or who were at high risk for vascular disease but who had LDL-cholesterol levels <100 mg/dL and moderately low HDL-cholesterol levels (<50 mg/dL). Among the 363 patients enrolled in the study, half were randomized to a treatment that further reduced LDL-cholesterol levels with the addition of ezetimibe (10 mg/daily) to statin therapy, while the other half were randomized to HDL-raising therapy with extended-release niacin (2000 mg/daily).

Coupled with the unique treatment approaches, many wondered how ezetimibe would fare given its rash of negative press from recent clinical trials, among them the controversial ENHANCE study and the SEAS trial.

In ARBITER 6-HALTS, men and women with known vascular disease or coronary-disease risk equivalents treated with statins for at least three months prior to randomization were included in the study. At baseline, the mean LDL-cholesterol level was 84 mg/dL and 81 mg/dL in the niacin- and ezetimibe-treatment arms, respectively. After 14 months of treatment, mean HDL-cholesterol levels among the niacin-treated patients increased 18.4% to 50 mg/dL. In the ezetimibe arm, LDL-cholesterol levels further declined 19.2% to 66 mg/dL.

Compared with ezetimibe, treatment with niacin resulted in significantly larger changes in the mean and maximal carotid IMT over 14 months. From baseline, niacin resulted in a significant regression of mean and maximal carotid IMT when measured at eight months and 14 months, whereas there was no significant change in mean or maximal IMT among those treated with ezetimibe. Although not powered for clinical outcomes, there were more major cardiovascular events in the ezetimibe arm compared with those in the niacin arm (nine events vs two events, respectively; p=0.04).

Addressing the results, Taylor said the findings answer an important clinical question in secondary prevention. "If my patient is on a statin, then where do I go from here?" he said. "These results suggest that niacin is superior in a head-to-head trial with ezetimibe."

Stein, a researcher with experience in IMT studies, said the amount of regression with niacin is significant.

"The difference between niacin and ezetimibe in the IMT measurements is very large," he told heartwire . "The difference of 0.017 mm over 14 months is on the order of statin therapy vs placebo. It's essentially as effective as a statin and would be expected to translate into a large difference in cardiovascular events, which was observed in this study, although they occurred in a study that was short and small."

In a post hoc analysis exploring the relationship between changes in LDL-cholesterol levels and mean carotid IMT, investigators observed a "significant inverse relationship" between changes in LDL-cholesterol levels and mean carotid IMT in the ezetimibe arm, "such that a paradoxical increase in the carotid IMT was seen in patients with greater reductions in LDL cholesterol."

Taylor said his group performed the post hoc analysis based on the null effect with ezetimibe because they wanted to determine whether any patients, particularly those with the lowest on-treatment LDL-cholesterol levels, might have benefited from the LDL-cholesterol–lowering drug. The inverse relationship is counterintuitive, he acknowledged, and while it is only a weak to modest association, he said it raises some concerns about possible unintended biologic effects with the agent.

Relying on Surrogate End Points for Clinical Decisions

Speaking with heartwire , Dr Sanjay Kaul (Cedars Sinai Medical Center, Los Angeles) cautioned against making too much of the overall results, especially since ARBITER 6-HALTS was a small, short-duration, surrogate-end-point study that was prematurely stopped (40% of patients did not undergo the final IMT measurement at 14 months). He said that physicians should take these issues into account when interpreting the findings.

He expressed particular concern about the study's early termination, as did an editorial by Drs Roger Blumenthal and Erin Michos (Johns Hopkins University, Baltimore, MD) [2], saying there are only three reasons a trial should be stopped, and these are futility, unacceptable safety profile, or a large treatment effect where the ethical imperative is to protect the trial participants.

While the treatment effect between niacin and ezetimibe achieved statistical significance at the time of the interim analysis, he said that differences in carotid IMT do not justify early termination, because it is unclear what these differences actually mean. Although he also criticized the early termination of JUPITER, the rosuvastatin study, in 2008, that study was at least terminated early because of differences in hard clinical outcomes.

"I don't think we should be relying on surrogate-end-point studies to make clinical decisions," he said. Kaul noted that the use of carotid IMT remains controversial and that the United States Preventive Services Task Force recently concluded that the evidence available to assess benefits and harms using nontraditional risk factors, including carotid IMT, as a risk-prediction tool in asymptomatic men and women is insufficient. He said it is still unknown at this point if the difference in IMT outcomes between ezetimibe and niacin will translate into clinically relevant outcomes.

"The results of this study do not provide any new insights and are unlikely to change my practice of prescribing ezetimibe only as a third-choice agent after trying statins as first choice and niacin, fibrates, or resins as second choice," he said.

To heartwire , Taylor said the trial was stopped because of a precisely defined prespecified interim analysis showing niacin to be superior to ezetimibe. Nissen called the discussion about the early termination "insider baseball," saying that while it can be debated whether or not the study should have been stopped, he said, "No reasonable person is going to look at the results and believe that the early termination had any impact on what happened. There are points to be made, but the real question is which strategy is best, and this study provides a hands-down winner."

Strengths and Weaknesses

To heartwire , Stein said the fact that such a large difference was able to be shown in such a short period of time tells doctors that the treatment effect was large. Although they differ on the significance of the IMT findings, Stein and Kaul both said the post hoc findings should be regarded with caution given the potential for confounding in these analyses.

According to Stein, while some might see the study as an indictment of ezetimibe, ARBITER 6-HALTS "tells us nothing about ezetimibe's effectiveness, because there was no placebo arm, but instead tells us that niacin is more effective than ezetimibe for preventing the progression of carotid atherosclerosis." One could argue, he said (although he doesn't believe the argument), that the lack of progression in the ezetimibe arm means the much-maligned drug was "doing something."

"At the end of the day, ARBITER 6 is really just an IMT study that looks at different strategies of lowering LDL vs raising HDL cholesterol," Stein told heartwire . "But we have to remember that niacin does a lot more than raise HDL cholesterol--that's what makes the study a little more complicated than saying it is a direct comparison of LDL lowering vs HDL raising. Niacin raises HDL cholesterol, but it also lowers LDL cholesterol, lowers triglycerides, and makes LDL particles bigger, so it’s really a multiple lipoprotein intervention."

To heartwire , Taylor agreed, but said that clinicians primarily select niacin to raise HDL cholesterol and rarely use the drug to lower LDL cholesterol or triglyceride levels. Data from clinical trials, including HATS, show the benefit of niacin to be primarily from changes in HDL cholesterol, he said.

Dr Richard Karas (Tufts Medical Center, Boston, MA), who was also not part of the study, told heartwire that given the relationship between HDL cholesterol and the risk of cardiovascular events, the results are in line with what would be expected from a drug that increases HDL cholesterol approximately 20%. By increasing HDL cholesterol to 50 mg/dL, clinicians are able to significantly decrease the residual risk of patients treated with statins alone, whereas the extra boost from LDL lowering has little impact on that risk. Like Stein, he said that ARBITER 6-HALTS tells clinicians little about ezetimibe and that they must wait until outcomes studies are completed.

The Outcomes Studies

IMPROVE-IT, the large clinical-outcomes study with ezetimibe, is expected in 2012 but likely to be later, while SHARP, a study of ezetimibe in patients with renal failure, is also under way. The two much-anticipated outcome studies for niacin are AIM-HIGH, due out in 2011, and HPS2-THRIVE, which is expected to be completed in 2013.

As an aside, editorialists Drs John Kastelein (Academic Medical Center, Amsterdam, the Netherlands) and Michel Bots (University Medical Center, Utrecht, the Netherlands) [3], as well as Nissen, raised concerns about whether IMPROVE-IT would ever reach completion. More than 5000 hard clinical end points are needed for the study to reach statistical significance, an unusually high number given that past studies, including JUPITER, required a few hundred events. Based on these concerns, many clinicians, among them Kaul and Nissen, reiterated their displeasure with an approval process that allowed ezetimibe to be on the market for more than a decade before any hard clinical end-point data are available.

Results Likely to Be Correct

In an editorial accompanying the published study, Kastelein and Bots write that the ARBITER findings are likely to be correct, although they, like others, suggest the magnitude of difference might be exaggerated because the trial was stopped early. Still, they argue in favor of a treatment approach with niacin.

"Together, the results available to date provide support for the concept that the use of statins to reduce LDL to target levels with the subsequent addition of a drug to raise HDL-cholesterol levels (niacin), rather than a drug to lower LDL-cholesterol levels (ezetimibe), is a more effective treatment for patients at high cardiovascular risk," they write.

In the second editorial, Blumenthal and Michos say there is substantial evidence for initial use of a statin in patients with an increased risk of vascular disease, but if the lipid goal can't be met with a statin alone, the choices of adjunctive therapy include a fibrate, niacin, a bile-acid sequestrant, n-3 fatty-acid supplements, or ezetimibe. For their money, though, they "support the use of niacin as the preferred adjunctive agent to be used in combination with the maximal dose of a potent statin in persons who have low levels of HDL cholesterol and established cardiovascular disease."

Abbott sponsored the ARBITER 6-HALTS study. Taylor reports receiving lecture fees from Abbott. Stein reports serving on the data monitoring committee for a nonniacin, Abbott-sponsored study, receiving a research grant from Siemens and SonoSite, and receiving royalties from the University of Wisconsin for carotid ultrasound and risk prediction not related to the ARBITER 6-HALTS study. Kastelein reports receiving consulting fees, lecture fees, and grant support from Merck and lecture fees from Schering-Plough. Bots reports lecture fees and grant support from AstraZeneca.


  1. Taylor AJ, Villines TC, Stanck EJ, et al. Extended-release niacin or ezetimibe and carotid intima-media thickness. N Engl J Med 2009; DOI:10.1056/NEJMoa907569. Available at:
  2. Blumenthal RS, Michos ED. The HALTS trials--halting atherosclerosis or halted too early? N Engl J Med 2009; 361:2178-2180.
  3. Kastelein JJ, Bots ML. Statin therapy with ezetimibe or niacin in high-risk patients. N Engl J Med 2009; 361: 2180-2183.
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No Benefits of Aspirin for Primary Prevention in Diabetics, Meta-Analysis Suggests

by Shelley Wood

Another meta-analysis--this one focused on diabetics--is questioning the role of aspirin for the primary prevention of cardiovascular events [1]. Writing in a paper published online November 6, 2009 in BMJ, Dr Giogria De Berardis (Consorzio Mario Negri Sud, Maria Imbaro, Italy) and colleagues conclude that "a clear benefit of aspirin in the primary prevention of major cardiovascular events in people with diabetes remains unproved."

We need to select very carefully the patients who are more likely to benefit.

De Berardis and colleagues point out that almost all of the major society guidelines recommend aspirin for primary prevention of cardiovascular events in people with diabetes, based on the evidence extrapolated from trials of high-risk patients. "Patients with diabetes have high cardiovascular risk, so it was supposed that aspirin was also effective in patients with diabetes," senior author Dr Antonio Nicolucci (Consorzio Mario Negri Sud) told heartwire . "But if we look at specific data coming from trials conducted in individuals with diabetes, quickly we realize that the evidence is not so strong."

Nicolucci, De Berardis, and their coinvestigators reviewed the literature for trials comparing aspirin with placebo or no aspirin in patients with diabetes and no known diagnosis of cardiovascular disease, ultimately identifying six eligible trials. When all of the data were combined, the authors found no statistically significant differences in the risk of major cardiovascular events, cardiovascular mortality, all-cause mortality, MI, or stroke, and "inconsistent" evidence of harm from aspirin use. In an analysis by sex, aspirin in men appeared to significantly reduce the risk of MI by 43%, but no significant reduction in MI was seen in women.

Effect of Aspirin Compared With Placebo or No Aspirin on Relative Risk of Clinical Events in Patients With Diabetes

End point Relative risk 95% CI p
Major cardiovascular events 0.90 0.81–1.00 0.06
MI 0.86 0.61–1.21 0.37
Stroke 0.83


0.60–1.14 0.25
Cardiovascular death 0.94 0.72–1.23 0.68
All-cause mortality 0.93 0.82–1.05 0.22
Any bleeding 2.50 0.76–8.21 NS

To heartwire , Nicolucci pointed to the meta-analysis [2] of aspirin for primary prevention published earlier this year in the Lancet by the AntithromboticTrialists' Collaboration and reported by heartwire --an update to their pivotal 2002 meta-analysis [3].

"It seems that not only in individuals with diabetes, but also in all other high-risk groups, the efficacy of aspirin for primary prevention is lower than expected. It doesn't mean that aspirin is not effective, it means that the efficacy is lower than expected, and that means we need to select very carefully the patients who are more likely to benefit."

Asked whether he thought guidelines should change, Nicolucci pointed out that guideline-writing committees are already softening their blanket recommendations.

"In the most recent guidelines from the Canadian Diabetes Association, for the first time they fully acknowledged the lack of definite data on the efficacy of aspirin, and they leave to the physician the decision of whether or not to use aspirin based on the characteristics of the individual patients. And the other [guideline groups] are starting to move from certainty to uncertainty as well."

Randomized Trial Results Needed

Two trials are currently trying to answer key questions about risk and benefit of aspirin for primary prevention in diabetic subjects: A Study of Cardiovascular Events in Diabetes (ASCEND) and the Aspirin and Simvastatin Combination for CardiovascularEvents Prevention Trial in Diabetes (ACCEPT-D).

In an accompanying editorial [4], Drs Richard Haynes, Louise Bowman, and Jane Armitage (Clinical Trial Service Unit, Oxford, UK) write that the evidence to date suggests "a modest but consistent reduction in the risk of vascular events with aspirin" but ongoing uncertainty as to whether these benefits are "clinically worthwhile" and outweigh the risks of bleeding.

Until clinical-trial results are in, they write, clinicians should use approaches "known to minimize cardiovascular risk (such as avoidance of smoking, [the use of] statins [and] ACE inhibitors, and good glucose control) before thinking about adding aspirin." Moreover, they note, "guidelines need to acknowledge the current equipoise and not recommend a treatment without supporting evidence, so that clinicians and their patients are fully aware of the evidence when making a decision."

To heartwire , Nicolucci points to another issue that warrants further exploration: whether there are specific characteristics of diabetic pathophysiology that make aspirin less likely to function as expected.

"There's strong basic research evidence suggesting that diabetes can represent a particular situation associated with poor response of platelets to aspirin, and there are many reasons for that," Nicolucci noted. "Diabetes is associated with hyperglycemia, hyperinsulinemia, insulin resistance, oxidative stress, and advanced glycation end products, and all these factors can be responsible for activation of platelets [via] different pathways that are not blocked by aspirin."

Nicolucci have disclosed no relevant financial relationships; he is principal investigator for ACCEPT-D. The editorialists having disclosed no relevant financial relationships; Armitage and Bowman are principal investigators for ASCEND.


  1. De Berardis G, Sacco M, Strippoli GFM, et al. Aspirin for primary prevention of cardiovascular events in people with diabetes: Meta-analysis of randomised controlled trials.  BMJ 2009; DOI:10.1136/bmj.b4531. Available at:
  2. Antithrombotic Trialists' (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009; 373:1849-1860.
  3. Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324:71-86.
  4. Haynes R, Bowman L, Armitage J. Aspirin for primary prevention of vascular disease in people with diabetes. BMJ 2009; DOI:10.1136/bmj.b4596. Available at:
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Pericardial fat a better predictor of CHD than BMI

Sunday, November 8, 2009

by Lisa Nainggolan

Winston-Salem, NC- A new study has shown that fat around the heart—so-called pericardial fat—predicts coronary heart disease (CHD) independent of conventional risk factors [1].

In fact, pericardial fat may be a better predictor of an individual's future risk of CHD than either body-mass index (BMI) or waist circumference, say Dr Jingzhong Ding (Wake Forest University School of Medicine, Winston-Salem, NC) and colleagues in their paper in the September 2009 issue of the American Journal of Clinical Nutrition.

Ding told heartwire: "We and other groups have previously found in cross-sectional studies that pericardial fat is related to coronary artery disease. Our new study extends the findings to demonstrate that pericardial fat predicts the future development of clinical events of CHD and that this kind of prediction is beyond that conferred by conventional obesity measures—the first time this has been shown."

Inflammatory cytokines secreted by pericardial fat could be the culprits

Ding et al conducted a case-cohort study in 998 individuals randomly selected from the more than 6000 participants of the Multi-Ethnic Study of Atherosclerosis (MESA), who had no history of CVD. The volume of pericardial fat was measured using cardiac CT scans performed at baseline in MESA.

Of the 998 individuals, 26 developed incident CHD during follow-up, from 2000 to 2005. Pericardial fat was positively correlated with both BMI (correlation coefficient=0.45; p<0.0001) and waist circumference (correlation coefficient=0.57; p<0.0001).

In unadjusted analyses, pericardial fat (relative hazard per one standard deviation increment 1.33), but not BMI (1.00), was associated with the risk of CHD. Waist circumference was marginally associated with CHD risk (1.14; p=0.1). The relation between pericardial fat and CHD remained significant after further adjustment for BMI and other cardiovascular disease risk factors (1.26).

"Our data support the idea that pericardial fat is a better predictor of incident CHD than are more general measures of adiposity (eg, BMI or waist circumference)," say Ding et al. "The present study extends the findings of other research in this field by relating pericardial fat to incident CHD in community-based adults without a history of CVD," they add.

Ding says he and his colleagues have a theory as to the possible mechanism underlying the link between pericardial fat and CHD. "The pericardial fat secretes many chemicals, such as inflammatory cytokines like IL-6," he noted. "We can postulate that direct secretion of such substances might lead to the development of atherosclerosis in the coronary arteries." Pericardial fat is also known to secrete such inflammatory cytokines at a higher rate than subcutaneous fat, he adds.

More research needed on pericardial fat

He told heartwire that much more research is needed on pericardial fat. In general, older people have been found to have more pericardial fat than younger ones, and the volume of pericardial fat does seem to correlate with BMI and other obesity measures, as shown in the current study. But slim people also have pericardial fat, he noted, and it is not known what amount is "normal," if any. Whether babies have pericardial fat present at birth, for example, is unclear. Nor is it known whether there is any kind of cutoff amount of this fat above which it becomes hazardous.

Future studies should also examine whether pericardial fat is the primary fat depot regarding the risk of developing CHD, after other regional fat depots are controlled for, say he and his colleagues. "If the hypothesis is confirmed, pericardial fat may serve as a more specific and sensitive marker of CHD than other fat measures."

However, they note that routine CT scans are not feasible for mass screenings at the present time, but the echocardiographic measurement of pericardial fat "has potential for CHD risk stratification."

"Ultimately, with a better understanding of the determinants of pericardial fat accumulation and the underlying mechanism of the link between pericardial fat and CHD, new therapeutic targets may be identified in the prevention of CHD," they conclude.


  1. Ding J, Hsu F-C, Harris TB, et al. The association of pericardial fat with incident coronary heart disease: the multi-ethnic study of atherosclerosis (MESA). Am J Clin Nutr 2009; 90:499-504.
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Drug-eluting stents for erectile dysfunction

by Shelley Wood

San Francisco, CA - Nine hospitals in the US are embarking on a stent trial that will no doubt perk the attention of interventionalists and patients alike. Amid all of the larger coronary stent trials making waves at TCT 2009 last week, Dr Jason H Rogers (UC Davis Medical Center, Sacramento, CA) got up and announced the launch of the ZEN trial, testing the use of a zotarolimus-eluting stent for the treatment of erectile dysfunction.

The trial, sponsored by Medtronic, is enrolling 50 men who've failed treatment with phosphodiesterase-5 (PDE-5) inhibitors and have angiographic evidence of internal pudendal artery disease amenable to percutaneous treatment.

Speaking with heartwire after TCT, Rogers reviewed the rationale for the trial. In four out of every five men with erectile dysfunction, he notes, the etiology is vasculogenic, and erectile dysfunction itself shares a host of risk factors with coronary artery disease, including age, diabetes, hypertension, dyslipidemia, and smoking.

"Up to 70% of men with coronary disease also have erectile dysfunction," Rogers said. "The development of erectile dysfunction predates the onset of symptomatic atherosclerotic disease by approximately 36 months, [yet] erectile dysfunction is not routinely screened by vascular specialists."

Correlation between vascular beds

Rogers and colleagues have already completed a pilot study, called the Pelvic Angiography in Non-Responders to PDE-5 Inhibitors (PANPI), which correlated angiographic evidence of coronary disease with pudendal arterial disease. In PANPI, 10 patients undergoing coronary angiography for CAD symptoms who also reported a poor response to PDE-5 inhibitors underwent a pelvic angiogram as well. Results showed that stenosis in the coronary arteries typically mirrored that of the pudendal artery, which ranged from a mean of 52% in the right internal pudendal artery to 60% in the left.

"We basically found a 100% correlation" between coronary artery disease and pudendal artery disease, Rogers told heartwire, "The pattern of disease is similar to that of the coronary arteries, and it appeared that it would be amenable to a stent."

Surprisingly—or not—men enrolled in PANPI were not overly interested in their coronary angiograms. "Despite the fact that we were diagnosing significant stenosis in the [left anterior descending] LAD, circumflex, and right coronary arteries, what they cared about was what the pudendal angiograms were showing," Rogers said.

Rogers noted that, to the best of his knowledge, there are no other studies looking at drug-eluting stents in the pudendal artery, although there were some early angioplasty studies that typically failed to demonstrate a long-term benefit due to problems of restenosis. Rogers would not reveal what stent is being used in ZEN, saying only that Medtronic was "leveraging technology in its inventory" and that this device was zotarolimus-eluting.

He also clarified: "This isn't stenting the penis," but rather the pudendal artery, which is located in the pelvis.

The ZEN trial represents a new opportunity for collaboration between urologists and cardiologists, Roger added—disciplines that have not interacted closely in the past. "A key message for cardiologists is that our practice is actually rich in patients with erectile dysfunction, and we don't do as good a job as we should at identifying people with erectile dysfunction," he told heartwire. "It's been shown that erectile dysfunction is a risk factor for CAD or CVD, and potentially, there may even be a therapy for this that cardiologists could deliver."

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Diuretics effective as second-line therapy for hypertension

by Lisa Nainggolan

Vancouver, BC - Diuretics, when given as second-line therapy to treat hypertension, reduce blood pressure to about the same extent as when they are used as first-line treatment, a new review shows.

The results also indicate that the BP-lowering effect of diuretics depends on the dose used but is independent of the type of first-line agent used; the latter being an unexpected finding, say Jenny MH Chen (University of British Columbia, Vancouver) and colleagues in a report published October 7, 2009 in the Cochrane Database of Systematic Reviews.

Hydrochlorothiazide (HCTZ) was the diuretic used in 92% of the studies included in this review, and it has recently been the subject of some criticism.

But Chen told heartwire she did not believe this to be warranted: "We believe that the recent criticism of HCTZ is misguided and not an accurate reflection of the evidence. Our review adds to the body of evidence demonstrating that HCTZ is indeed effective in lowering trough blood pressure; it can be given as a single daily pill and is an excellent drug choice for patients as the first or second drug."

Dr Franz Messerli (St Luke's Roosevelt Hospital, New York, NY), the lead author of a recent meta-analysis that concluded that HCTZ is a "paltry" antihypertensive at the usual doses prescribed (12.5-25 mg), told heartwire: "The meta-analysis of Chen et al is thorough and comprehensive, as one expects from this well-experienced team." But, he says, it is outcomes that are important, not merely lowering blood pressure, and there are no outcome data as yet for HCTZ 12.5 to 25 mg. "All outcome data with so-called 'thiazides' are based on chlorthalidone and indapamide."

Better information about BP-lowering effects of diuretics used second-line

Chen and colleagues say diuretics are widely prescribed for hypertension, not only as initial therapy but also as second-line treatment. This new analysis is the first to look at the additional reduction in BP with diuretics when given in combination with other antihypertensive drugs, they explain.

"It is possible for the effect of a diuretic as a second-line drug to be additive, subadditive, or synergistic," they observe. The aims of the review were to quantify the additional BP reduction achieved with a diuretic as a second drug vs placebo and to compare withdrawals due to adverse effects between a diuretic as a second drug and placebo.

"This review should be able to provide clinicians with better information about the magnitude of BP lowering when a diuretic is given as second-line therapy in the management of elevated blood pressure," they note.

There were 53 double-blind, randomized controlled trials evaluating a thiazide in 15 129 hypertensive patients (average baseline BP 156/101 mm Hg) included in the review. HCTZ was the thiazide used in 49 of the 53 (92%) included studies.

Thiazides as a second-line drug reduced BP by 6/3 mm Hg and 8/4 mm Hg at doses of one and two times the manufacturer's recommended starting dose, respectively. The antihypertensive effect was dose related and similar to that obtained when thiazides are used as a single agent.

Adding a thiazide diuretic as a second-line agent in combination resulted in greater reduction in BP compared with monotherapy without a thiazide.

Only three double-blind trials using loop diuretics were identified. This type of diuretic appeared to have a similar BP-lowering dose as thiazides at the recommended starting dose, the researchers say, although they acknowledge the evidence for this particular drug class is "weak." And due to wide confidence intervals, it was not possible to assess how loop diuretics compared with thiazides, they note.

Effect independent of first-line drug, or not?

Chen et al also showed that the BP-lowering effect of thiazides, particularly HCTZ, is independent of the type of first-line drug used, "a finding that was not expected," they say.

Based on the proposed mechanism of action, most doctors believe that adding a thiazide to an ACE inhibitor or an angiotensin receptor blocker (ARB) would have a greater effect than adding it to a calcium-channel blocker (CCB), they explain.

But Messerli says the claim that HCTZ's antihypertensive efficacy as an add-on was independent of the first-line drug used was "only true when 25 mg was given, whereas at lower doses (12.5 mg) the addition of HCTZ elicited a greater response in patients who were taking a renin angiotensin system (RAS) blocker [ACE inhibitor or ARB] than in those on a CCB. The authors shrug off these findings as being due to chance," he observes.

Unable to evaluate long-term side effects

Unfortunately, because of the short duration of trials and lack of reporting of adverse events, this review "does not provide a good estimate of the incidence of adverse effects of diuretics given as a second-line drug," Chen et al say. The trials were also carried out in predominantly white populations; therefore, further research of the BP-lowering effects of thiazides in people of other ethnicities is needed.

Chen commented to heartwire: "We agree that our data were not good at estimating side effects with long-term therapy. They did suggest that diuretics did not increase the rate of withdrawals due to adverse effects in the first three- to 12-week treatment period and thus appear well-tolerated at least for short-term therapy."

But, "Fortunately, there are also long-term trials showing the benefits of first-line thiazides in reducing mortality and morbidity, so we do not think our inability to estimate side effects is an important limitation," she added.

In conclusion, she told heartwire: "Thiazide diuretics are recommended as first-line agents in the treatment of hypertension" because "the evidence for the other classes of drugs such as beta blockers, ACE inhibitors, and CCBs, for example, is less robust."

However, Messerli begs to differ: "The authors get carried away by stating that thiazide diuretics are recommended as first-line agents because the evidence for other drug classes is less robust," but they "seem to forget that there are no outcome data for HCTZ in doses of 12.5 to 25 mg. Most important, we should remember that outcome data comparing combination therapy are scarce.

"The only convincing study is ACCOMPLISH, in which a fixed combination of amlodipine and benazepril was clearly superior to a fixed combination of benazepril and HCTZ with regard to morbidity and mortality. Since BP was lowered to the same extent in both treatment arms, this would indicate that antihypertensive effect per se is of limited value when assessing combination therapy," he concludes.


  1. Chen JMH, Heran BS, Wright JM, et al. Blood pressure lowering efficacy of diuretics as second-line therapy for primary hypertension. Cochrane Database Syst Rev 2009; 4:CD007187.
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ARBs, Diuretics, and Noise -- Plus New Guidelines for Children

by Linda Brookes, MSc

Most of the news this month comes from the European Society of Cardiology conference that was held in Barcelona, Spain, August 29-September 2, 2009. Two Japanese trials investigated the benefits of angiotensin receptor blockers (ARBs), which appear to have benefit in angina and stroke, but not myocardial infarction. Is it because of their ability to lower blood pressure or is it the drug class itself that is responsible for these effects? The second trial --Valsartan Amlodipine Randomized Trial (VART) repeated the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial, but this time with equal blood pressure lowering achieved for the ARB and the dihydropyridine calcium channel blocker (CCB); the results showed no difference in the cardiovascular endpoints. There was some speculation that the results provide further evidence that the renin-angiotensin system (RAS) has a larger role in vascular reactivity (angina, stroke) than in coronary disease where rupture of atheromas and thrombosis are major determinants, but the patient enrollments were different enough (younger, lower risk in VART) to make the comparison difficult. Further analysis of hypertension trials reporting a heart failure incidence looked at results in 217,387 patients and found that a diuretic (chlorthalidone preferred!) plus a RAS inhibitor are the best prevention. Although this appears to support the results of ALLHAT, the authors remain critical of that trial. Finally, the European Society of Hypertension (ESH) has formally published the new pediatric hypertension guidelines, first announced during the ESH conference in June, and in a wholly separate vein, a study has found that the higher the environmental noise in a child's living situation, the higher the mean blood pressure and the higher the risk fordisease later in life.

Valsartan Prevents Angina and Stroke but not Myocardial Infarction in High-Risk Japanese Hypertensive Patients

A large Japanese clinical study with valsartan in hypertensive patients has confirmed the efficacy of an ARB in lowering blood pressure and preventing stroke, but has failed to answer the lingering question about the efficacy of ARBs in preventing coronary events. The results of the KYOTO HEART study were presented by principal investigator Hiroaki Matsubara, MD (Kyoto Prefectural University School of Medicine) at the recent 2009 Congress of the European Society of Cardiology (ESC) in Barcelona, Spain[1] and published simultaneously in the European Heart Journal.[2] The study, which was carried out between January 2004 and January 2009, was funded by the Kyoto Prefectural University School of Medicine.

The study involved 3031 Japanese patients (43% women, mean age 66 years) with treated but uncontrolled hypertension (mean sitting systolic blood pressure [SBP] ≥ 140 mm Hg and/or diastolic blood pressure [DBP] ≥ 90 mmHg) and ≥ 1 additional risk factor. Following a prospective, randomized, open-label, blinded endpoints (PROBE) design, patients received either valsartan add-on or non-ARB treatment (conventional antihypertensive treatment other than ARBs or angiotensin converting enzyme [ACE] inhibitors) to reach the blood pressure goal of < 140/90 mm Hg or < 130/80 mm Hg in patients with diabetes mellitus or renal disease.[3] Valsartan was started at a dose of 40-80 mg and titrated to 100-160 mg as necessary to reach the target blood pressure (< 140/90 mm Hg or < 130/80 mm Hg in patients with renal disease).

The study was stopped early after a median follow-up of 3.27 years because of an unequivocal benefit seen with valsartan. During this time mean blood pressure was lowered from 157/88 mm Hg to 133/76 mm Hg. Compared with non-ARB treatment, valsartan add-on was associated with a 45% reduction in the primary endpoint of the trial, a composite of cardiovascular and cerebrovascular events (83 vs 155; hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.42-0.72; P = .00001). This difference was mainly attributable to a 49% reduction in angina pectoris (P = .01 vs non-ARB) and a 45% reduction in stroke/transient ischemic attack (TIA) (P < .05 vs non-ARB). There were no significant differences in acute myocardial infarction (MI), heart failure, aortic dissection, and other endpoint components or in all-cause mortality or cardiovascular mortality. The incidence of new-onset diabetes was significantly lower with valsartan (P = .0282).

In the European Heart Journal, Prof. Matsubara and his colleagues speculated that the RAS has a larger role in the development of angina than in MI, in which rupture of atheromas and thrombosis are major determinants They suggested that sincevalsartan has been shown to have the highest selectivity for the angiotensin type 1 (AT1) receptor vs the AT2 receptor compared with other ARBs, AT2 receptor-mediated vascular protection via activation of bradykinin/NO system is more enhanced with valsartan treatment. They note that AT2 receptor is expressed in atherosclerotic lesions and that valsartan treatment effectively blocks coronary artery thickening and perivascular fibrosis.


Referring to this as the "ARB paradox" in Barcelona, ESC designated discussant, Frank Ruschitzka, MD (University Hospital, Zurich, Switzerland) called the results of the KYOTO HEART study "impressive, but almost too good to be true." Angina was a weak endpoint in the study, and he regarded it as being of minor value, particularly on the background of no benefit on MI. In an editorial in the European Heart Journal,[4] Dr Ruschitzka, along with coauthors Franz H. Messerli (St Luke's Roosevelt Hospital and Columbia University, New York) and Sripal Bangalore, MD (Brigham and Women's Hospital, Boston), described a meta-analysis that they carried out on 26 randomized non-heart failure trials of ARBs involving > 100,000 patients.[4] The analysis included the most recently reported trials, including TRANSCEND,[5] PRoFESS,[6] CASE-J,[7] HIJ-CREATE,[8] JIKEI,[9] as well as the KYOTO HEART study. Overall, they found a 13% reduction in the risk for stroke (P = .022) but a trend toward increased risk for MI (P = .06).

ARBs as a class have come of age and can be considered as preferred or baseline therapy in hypertension with regards to safety and efficacy, if efficacy is defined as blood pressure reduction, Dr Ruschitzka and his co-authors said. However, if efficacy is defined as a reduction in overall cardiovascular events and mortality, in view of the data in aggregate, ARBs should not be preferred, "or perhaps, not yet."

Effects of Valsartan and Amlodipine Differ in Japanese Hypertensive Patients in the Valsartan Amlodipine Randomized Trial

The results of another Japanese clinical trial involving valsartan in hypertensive patients, the Valsartan Amlodipine Randomized Trial (VART) were presented at ESC 2009 in Barcelona by Hiroya Narumi, MD (Chiba University Graduate School of Medicine, Chiba, Japan).[10] Similar to the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial,[11] VART compared valsartan with the CCB amlodipine, but following a PROBE design.[12]

VART was a multicenter trial involving a total of 1021 patients (mean age 60 years) enrolled at 92 medical facilities between June 2002 and March 2006. All patients were 30 years of age or older and newly diagnosed with hypertension (sitting SBP ≥ 140 mm Hg or DBP ≥ 90 mm Hg) or already being treated with antihypertensive drugs. Patients were followed until March 2008. After discontinuation of any previous antihypertensive therapy, patients initially received valsartan 80 mg/day or amlodipine 5 mg/day. These doses were increased to 160 mg and 10 mg, respectively, and alpha-blockers, beta-blockers, or diuretics were added if blood pressure was > 135/85 mm Hg. After registration, patients were followed up for 3 years for cardiovascular events (Primary endpoints), with use of echocardiography, laboratory tests, and blood pressure, plus 123I-metaiodobenzylguanidine (123I-MIBG) imaging (to depict myocardial sympathetic activity) for 1 year.

Blood pressure levels were controlled and remained equal in both treatment groups. At 36 months, mean blood pressure was 135 ± 13/80 ± 19 mm Hg in the patients on valsartan; and 135 ± 14/80 ± 10 mm Hg in the patients on amlodipine. There was no significant difference between the 2 treatment arms for the primary endpoint, a composite of all-cause death and cerebrovascular, cardiac, vascular, and renal events (HR, 1.0; 95% CI, 0.57-1.97; P = .943). Additionally there was no significant difference in the individual endpoints that made up the composite, including acute MI, stroke, and heart failure.

However, significant improvements were seen in a number of secondary endpoints. At 36 months, left ventricular mass index (LVMI) was decreased in both groups, but the percent change in the valsartan group was significantly greater compared with the amlodipine group (P < .05). Plasma norepinephrine was significantly decreased with valsartan (P = .00495), but there was no significant change with amlodipine. At 24 months, 123I-MIBG uptake, calculated as the heart/mediastinum ratio, was significantly increased in the valsartan group (P < .0001) but not in the amlodipine group. At 36 months, there was significant increase in the urinary albumin/creatinine ratio (UACR) in the amlodipine group (P < .0001), but not in the valsartan group. Diagnoses of new-onset diabetes mellitus were recorded in only 1.7% of the valsartan group vs 3.4% of the amlodipine group (odds ratio [OR] 0.47, 0.20-1.11), although the increase did not reach statistical significance in either group. Dr Narumi concluded that the results suggested that valsartan has more beneficial effects on the heart and kidney of Japanese hypertensive patients than amlodipine.


ESC session co-chair Roland E Schmieder, MD (University of Erlangen-Nuremberg, Germany) called the VART results "very important data," and asked why the striking differences seen in intermediate endpoints in the trial did not translate into a better prognosis. Dr Narumi suggested that the reasons might be that the VART patients were younger compared with those in other large-scale clinical trials such as VALUE (mean age 67 years),[11] and that the patients in other trials were at higher risk. For example, the percentage of patients with diabetes in VART (about 8%) was lower than in other trials. He also noted that most of the patients in VART (about 70%) were on monotherapy.

Diuretics Best for Prevention of Congestive Heart Failure in Hypertension

Diuretics are the most effective antihypertensive drugs for prevention of heart failure, closely followed by ARBs and ACE inhibitors, according to the results of a large network meta-analysis presented at ESC 2009.[13] Presenting the data in Barcelona, Sebastiano Sciarretta, MD (University of Rome "La Sapienza," Italy), said that their network meta-analysis, the largest ever performed in essential hypertension, showed that all antihypertensive strategies, with the exception of those based on alpha-blockers, were more effective than placebo in preventing heart failure. CCBs were significantly less effective than diuretics as first-line agents and they also tended to be inferior to RAS blockers and beta-blockers, with the differences being very close to statistical significance, Dr. Sciarretta reported.

Hypertension is a major risk factor for the development of heart failure. Estimates from the Framingham Heart Study indicate that persistent hypertension is the predominant contributory factor in 40% of men and 60% of women in whom heart failure develops. Despite all the evidence, however, heart failure is usually considered a "soft" endpoint in hypertension clinical trials and greater attention has been given to MI and stroke, Dr. Sciarretta noted. He and his colleagues recently showed in another meta-analysis of hypertension trials that the overall incidence of heart failure was comparable with other measured cardiovascular events, and not significantly different from that for stroke.[14]

"Since there was no conclusive evidence about the optimal antihypertensive therapy among different classes of drugs in heart failure prevention in hypertensive subjects," Dr. Sciarretta said, he and his colleagues carried out a network meta-analysis of recent trials in hypertension to investigate the most effective antihypertensive strategies in heart failure prevention. They used computerized searches of PubMed and Embase databases to find clinical studies published in peer-reviewed English-language journals between 1997 and December 2008. The investigators identified 25 trials involving patients with hypertension or at high cardiovascular risk with a predominant presence of hypertensive patients (> 65%), involving ≥ 200 subjects, with a duration of follow-up of ≥ 2 years that reported the absolute incidence of heart failure and other major cardiovascular events. Dr. Sciarretta explained that the Bayesian network meta-analysis that they performed is a more powerful meta-analytic technique that combines direct evidence provided by clinical trials with indirect evidence constructed from studies that have treatments in common.

The 25 trials identified involved a total of 217,387 subjects. Among these individuals, 40.3% were randomized to receive "traditional" antihypertensive therapy, including mostly diuretics and anti-adrenergic agents; 18.6% of patients were assigned to diuretic-based therapy, 4.1% patients to alpha-blockers, and 2.2% to beta-blockers. The remaining patients were treated with the "newer" antihypertensive drug classes, including CCBs, ACE-inhibitors, and ARBs. In addition, 7.1% of patients were randomized to receive placebo or the best standard treatment for their condition. The trials used different definitions of heart failure, which was most often a secondary endpoint.

A total of 8291 new heart failure cases occurred in the trials. All the antihypertensive therapies with the exception of those based on alpha-blockers were more effective in preventing heart failure onset compared with placebo. Diuretics were the most effective class of drugs (OR, 0.56; 95% CI, 0.44-0.69), followed by ARBs (OR, 0.67; 95% CI, 0.52-0.80) and ACE-inhibitors (OR, 0.67; 95% CI, 0.56-0.79). CCBs appeared to have the smallest effect (0.78; 0.62-0.92). From direct comparisons in trials, diuretics appeared to be significantly more effective than ACE inhibitors, CCBs, and beta-blockers; although more effective than ARBs, this difference was not significant.

Because the trials used different definitions of heart failure, the investigators performed 3 subanalyses. The first included only studies that did not enroll patients with heart failure at baseline; the second excluded the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) studies (because of criticism about the diagnosis of heart failure in this study); and the third excluded the ALLHAT studies and other trials that also included an endpoint of non-hospitalized heart failure. However, the results of these subanalyses did not differ from those of the main analysis, in that diuretics still appeared to be the most effective compared with the other drug classes and CCBs appeared to be less effective than the others.


Dr. Sciarretta noted that this meta-analysis was unable to reveal any information about the influence of differences in blood pressure, but he noted that previous landmark meta-analyses showed that heart failure prevention was independent of blood pressure reduction.[15,16] He suggested that the most effective first-line therapy for prevention of heart failure in hypertensive patients is a combination of a low-dose diuretic and a RAS inhibitor.

Commenting on the results of the analysis, ESC session co-chair, Prof. Schmieder pointed out that diuretics differ substantially with respect to the duration of effect on blood pressure and dosage. "We know well from hypertension trials like ALLHAT[17] that chlorthalidone has a long-lasting effect at low dose, and it has been said that we will never see that result with hydrochlorothiazide (HCTZ)," he said. He noted that chlorthalidone is not used as much in Europe as it is in the United States, and not at doses > 25 mg because of potential adverse metabolic effects.

European Society of Hypertension Issues First Pediatric Hypertension Guidelines

The European Society of Hypertension's guidelines for the management of hypertension in children and adolescents, first announced at the European Meeting on Hypertension in May, have been published as a position statement in the Journal of Hypertension.[17] The guidelines comprise recommendations for diagnosis and treatment of hypertension in patients aged ≤ 18 years, a group largely omitted from previous European hypertension guidelines.[18] The new guidelines are aimed primarily at pediatricians and general practitioners.

These guidelines were prepared by a Task Force chaired by Empar Lurbe, MD, PhD (Consorcio Hospital General, University of Valencia, Spain). They represent a consensus among specialists involved in the detection and control of high blood pressure in children and adolescents. They include:

  • Definition and classification of hypertension;
  • Diagnostic evaluation;
  • Preventative measures;
  • Evidence for therapeutic management;
  • Therapeutic strategies and approaches under special conditions;
  • Treatment of associated risk factors; and
  • Screening for secondary forms of hypertension.

In the definition and classification of hypertension, Prof. Lurbe and co-authors acknowledge that because of the large amount of data available, the 2004 US national guidelines on hypertension in children and adolescents remain "the study of reference." However, they point out that the data of the US Task Force do not refer to a European population and that at all ages, blood pressure values are several millimeters of mercury lower than those measured by the same auscultatory method in several European studies. Both reports define normal blood pressure in children as SBP and DBP less than 90th percentile for age, sex, and height, and hypertension as SBP and/or DBP persistently at the 95th percentile or higher, measured on ≥ 3 separate occasions with the auscultatory method. Children with average SBP or DBP 90th percentile or more but < 95th percentile are classified as having high-normal blood pressure; adolescents with blood pressure 120/80 mm Hg, even if less than 90th percentile, are also considered as having high-normal blood pressure.

Blood pressure targets are < 90th percentile for age, gender, and height. In children with chronic kidney disease, the target is blood pressure < 75th percentile in children without proteinuria and < 50th percentile in cases of proteinuria. Data from lifestyle intervention trials in children on which to base recommendations are limited at present, but most recommendations, including moderate to vigorous aerobic physical activity, are "obvious and common sense," the Task Force says. The decision to initiate antihypertensive treatment should not be taken on blood pressure levels alone, but should also consider the presence or absence of target organ damage, other risk factors, or diseases such as obesity, renal diseases, or diabetes mellitus.

Pharmacologic therapy should be initiated when patients have symptomatic hypertension, hypertensive target organ damage, secondary hypertension, or diabetes mellitus type 1 or 2 at the time of presentation. Although clinical studies are under way, there are currently limited data from trials of antihypertensive drugs in children and recommendations are based on a few industry-sponsored studies, and mostly on single-center case series, collective clinical experience, expert opinion, and extrapolation from data obtained in adults. Pediatric studies have been conducted with a limited number of beta-blockers, CCBs, ACE inhibitors, and ARBs, but only 1 very small study has been conducted on a diuretic (chlorthalidone, in 1984), the guidelines note. Recent European Union regulations have provided incentives for pharmaceutical companies to carry out pediatric studies of cardiovascular drugs, and this is expected to increase the availability of these medications authorized for children. For selecting combination therapy, the guidelines recommend following these choices presented in the 2007 ESH/ESC hypertension guidelines.

Finally, the Task Force calls attention to the burden of hypertension in children and adolescents, and its contribution to the current epidemic of cardiovascular disease.

"These guidelines should encourage public policy makers, to develop a global effort to improve identification and treatment of high blood pressure among children and adolescents," the Task Force says.

Traffic Noise at Home May Affect Children's Blood Pressure

Data on the effects of exposure to road traffic noise on blood pressure in children are contradictory. The latest study, published in Science of the Total Environment,[21] appears to show small increases in SBP and DBP in children exposed to noise from busy streets at home. These increases were not clinically significant at the time, but they may predict rises in blood pressure later in life that might be damaging to health, the investigators believe.

Wolfgang Babisch, PhD (Federal Environment Agency), and colleagues in Berlin, Germany, investigated the effect of road traffic noise on a random sample of children aged 8-14 years from the German Environmental Survey for Children (GerES IV), carried out by the Agency between 2003 and 2006. The sample of 1048 children was representative of children in this age group living in Germany with respect to gender, community size, and geographic region. All the children had had a hearing test. Blood pressure was measured under standardized conditions at clinical study centers. During home visits, exposure to road traffic noise was determined by the parent's classification of the type of road in front of the children's room, and by orientating short-term noise measurements carried out during the day in front of the children's room window. The children and their parents were asked about leisure activities, housing conditions, and environmental factors. Blood pressure measurements were carried in ad hoc medical clinics so the resting blood pressure measurement reflected a chronic state of the children's circulatory system, which was not affected by the acute noise situation at home.

The lowest blood pressure readings were found in children whose room was facing a street with 'low traffic.' The highest readings were found in the group where the children's rooms were facing a street with a 'high or extremely high traffic' volume. After adjustment for age, gender, area, socioeconomic status, migrant status, agglomeration size, height, weight, and physical activity, higher blood pressure readings were found in the children exposed to noise in the highest categories. The difference between children who lived on a "busy traffic street" and an "extremely busy traffic street" and those living on a "low traffic street" was statistically significant for SBP (1.8 mm Hg, P = .036) but not for DBP (0.5 mm Hg). Short-term noise was associated with significant increases of 1.0 mm Hg (P = .004) in SBP and 0.6 mm Hg (P = .025) in DBP per 10 dB(A) increment of the noise level. The association between the noise level and SBP was 1.39 mm Hg per 10 dB(A) (P = .001)). No noise effects on heart rate were identified.

"J-shaped" associations were found when the presumably quietest category ("no street") was considered as the reference group. This group had a slightly higher SBP and DBP on average -- 0.6 and 0.5 mm Hg, respectively -- than the "low traffic" group. This may be due to road traffic in the distance when there was no street right in front of the children's bedroom, Dr Babisch and co-authors suggest. Although the 15-minute short-term noise measurements did not reveal a difference in the average equivalent sound pressure level between those groups, children from the "no street" group were slightly more annoyed by road traffic noise than the 'low traffic' group.

Dr. Babisch believes that the arteriosclerotic manifestations of increased blood pressure were unlikely to have been present in these children. "The effect may rather be due to sympathetic arousal, which is more pronounced in SBP," he suggests. The results confirm the findings of other studies where slightly higher blood pressure readings were found in children exposed to high noise levels at home or at school/day care centers.

With regard to possible health risks in later life, the findings in children are difficult to interpret, the researchers admit. "The effect may be of a temporary nature and may not be relevant to permanent health damage. On the other hand, there is evidence that during childhood and adulthood the blood pressure level at an early age is an important predictor of the blood pressure level at a later age," they say.


  1. Matsubara H. Effects of valsartan on morbidity and mortality in uncontrolled hypertensive patients with high risk of cardiovascular events (KYOTO Heart Study). Presented at ESC 2009, August 29-September 2, 2009, Barcelona, Spain.
  2. Sawada T, Yamada H, Dahlöf B, Matsubara H; the KYOTO HEART Study Group. Effects of valsartan on morbidity and mortality in uncontrolled hypertensive patients with high cardiovascular risks: KYOTO HEART Study. Eur Heart J. Published online ahead of print August 31, 2009.
  3. Sawada T, Takahashi T, Yamada H, et al; the KYOTO HEART Study Group. Rationale and design of the KYOTO HEART study: effects of valsartan on morbidity and mortality in uncontrolled hypertensive patients with high risk of cardiovascular events. J Hum Hypertens. 2009;23:188-195. Abstract
  4. Messerli FH, Bangalore S, Ruschitzka F. Angiotensin receptor blockers: baseline therapy in hypertension? Eur Heart J. Published online before print, August 31, 2009.
  5. The Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) Investigators.Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial. Lancet. 2008;372:1174-1183. Abstract
  6. Yusuf S, Diener HC, Sacco RL, et al; PRoFESS Study Group. Telmisartan to prevent recurrent stroke and cardiovascular events. N Engl J Med. 2008;359:1225-1237. Abstract
  7. Ogihara T, Nakao K, Fukui T, et al. Effects of candesartan compared with amlodipine in hypertensive patients with high cardiovascular risks: candesartan antihypertensive survival evaluation in Japan trial. Hypertension. 2008;51:393-398. Abstract
  8. Kasanuki H, Hagiwara N, Hosoda S,et al. Angiotensin II receptor blocker based vs. non-angiotensin II receptor blocker-based therapy in patients with angiographically documented coronary artery disease and hypertension: the Heart Institute of Japan Candesartan Randomized Trial for Evaluation in Coronary Artery Disease (HIJ-CREATE). Eur Heart J. 2009;30:1203-1212.
  9. Mochizuki S, Dahlöf B, Shimizu M, et al. Valsartan in a Japanese population with hypertension and other cardiovascular disease (Jikei Heart Study): a randomised, open-label, blinded endpoint morbidity-mortality study. Lancet. 2007;369:1431-1439. Abstract
  10. Narumi H, Takano H, Shindo S, et al. Effects of valsartan and amlodipine on cardio-renal protection in Japanese hypertensive patients: Valsartan Amlodipine Randomized Trial (VART). Eur Heart J. 2009;30:861. Abstract: 5001
  11. Julius S, Kjeldsen SE, Weber M, et al; VALUE trial group. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet. 2004;363:2022-2031. Abstract
  12. Nakayama K, Kuwabara Y, Daimon M, et al. Valsartan Amlodipine Randomized Trial (VART): design, methods, and preliminary results. Hypertens Res. 2008;31:21-28. Abstract
  13. Sciarretta S, Palano F, Paneni F, et al. Prevention of congestive heart failure in hypertension: a bayesian network meta-analysis involving more than 210.000 subjects. Eur Heart J. 2009;30:861. Abstract: 5002
  14. Tocci G, Sciarretta S, Volpe M. Development of heart failure in recent hypertension trials. J Hypertens. 2008;26:1477-1486. Abstract
  15. Psaty BM, Lumley T, Furberg CD, et al. Health outcomes associated with various antihypertensive therapies used as first-line agents: a network meta-analysis. JAMA. 2003;289:2534-2544. Abstract
  16. Blood Pressure Lowering Treatment Trialists' Collaboration. Blood pressure-dependent and independent effects of agents that inhibit the renin-angiotensin system. J Hypertens. 2007;25:951-958. Abstract
  17. Davis BR, Piller LB, Cutler JA, et al. Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial Collaborative Research Group. Role of diuretics in the prevention of heart failure: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Circulation. 2006;113:2201-2210. Abstract
  18. Lurbe E; Cifkova R; Kennedy JK, et al. Management of high blood pressure in children and adolescents: recommendations of the European Society of Hypertension. Journal of Hypertens. 2009;27:1719-1742.
  19. Mancia G, De Backer G, Dominiczak A, et al; Management of Arterial Hypertension of the European Society of Hypertension; European Society of Cardiology. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2007;25:1105-1187. Abstract
  20. National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics 2004;114:555–576.
  21. Babisch W, Neuhauser H, Thamm M, Seiwert M. Blood pressure of 8-14 year old children in relation to traffic noise at home -- Results of the German Environmental Survey for Children (GerES IV). Sci Total Environ. Published online ahead of print September 1.
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Brugada Syndrome

Tuesday, October 27, 2009


  • Sudden unexpected nocturnal death
  • Includes only idiopathic cases of Sudden Cardiac Death


  1. Incidence: Uncommon
  2. Accounts for <5% of Sudden Cardiac Death cases
  3. Family History of sudden death events often present
  4. Most common in men
  5. Greater Incidence in Southeast asia
    • Northeastern Thailand (40/year per 100,000)
    • Japan
    • Philipines


Inherited disorder of myocardial sodium channels

Associated EKG findings

  1. Prolonged QT Interval
  2. Brugada Sign
    • Seen best in the right precordial leads (V1-V3)
    • End of QRS marked by significant upward deflection
    • ST segment elevation
  3. Associated with Right Bundle Branch Block


  1. Often asymptomatic until terminal event (40%)
  2. Exertional Syncope history may be present


  1. Antzelevitch (2003) J Am Coll Cardiol 41(10):1665
  2. Brugada (1992) J Am Coll Cardiol 20(6):1391
  3. Littmann (2003) Am Heart J 145(5):768
  4. Meyer (2003) Am Fam Physician 68(3):483

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Diabetes Mellitus, Type 2 - A Review

Sunday, October 11, 2009

Scott R Votey, MD, Assistant Dean for Graduate Medical Education, Professor of Medicine/Emergency Medicine, David Geffen School of Medicine at UCLA, UCLA Medical Center
Anne L Peters, MD, CDE, Director of Clinical Diabetes Programs, Professor, Department of Medicine, University of Southern California, Keck School of Medicine, Los Angeles, California, Los Angeles County/University of Southern California Medical Center



Diabetes mellitus is a chronic disease that requires long-term medical attention both to limit the development of its devastating complications and to manage them when they do occur. It is a disproportionately expensive disease; in 2002, the per-capita cost of healthcare was $13,243 for people with diabetes, while it was $2560 for those without diabetes.

This article focuses on the ED evaluation and treatment of the acute and chronic complications of diabetes other than those directly associated with hypoglycemia and severe metabolic disturbances such as diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS). (Please see Hypoglycemia, Diabetic Ketoacidosis, and Hyperosmolar Hyperglycemic Nonketotic Coma for more information on these disorders.)


The 2 basic types of diabetes mellitus are type 1 and type 2. Type 1 diabetes mellitus is reviewed more fully in a separate eMedicine article (see Diabetes Mellitus, Type 1 - A Review).

Type 2 diabetes mellitus was once called adult-onset diabetes. Now, because of the epidemic of obesity and inactivity in children, type 2 diabetes mellitus is occurring at younger and younger ages. Although type 2 diabetes mellitus typically affects individuals older than 40 years, it has been diagnosed in children as young as 2 years of age who have a family history of diabetes.

Type 2 diabetes is characterized by peripheral insulin resistance with an insulin-secretory defect that varies in severity. For type 2 diabetes mellitus to develop, both defects must exist: all overweight individuals have insulin resistance, but only those with an inability to increase beta-cell production of insulin develop diabetes. In the progression from normal glucose tolerance to abnormal glucose tolerance, postprandial glucose levels first increase. Eventually, fasting hyperglycemia develops as inhibition of hepatic gluconeogenesis declines.

About 90% of patients who develop type 2 diabetes mellitus are obese. Because patients with type 2 diabetes mellitus retain the ability to secrete some endogenous insulin, those who are taking insulin generally do not develop DKA if it is stopped. Therefore, they are considered to require insulin but not to depend on insulin. Moreover, patients with type 2 diabetes mellitus often do not need treatment with oral antidiabetic medication or insulin if they lose weight or stop eating.

Maturity-onset diabetes of the young (MODY) is a form of type 2 diabetes mellitus that affects many generations in the same family with an onset in individuals younger than 25 years. Several types exist. Some of the genes responsible can be detected by using commercially available assays.
Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance with onset or first recognition during pregnancy. GDM is a complication in approximately 4% of all pregnancies in the United States, though the rates may be 1-14% depending on the population studied. Untreated GDM can lead to fetal macrosomia, hypoglycemia, hypocalcemia, and hyperbilirubinemia. In addition, mothers with GDM have increased rates of cesarean delivery and chronic hypertension. To screen for GDM, a 50-g glucose screening test should be done at 24-28 weeks of gestation. This is followed by a 100-g, 3-hour oral glucose tolerance test if the patient's plasma glucose concentration at 1 hour after screening is greater than 140 mg/dL.

United States

In 2005, people with diabetes were estimated to account for 7% of the US population, or approximately 20.8 million people. Of these 20.8 million people, 14.6 million have a diagnosis of diabetes, and diabetes is undiagnosed in another 6.2 million. Approximately 10% have type 1 diabetes, and the rest have type 2. Additionally, an estimated 54 million people have pre-diabetes. Pre-diabetes, as defined by the American Diabetes Association, is that state in which blood glucose levels are higher than normal but not high enough to be diagnosed as diabetes.


The morbidity and mortality associated with diabetes are related to the short- and long-term complications. Complications include the following:

  • Hypoglycemia and hyperglycemia
  • Increased risk of infections
  • Microvascular complications (eg, retinopathy, nephropathy)
  • Neuropathic complications
  • Macrovascular disease (eg, coronary artery disease, stroke)

Diabetes is the major cause of blindness in adults aged 20-74 years, as well as the leading cause of nontraumatic lower-extremity amputation and end-stage renal disease (ESRD).


Type 2 diabetes mellitus is more prevalent among Hispanics, Native Americans, African Americans, and Asians/Pacific Islanders than in non-Hispanic whites.


The incidence is essentially equal in women and men in all populations.

  • Type 2 diabetes mellitus is becoming increasingly common because people are living longer, and the prevalence of diabetes increases with age.
  • It is also seen more frequently now than before in young people, in association with the rising prevalence of childhood obesity.
  • Although type 2 diabetes mellitus still occurs most commonly in adults aged 40 years or older, the incidence of disease is increasing more rapidly in adolescents and young adults than in other age groups.



Correctly determining whether a patient has type 1 or type 2 diabetes is important because patients with type 1 diabetes are dependent on a continuous source of exogenous insulin and carbohydrates for survival. Patients with type 2 diabetes may not need treatment for hyperglycemia during periods of fasting or decreased oral intake. A patient whose diabetes is controlled with diet or an oral antidiabetic agent clearly has type 2 diabetes. A lean patient who has had diabetes since childhood, who has always been dependent on insulin, or who has a history of DKA almost certainly has type 1 diabetes.

Distinguishing the type of diabetes can be difficult in (1) patients who are treated with insulin and are young but clinically appear to have type 2 diabetes and (2) older patients with late onset of diabetes who nonetheless take insulin and seem to share characteristics of patients with type 1 diabetes. (This latter group is now said to have latent autoimmune diabetes of the adult [LADA]). When in doubt, treat the patient with insulin and closely monitor his or her glucose levels. Some adolescents or young adults, mostly Hispanic or African American patients, who present as with classic DKA are subsequently found to have type 2 diabetes.

Many patients with type 2 diabetes are asymptomatic, and their disease is undiagnosed for many years. Studies suggest that the typical patient with new-onset type 2 diabetes has had diabetes for at least 4-7 years before it is diagnosed. Among patients with type 2 diabetes, 25% are believed to have retinopathy; 9%, neuropathy; and 8%, nephropathy at the time of diagnosis.

Pre-diabetes often precedes overt type 2 diabetes. Pre-diabetes is defined by a fasting blood glucose level of 100-125 mg/dL or a 2-hour post oral glucose tolerance test (OGTT) glucose level of 140-200 mg/dL. Patients who have pre-diabetes have an increased risk for macrovascular disease as well as diabetes.

Often confused with pre-diabetes is the metabolic syndrome (also called syndrome X or the insulin-resistance syndrome). Metabolic syndrome, thought to be due to insulin resistance, can occur in patients with overtly normal glucose tolerance, prediabetes, or diabetes. It is characterized by central obesity, then by dyslipidemia. Hypertension is a common feature. Eventually, clinically apparent insulin resistance develops. Unfortunately, insulin resistance is not measured clinically, except in research settings. An elevated fasting blood glucose level is the first indication of insulin resistance, but fasting insulin levels are generally increased long before this occurs. Measurement of fasting insulin levels are not yet recommended for the diagnosis of insulin resistance. An effort to standardize insulin assays is underway and may allow for the use of fasting insulin levels to diagnose insulin resistance in the future.

See Workup for more information on diagnosis of diabetes. See Diabetes Mellitus, Type 1 - A Review for more information on the symptomatic patient with diabetes.

During history taking, inquire about the type and duration of the patient's diabetes and about the care the patient is receiving for diabetes.

  • Type and estimated duration of diabetes: This information helps to determine if the patient is insulin dependent. The diagnosis is based on history, therapy, and clinical judgment, as described above.
  • Diabetes care: Inquire about the patient's current treatment of diabetes and about his or her usual blood glucose levels based on self-monitoring and/or recent measurements of hemoglobin A1C (A 1C , an indicator of long-term glucose control).

A focused diabetes history should include the following questions:

  • Is the patient's diabetes generally well controlled (with near-normal blood sugar levels)? Patients with poorly controlled blood glucose levels heal more slowly and are at increased risk for infection and other complications.
  • Does the patient have severe hypoglycemic reactions? If the patient has episodes of severe hypoglycemia and therefore is at risk for losing consciousness, this possibility must be addressed, especially if the patient drives.
  • Does the patient have peripheral neuropathy?
  • Does the patient have any unrecognized foot ulcers or lesions that need treatment?
  • Does the patient have diabetic nephropathy that might alter use of medications or intravenous radiographic contrast material?
  • Does the patient have macrovascular disease, such as coronary artery disease (CAD), that should be considered in the ED?

As circumstances dictate, additional questions may be warranted.

  • Diabetes care
    • What is the patient's diet? Does he or she use oral antidiabetic agents, insulin, or both? If so, what are the doses and frequencies of the medications?
    • Does the patient self-monitor his or her glucose levels? If yes, what is the frequency and the usual range of values at each time of day?
    • When was the patient's A 1C level last measured? What was it?
    • Does the patient adhere to a specific diet or exercise regularly?
  • Hyperglycemia: Ask about polyuria, polydipsia, nocturia, weight loss, and fatigue.
  • Hypoglycemia
    • Does patient have episodes of hypoglycemia? Are these episodes explicable? Are these episodes mild or severe?
    • Does the patient require the assistance of another person for treatment?
    • When and how often do these episodes occur? How does the patient treat them?
    • Does the patient have hypoglycemia unawareness (ie, does the patient lack the adrenergic warning signs of hypoglycemia)? Hypoglycemia unawareness indicates an increased risk of subsequent episodes of hypoglycemia.
  • Microvascular complications
    • Retinopathy: When was the patient's last dilated eye examination? What were the results? Any recent deterioration in vision?
    • Nephropathy: Does the patient have known kidney disease? What were the results and dates of the last measurements of urine protein and serum creatinine levels? If urine protein has been negative to trace, has a microalbumin-to-creatinine ratio been assessed within the past year?
  • Neuropathy: Does the patient have any history of neuropathy or symptoms of peripheral neuropathy or autonomic neuropathy (including impotence if the patient is male)?
  • Macrovascular complications
    • Hypertension: Does the patient have hypertension (defined as a BP of >130/80 mm Hg)? What medications are taken?
    • CAD: Does the patient have CAD? Does the patient have a family history of CAD?
    • Peripheral vascular disease: Does the patient have symptoms of claudication or a history of vascular bypass?
    • Cerebrovascular disease: Has the patient had a stroke or transient ischemic attack?
    • Hyperlipidemia: What are the patient's most recent lipid levels? Is the patient taking lipid-lowering medication?
  • Diabetic foot disease: Does the patient have a history of foot ulcers or amputations? Are any foot ulcers present?
  • Infections: Are frequent infections a problem? At what site?

A diabetes-focused examination includes vital signs, funduscopic examination, limited vascular and neurologic examinations, and a foot assessment. Other organ systems should be examined as indicated by the patient's clinical situation.

  • Assessment of vital signs
    • Is the patient hypertensive or hypotensive? Orthostatic vital signs may be useful in assessing volume status and in suggesting the presence of an autonomic neuropathy.
    • If the respiratory rate and pattern suggest Kussmaul respiration, DKA must be considered immediately, and appropriate tests ordered.
  • Funduscopic examination
    • The funduscopic examination should include a careful view of the retina, including both the optic disc and the macula.
    • If hemorrhages or exudates are seen, the patient should be referred to an ophthalmologist as soon as possible. Examiners who are not ophthalmologists tend to underestimate the severity of retinopathy, especially if the patients' pupils are not dilated.
  • Foot examination
    • The dorsalis pedis and posterior tibialis pulses should be palpated and their presence or absence noted. This is particularly important in patients who have foot infections because poor lower-extremity blood flow can delay healing and increase the risk of amputation.
    • Documenting lower-extremity sensory neuropathy is useful in patients who present with foot ulcers because decreased sensation limits the patient's ability to protect the feet and ankles. This can be assessed with a monofilament, or more readily by assessment of reflexes, position, and vibration sensation.
    • If peripheral neuropathy is found, the patient should be made aware that foot care (including daily foot examination) is very important for the prevention of foot ulcers and lower-extremity amputation.

The major risk factors for type 2 diabetes mellitus are the following:

  • Age - Older than 45 years (though, as noted above, type 2 diabetes mellitus is occurring with increasing frequency in young individuals)
  • Obesity - Weight greater than 120% of desirable body weight (true for approximately 90% of patients with type 2 diabetes mellitus)
  • Family history of type 2 diabetes in a first-degree relative (eg, parent or sibling)
  • Hispanic, Native American, African American, Asian American, or Pacific Islander descent
  • History of previous impaired glucose tolerance (IGT) or impaired fasting glucose (IFG)
  • Hypertension (>140/90 mm Hg) or dyslipidemia (high-density lipoprotein [HDL] cholesterol level <40 mg/dL or triglyceride level >150 mg/dL)
  • History of GDM or of delivering a baby with a birth weight of >9 lb
  • Polycystic ovarian syndrome (which results in insulin resistance)

Differential Diagnoses

Diabetes Mellitus, Type 1 - A Review
Diabetic Ketoacidosis
Hyperosmolar Hyperglycemic Nonketotic Coma


Laboratory Studies
  • A fingerstick glucose test is appropriate in the ED for virtually all patients with diabetes. All other laboratory studies should be individualized to the clinical situation.
  • In patients who present with symptoms of uncontrolled diabetes (eg, polyuria, polydipsia, nocturia, fatigue, weight loss) with a confirmatory random plasma glucose level of >200 mg/dL, diabetes can be diagnosed.
  • In asymptomatic patients whose random serum glucose level suggests diabetes (>140 mg/dL), a fasting plasma glucose (FPG) concentration should be measured. The oral glucose tolerance test no longer is recommended for the routine diagnosis of diabetes.
    • An FPG level of >126 mg/dL on 2 separate occasions is diagnostic for diabetes.
    • An FPG level of 100-125 mg/dL is considered impaired IFG.
    • An FPG level of <100 mg/dL is considered normal glucose tolerance.
  • A fasting C-peptide level >1 ng/dL in a patient who has had diabetes for more than 1-2 years is suggestive of type 2 diabetes (ie, residual beta-cell function).
  • Autoantibodies can be useful in differentiating between type 1 diabetes and type 2 diabetes. 
    • Islet-cell autoantibodies (IA2) are present in children with new-onset type 1 diabetes but not type 2 diabetes. These antibodies are positive for approximately 6 months after diagnosis.
    • Anti-GAD65 antibodies are present in 80% of adult patients with new-onset type 1 diabetes (known as latent autoimmune diabetes of the adult [LADA]). These antibodies remain positive over time.
Other Tests
  • A glucose tolerance test usually is not necessary, except when GDM or IGT is being diagnosed.


Emergency Department Care

The ED care of patients with type 2 diabetes requires attention to both the patient's glycemic control and any of the numerous complications of diabetes the patient may have.

  • New-onset diabetes
    • Most patients with diabetes have type 2, and most of those are asymptomatic at diagnosis. Initial treatment of these patients is a trial of medical nutrition therapy (MNT, diet therapy) plus metformin. Therefore, if an asymptomatic patient is incidentally found to have an elevated blood glucose level in the ED, the patient's primary care provider can perform follow-up. Patients with mild symptoms of poorly controlled and previously undiagnosed diabetes can usually be treated on an outpatient basis.
    • The treatment of markedly symptomatic patients with newly discovered type 2 diabetes and glucose levels greater than 400 mg/dL is controversial. If close follow-up can be arranged, maximal doses of a sulfonylurea agent can be started, and they can be treated on an outpatient basis. Patients generally feel better in 1-2 days, and in a week, their blood glucose levels are markedly lower. The sulfonylurea dose can be tapered as they comply with MNT and metformin is added; in some, diabetes can be controlled with diet alone. Patients who cannot drink adequate amounts of fluid, those with serious coexisting medical conditions (eg, myocardial infarction [MI], systemic infection), and those without reliable follow-up should generally be hospitalized to start therapy. Alternately, insulin therapy can be initiated and doses adjusted in either an inpatient setting or an outpatient setting.
  • Abnormalities caused by hyperglycemia
    • Acute hyperglycemia, even when not associated with DKA or hyperglycemic hyperosmolar nonketotic syndrome (HNKS), is harmful for a number of reasons. If the blood glucose level exceeds the renal threshold for glucose, an osmotic diuresis ensues, with loss of glucose, electrolytes, and water. Hyperglycemia impairs leukocyte function through a variety of mechanisms. Patients with diabetes have an increased rate of wound infection, and hyperglycemia may impair wound healing.
    • In patients with known type 2 diabetes that is poorly controlled, no absolute level of blood glucose elevation requires admission to the hospital or administration of insulin in the ED. If the patient is severely symptomatic or if the precipitating cause of hyperglycemia cannot be treated adequately in the ED, the patient may need to be admitted. In general, lowering the patient's blood glucose level in the ED does not correct the underlying cause and has no long-term effects on the patient's blood glucose levels. Therefore, a plan for lowering and monitoring the patients' glucose levels is needed. Adequacy of follow-up is extremely important. Whether insulin is given in the ED is of less consequence and can be decided on an individual basis.
  • Hyperglycemia during medical illness and surgery
    • Serious medical illness and surgery produce a state of increased insulin resistance. Hyperglycemia can occur, even in patients who do not have diabetes, because of stress-induced insulin resistance plus the use of dextrose-containing intravenous fluids. Increases in glucagon, catecholamines, cortisol, and growth hormone levels antagonize the effects of insulin, and the alpha-adrenergic effect of increased catecholamine levels inhibits insulin secretion. Counterregulatory hormones also directly increase hepatic gluconeogenesis.
    • Increasing evidence shows the benefits of treatment of hyperglycemia in severely ill patients with or without preexisting diabetes. In ICU patients, in patients before and after coronary artery bypass grafting (CABG), and in those with an acute MI, morbidity and mortality are reduced when they receive glucose-insulin-potassium infusion (GIK infusion) designed to maintain glucose levels in the reference range. Many hospitals are implementing GIK-infusion protocols for patients in ICU, surgical ICU, and critical care unit (CCU) settings.
    • Treatment regimens must be modified for patients not requiring an ICU setting to compensate for both decreased caloric intake and increased physiologic stress. Blood glucose levels of 100-150 mg/dL should be maintained in medical and surgical patients with diabetes for the following reasons:
      • To prevent electrolyte abnormalities and volume depletion secondary to osmotic diuresis
      • To prevent the impairment of leukocyte function that occurs when blood glucose levels are elevated
      • To prevent the impairment of wound healing that occurs when blood glucose levels are elevated
    • Cardiovascular disease (CVD) or renal dysfunction increases surgical morbidity and mortality in patients with or without diabetes, and diabetic autonomic neuropathy increases the risk of cardiovascular instability. The ED clinician caring for the patient with diabetes who requires emergency surgery must notify the surgeon and the anesthesiologist of the patient's condition, consult medical specialists when appropriate, and promptly initiate a thorough medical evaluation to avoid delaying surgery.
  • Infections in general
    • Infections cause considerable morbidity and mortality in patients with diabetes. Infections may precipitate metabolic derangements and, conversely, the metabolic derangements of diabetes may facilitate infection.
    • A few infections, such as malignant otitis externa, rhinocerebral mucormycosis, and emphysematous pyelonephritis, occur almost exclusively in patients with diabetes. Infections, such as staphylococcal sepsis, occur more frequently and result in greater mortality in patients with diabetes than in others. Infections such as pneumococcal pneumonia affect patients with diabetes and others the same.
    • Hyperglycemia and acidemia exacerbate impairments in humoral immunity and polymorphonuclear leukocyte and lymphocyte functions but are substantially, if not entirely, reversed when pH and blood glucose levels return to normal. Although the exact level above which leukocyte function is impaired is not defined, in vitro evidence suggests that glucose levels greater than 200 mg/dL impair leukocytic function.
    • Patients with long-standing diabetes tend to have microvascular and macrovascular disease with resulting poor tissue perfusion and increased risk of infection. The ability of the skin to act as a barrier to infection may be compromised when the diminished sensation of diabetic neuropathy results in unnoticed injury.
  • Ear, nose, and throat infections
    • Two head and neck infections that are associated with high rates of morbidity and mortality are malignant otitis externa and rhinocerebral mucormycosis; these are seen almost exclusively in patients with diabetes.
    • Malignant or necrotizing otitis externa principally occurs in patients with diabetes who are older than 35 years and is almost always due to Pseudomonas aeruginosa.
      • Infection starts in the external auditory canal and spreads to adjacent soft tissue, cartilage, and bone. Patients typically present with severe ear pain and otorrhea. Although they often have preexisting otitis externa, progression to invasive disease is usually rapid.
      • Examination of the auditory canal may reveal granulation tissue, but spread of infection to the pinna, preauricular tissue, and mastoid often makes the diagnosis apparent. Involvement of the cranial nerves, particularly the facial nerve, is common; when infection extends to the meninges, it is often lethal.
      • CT helps define the extent of disease.
      • Prompt surgical consultation is mandatory for malignant otitis externa because surgical debridement is often an essential part of therapy. Intravenous antipseudomonal antibiotics should be started immediately in patients with invasive disease. Patients with diabetes with severe otitis externa but no evidence of invasive disease can be treated with an otic antibiotic drop and oral ciprofloxacin; they require close follow-up.
    • Mucormycosis collectively refers to infections caused by various ubiquitous molds. Invasive disease occurs in patients with poorly controlled diabetes, especially with DKA. Organisms colonize the nose and paranasal sinuses, spreading to adjacent tissues by invading blood vessels and causing soft tissue necrosis and bony erosion.
      • Patients usually present with periorbital or perinasal pain, swelling, and induration. Bloody nasal discharge may be present. Involvement of the orbits, with lid swelling, proptosis, and diplopia, is common.
      • The nasal turbinates may appear dusky red or frankly necrotic. Black necrotic tissue is an important visual clue. The infection may invade the cranial vault through the cribriform plate, resulting in cerebral abscess, cavernous sinus thrombosis, or thrombosis of the internal carotid artery.
      • Wet smears of necrotic tissue often reveal broad hyphae and distinguish mucormycosis from severe facial cellulitis. CT helps delineate the extent of disease.
      • Treatment consists of controlling the predisposing hyperglycemia and acidemia, administering intravenous amphotericin B, and immediate surgical debridement. Until the diagnosis is confirmed, antistaphylococcal antibiotic therapy is appropriate.
  • Urinary tract infections
    • Patients with diabetes have increased risk of cystitis and, more important, of serious upper urinary tract infection. Intrarenal bacterial infection should be considered in the differential diagnosis of any patient with diabetes who presents with flank or abdominal pain.
    • The treatment of cystitis is essentially the same as that in patients without diabetes, except that longer courses of therapy are generally recommended (eg, 7 d for uncomplicated cystitis). Individuals with a neurogenic bladder due to diabetic neuropathy may not empty their bladder well and may require urologic referral. Sulfonamide antibiotics can cause hypoglycemia in patients taking sulfonylurea agents by displacing the sulfonylurea agents from their binding sites and increasing their hypoglycemic effect.
    • Treatment of pyelonephritis does not differ for patients with diabetes, but a lower threshold for hospital admission is appropriate. First, pyelonephritis makes control of diabetes more difficult by causing insulin resistance; in addition, nausea may limit the patient's ability to maintain normal hydration. The ensuing hyperglycemia further compromises their immune response. Second, patients with diabetes are more susceptible than others to the complications of pyelonephritis (eg, renal abscess, emphysematous pyelonephritis, renal papillary necrosis, gram-negative sepsis).
    • More than 70% of cases of emphysematous pyelonephritis occurred in patients with diabetes. Emphysematous pyelonephritis is an uncommon necrotizing renal infection caused by Escherichia coli, Klebsiella pneumoniae, or other organisms capable of fermenting glucose to carbon dioxide. The presentation is usually similar to that of uncomplicated pyelonephritis, and the diagnosis is established by identifying renal gas on plain radiography or sonography. Surgery is indicated at diagnosis.
  • Skin and soft tissue infections
    • Sensory neuropathy, atherosclerotic vascular disease, and hyperglycemia all predispose patients with diabetes to skin and soft tissue infections. These can affect any skin surface but most commonly involve the feet.
    • Blood glucose levels greater than 250 mg/dL significantly increase a patient's risk of soft tissue infection.
    • Cellulitis; lymphangitis; and, most ominously, staphylococcal sepsis can complicate even the smallest wound. Minor wound infections and cellulitis are typically caused by Staphylococcus aureus or hemolytic streptococci. Treatment with a penicillinase-resistant synthetic penicillin or a first-generation cephalosporin has been effective for the outpatient treatment of minor infections, but the increasing prevalence of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) must now be considered when selecting an antibiotic. Patients with diabetes do not appear to have a higher prevalence of CA-MRSA than comparable patients without diabetes.
    • Outpatient treatment of minor infections is appropriate for patients who are reliable, who monitor their blood glucose, and who have access to close follow-up.
    • Necrotizing infections of the skin, subcutaneous tissues, fascia, or muscle can also complicate wounds and particularly cutaneous ulcers. These infections are typically polymicrobial, involving group A streptococci, enterococci, S aureus, Enterobacteriaceae, and various anaerobes. Radiographs of any spreading soft tissue infection in a patient with diabetes should be obtained to look for the soft tissue gas that characterizes necrosis. Surgical debridement is necessary for necrotizing infections. Gram stains and surface cultures are not helpful; antibiotic coverage should reflect the range of potential pathogens.
  • Osteomyelitis
    • Contiguous spread of a polymicrobial infection from a skin ulcer to adjacent bone is common in patients with diabetes.
    • In one study, osteomyelitis was found in the bone under 68% of diabetic foot ulcers, and findings on physical examination and plain radiographs did not help in diagnosing one half of the cases. Unfortunately, these diagnostic modalities are often the only ones available in the ED, and the diagnosis might be suspected but not established. MRI, if available on an emergent basis, has better sensitivity and specificity in diagnosing osteomyelitis. 
    • If osteomyelitis is apparent on radiography or physical examination (eg, if the wounds are deep enough to expose tendons or bone), the patient should be admitted for intravenous antibiotics. If osteomyelitis is suspected but the soft tissue infection or metabolic disturbances do not warrant admission, the patient can be discharged for outpatient workup.
  • Other infections
    • Although cholecystitis is probably no more common in patients with diabetes than in the general population, severe fulminating infection, especially with gas-forming organisms, is more common. The early clinical manifestations of emphysematous cholecystitis are indistinguishable from those of usual cholecystitis. The diagnosis can be made by finding gas in the gallbladder lumen, wall, or surrounding tissues. Even with immediate surgery, the rate of mortality is high. Clostridial species are found in more than 50% of cases.
    • The incidence of staphylococcal and K pneumoniae infections is greater in people with diabetes than people without diabetes.
    • Diabetes is a risk factor for reactivation of tuberculosis.
    • Cryptococcal infections and coccidioidomycoses are more virulent in patients with diabetes than in others.
  • Ophthalmologic complications
    • Diabetes can affect the lens, vitreous, and retina, causing visual symptoms that may prompt the patient to come to the ED. Visual blurring may develop acutely as the lens changes shape with marked changes in blood glucose concentrations. This effect, which is caused by osmotic fluxes of water into and out of the lens, usually occurs as hyperglycemia increases, but it also may be seen when high glucose levels are lowered rapidly. In either case, recovery to baseline visual acuity can take up to a month, and some patients are almost completely unable to read small print or do close work during this period.
    • Patients with diabetes also tend to develop senile cataracts sooner than persons without diabetes, though this is not related to the degree of glycemic control.
    • Whether patients develop diabetic retinopathy depends on the duration of their diabetes and on the level of glycemic control maintained. Because the diagnosis of type 2 diabetes often is delayed, 20% of these patients have some degree of retinopathy at diagnosis. The following are the 5 stages in the progression of diabetic retinopathy:
      1. Dilation of the retinal venules and formation of retinal capillary microaneurysms
      2. Increased vascular permeability
      3. Vascular occlusion and retinal ischemia
      4. Proliferation of new blood vessels on the surface of the retina
      5. Hemorrhage and contraction of the fibrovascular proliferation and the vitreous
    • The first 2 stages of diabetic retinopathy are known as background or nonproliferative retinopathy.
      • Initially, the retinal venules dilate, then microaneurysms, (tiny red dots on the retina that cause no visual impairment) appear.
      • As the microaneurysms or retinal capillaries become more permeable, and hard exudates appear, reflecting the leakage of plasma. Rupture of intraretinal capillaries results in hemorrhage. If a superficial capillary ruptures, a flame-shaped hemorrhage appears.
      • Hard exudates are often found in partial or complete rings (circinate pattern), which usually include multiple microaneurysms. These rings usually mark an area of edematous retina.
      • The patient may not notice a change in visual acuity unless the center of the macula is involved. Macular edema can cause visual loss; therefore, all patients with suspected macular edema must be referred to an ophthalmologist for evaluation and possible laser therapy. Laser therapy is effective in decreasing macular edema and preserving vision but is less effective in restoring lost vision.
    • Preproliferative and proliferative diabetic retinopathy are the next stages in the progression of the disease. Cotton-wool spots can be seen in preproliferative retinopathy. These represent retinal microinfarcts caused by capillary occlusion and appear as patches that range from off-white to gray and have poorly defined margins.
    • Proliferative retinopathy is characterized by neovascularization, or the development of networks of fragile new vessels that often are seen on the optic disc or along the main vascular arcades. The vessels undergo cycles of proliferation and regression. During proliferation, fibrous adhesions develop between the vessels and the vitreous. Subsequent contraction of the adhesions can result in traction on the retina and retinal detachment. Contraction also tears the new vessels, which hemorrhage into the vitreous. Patients may notice a small hemorrhage, which appears as a floater, though a large hemorrhage may result in marked visual loss.
    • Patients with preproliferative or proliferative retinopathy must immediately be referred for ophthalmologic evaluation because laser therapy can be effective in this condition, especially before actual hemorrhage occurs. Patients with retinal hemorrhage should be advised to limit their activity and to keep their head upright (even while sleeping) so that the blood settles to the inferior portion of the retina, minimizing obscuration of their central vision.
    • Patients with active proliferative diabetic retinopathy are at increased risk of retinal hemorrhage if they receive thrombolytic therapy; therefore, this condition is a relative contraindication to the use of thrombolytic agents.
  • Nephropathy
    • Patients with type 2 diabetes account for most patients with diabetes with ESRD. All patients with diabetes should be considered to have the potential for renal impairment unless proven otherwise. Therefore, extreme care should be exercised when using any nephrotoxic agent in a patient with diabetes.
    • The use of contrast media can precipitate acute renal failure in patients with underlying diabetic nephropathy. Caution should be used when contrast-enhanced studies are being considered in patients with diabetes with a creatinine level greater than 2 mg/dL; such studies should absolutely be avoided in patients with a creatinine level greater than 3 mg/dL. Although most recover within 10 days, some develop irreversible renal failure. Patients with diabetes who must undergo such studies should be well hydrated before, during, and after the study, and their renal function should be carefully monitored. A better solution is to seek equivalent clinical information by using an alternative study that does not require the use of contrast material (eg, sonography, noncontrast CT, MRI).
    • Potentially nephrotoxic drugs should be avoided whenever possible. Renally excreted or potentially nephrotoxic drugs should be given at reduced dosage as appropriate to the patient's serum creatinine level.
    • Because chronically elevated blood pressure contributes to the decline in renal function, hypertensive patients with diabetes must be referred for long-term management of the blood pressure. If antihypertensive therapy is started in the ED, an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) are recommended because these agents decrease proteinuria and slow decline in renal function independent of their effect on blood pressure. ACE inhibitors and ARBs tend to increase the serum potassium level and therefore should be used with caution in patients with renal insufficiency or elevated serum potassium levels.
  • Neuropathy
    • Of the many types of peripheral and autonomic diabetic neuropathy, distal symmetric sensorimotor polyneuropathy (in a glove-and-stocking distribution) is the most frequent. Besides causing pain in its early stages, this type of neuropathy eventually results in the loss of peripheral sensation. The combination of decreased sensation and peripheral arterial insufficiency often leads to foot ulceration and eventual amputation.
    • Acute-onset mononeuropathies in diabetes include acute cranial mononeuropathies, mononeuropathy multiplex, focal lesions of the brachial or lumbosacral plexus, and radiculopathies. Of the cranial neuropathies, the third cranial nerve (oculomotor) is most commonly affected, followed by the sixth nerve (abducens) and the fourth nerve (trochlear). Patients can present with diplopia and eye pain.
    • In diabetic third-nerve palsy, the pupil is usually spared, whereas in third-nerve palsy due to intracranial aneurysm or tumor, the pupil is affected in 80-90% of cases.
    • Consideration of nondiabetic causes of cranial nerve palsies is important because 42% are due to causes other than diabetes. Therefore, evaluation should include nonenhanced and contrast-enhanced CT or, preferably, MRI. Neurologic consultation is recommended. Acute cranial-nerve mononeuropathies usually resolve in 2-9 months. Acute thrombosis or ischemia of the blood vessels supplying the structure involved is thought to cause these neuropathies.
    • Autonomic dysfunction can involve any part of the sympathetic or parasympathetic chains and produce myriad manifestations. Patients likely to seek care in the ED are those with diabetic gastroparesis and vomiting, severe diarrhea, bladder dysfunction and urinary retention, or symptomatic orthostatic hypotension.
      • Treatment of gastroparesis is symptomatic, and symptoms tend to wax and wane. Patients with gastroparesis may benefit from metoclopramide or erythromycin. Before these therapies are started, the degree of dehydration and metabolic imbalance must be assessed, and other serious causes of vomiting must be excluded. In severe cases, gastric pacing has been used.
      • Patients with disabling orthostatic hypotension may be treated with salt tablets, support stockings, or fludrocortisone.
      • Alleviating the functional abnormalities associated with the autonomic neuropathy is often difficult and frustrating and requires a long-term treatment plan with input from all of the patient's healthcare team.
  • Diabetic foot disease
    • About 50-70% of all nontraumatic lower-extremity amputations occur in patients with diabetes. The insensate, poorly perfused foot is at risk for ulcers from pressure necrosis or inflammation from repeated skin stress and unnoticed minor trauma. These can evolve into cellulitis, osteomyelitis, or nonclostridial gangrene and end in amputation.
    • Patients with diabetes who present with wounds, infections, or ulcers of the foot should be treated intensively. In addition to appropriate use of antibiotics, avoidance of further trauma to the healing foot is mandatory. This can be achieved by immobilization in a boot and/or using crutches, a wheelchair, or bed rest. Patients should be treated by a podiatrist or an orthopedist with experience in the care of diabetic foot disease. If bone or tendon is visible, osteomyelitis is present, and hospitalization for intravenous antibiotics is often necessary. Many patients need a vascular evaluation in conjunction with local treatment of the foot ulcer because a revascularization procedure may be required to provide adequate blood flow for wound healing.
    • Because curing ulcers and foot infections is difficult, their prevention is extremely important. At one clinic, the rate of amputation was halved after patients were required to remove their shoes and socks at every visit. ED clinicians can facilitate this practice by briefly inspecting the feet of each patient with diabetes and by educating them about the need for proper foot care. Patients with distal sensory neuropathy to pinprick or light touch, decreased peripheral pulses, moderate-to-severe onychomycosis, or impending skin breakdown should be referred to a podiatrist.
  • Macrovascular disease
    • This is the leading cause of death in patients with diabetes, causing 75% of deaths in this group but approximately 35% of deaths in people without diabetes. Diabetes increases the risk of myocardial infarction (MI) 2-fold in men and 4-fold in women, and many patients have other risk factors for MI as well. The risk of stroke in patients with diabetes is double that of people without diabetes, and the risk of peripheral vascular disease is 4 times that of people without diabetes. Subtle differences in the pathophysiology of atherosclerosis in patients with diabetes result in both earlier development and a more malignant course. Therefore, lipid abnormalities must be treated aggressively to lower the risk of serious atherosclerosis. Findings suggest that statin therapy should be started in all patients with type 2 diabetes, regardless of their lipid levels, to lower their risk of CVD.
    • Hypertension, which also increases the risk of atherosclerosis, is twice as common in patients with type 2 diabetes as in persons without diabetes. In patients with diabetes, hypertension must be treated aggressively to lower their risk of serious atherosclerosis. ACE inhibitors and angiotensin II–receptor blockers (ARBs) may also reduce CVD risk independent of its effects on blood pressure. Many advocate their use, in addition to statins, in most patients with type 2 diabetes.
    • Patients with diabetes may have an increased incidence of silent ischemia. However, silent ischemia is common in many patients with CAD, and the apparently increased incidence may be because patients with diabetes are more likely than others to have CAD to begin with. Nevertheless, an ECG is prudent in patients with diabetes and a serious illness or who present with generalized weakness, malaise, or other nonspecific symptoms that are not expected to be due to myocardial ischemia.
    • Diastolic dysfunction is common in patients with diabetes and should be considered in the patient with symptoms of congestive heart failure and a normal ejection fraction.


Target glucose levels

Chronic hyperglycemia is associated with an increased risk of microvascular complications, as shown in the Diabetes Control and Complications Trial (DCCT) in individuals with type 1 diabetes and the United Kingdom Prospective Diabetes Study (UKPDS) in people with type 2 diabetes. In the DCCT, intensive therapy to maintain normal blood glucose levels greatly reduced the development and progression of retinopathy, microalbuminuria, and neuropathy over 7 years.
The ongoing Epidemiology of Diabetes Interventions and Complications Study (EDIC), an observational study that continues to follow the patients previously enrolled in the DCCT, demonstrates that benefit has continued since the DCCT trial ended in 1993. Intensive therapy was not associated with increased mortality or incidence of major macrovascular events and did not decrease the quality of life, though it did increase the likelihood of severe hypoglycemic episodes. Furthermore, in the EDIC study, a long-term follow-up of the DCCT, over time those who had been in the intensively treated group had a reduction in the risk of CVD compared with those in the conventionally treated group.

In the UKPDS, more than 5000 patients with type 2 diabetes were followed up for up to 15 years. Those in the intensely treated group had a significantly lower rate of progression of microvascular complications than that of those receiving standard care. Rates of macrovascular disease were not altered except in the metformin-monotherapy arm in obese individuals, in which the risk of MI was significantly decreased. Moreover, severe hypoglycemia occurred less often than it did in patients with type 1 diabetes in the DCCT.

Kooy et al found an improved body weight, glycemic control, and insulin requirements when metformin was added to insulin in type 2 diabetes mellitus. No improvement of an aggregate of microvascular and macrovascular morbidity and mortality was observed; however, risk reduction of macrovascular disease was evident after a follow-up period of 4.3 years. Because of these sustained beneficial effects, it is important to support the policy to continue metformin treatment after the introduction of insulin in type 2 diabetes mellitus unless contraindicated.1
The goal of oral antidiabetic therapy is to lower blood glucose levels to near-normal (preprandial levels of 90-130 mg/dL and A1C levels <7%) and to maintain them in this range for the patient's lifetime. Optimal diabetic control requires self-monitoring of blood glucose levels.

The Agency for Healthcare Research and Quality (AHRQ) reviewed the published evidence (from short-term studies but applicable to long-term use) regarding the comparative effectiveness of oral diabetes medications in controlling blood glucose levels and other aspects of diabetes. The AHRQ found little evidence to support predictions of whether a particular medication is more likely to be effective in a given patient subgroup or to cause adverse effects in a particular patient. The AHRQ concluded that, when used as monotherapy, most oral diabetes medications (with the exception of the less-effective nateglinide and alpha-glucosidase inhibitors) produce similar reductions in HbA1c, and that older medications (eg, metformin and second-generation sulfonylureas) can reasonably be used before newer ones (eg, glitazones or meglitinides), especially when cost is a factor.2

Patients with no or mild symptoms should initially be treated with MNT (diet therapy) plus metformin, and MNT should be encouraged throughout treatment. In the ED, drugs are typically started only when a patient presents with moderate-to-marked symptoms of diabetes, but it is also reasonable to initiate metformin (after ensuring that the serum creatinine level is <1.5 [men] or <1.4 [women]) in moderately hyperglycemic asymptomatic individuals if appropriate follow-up can be arranged.

Treatment of type 2 diabetes is aimed at lowering insulin resistance and increasing function of beta cells. In many patients, beta-cell dysfunction worsens over time, necessitating exogenous insulin. Because patients with type 2 diabetes have both insulin resistance and beta-cell dysfunction, oral medication to increase insulin sensitivity (eg, metformin or a thiazolidinedione [TZD]) is often given with an intermediate-acting insulin (eg, neutral protamine Hagedorn [NPH]) at bedtime or a long-acting insulin (eg, glargine [Lantus] insulin or insulin detemir [Levemir]) given once daily; glargine can be given in either the morning or the evening; detemir should be given in the evening.) An insulin secretagogue, such as a sulfonylurea agent, can also be given to increase preprandial insulin secretion.

The US Food and Drug Administration (FDA) has issued an early communication to health care practitioners regarding 4 recently published observational studies that describe the possible association of insulin glargine (Lantus) with an increased risk of cancer.3 Insulin glargine is a long-acting human insulin analogue approved for once-daily dosing.

  • The observational studies evaluated large patient databases, and all reported some association between insulin glargine and other insulin products with various types of cancer. The duration of the observational studies was shorter than what is considered necessary to evaluate for drug-related cancers. Additionally, findings were inconsistent within and across the studies, and patient characteristics differed across treatment groups. These issues raise further questions about the risk that actually exists and therefore warrants further evaluation.
  • The FDA states that patients should not stop taking their insulin without consulting their physician. An ongoing review by the FDA will continue to update the medical community and consumers with additional information as it emerges. Statements from the American Diabetes Association and the European Association for the Study of Diabetes called the findings conflicting and inconclusive and cautioned against overreaction.

The goal of these combined daytime oral agent plus once-a-day insulin is to lower the fasting glucose level to 100 mg/dL by titrating the insulin. When this target is achieved, the oral agents can be effective in maintaining preprandial and postprandial blood glucose levels throughout the day. If a regimen combining oral agents and insulin fails to lower glucose levels into the normal range, patients should be switched to a daily multiple-injection schedule with a premeal rapid-acting insulin and a longer-acting basal insulin.
Throughout treatment for type 2 diabetes, adherence to MNT and exercise should be stressed because behavior modification can have a large effect on the degree of diabetic control they achieve.

Some patients should not aim for near-normal blood glucose levels. In elderly patients who have a life expectancy of less than 5 years or in any patient with a terminal disease, tight control may be unnecessary. Patients with known CAD or cerebrovascular disease also may need higher preprandial blood glucose targets (eg, 100-160 mg/dL) to prevent extreme hypoglycemia. Patients with advanced microvascular and neuropathic diabetic complications may not particularly benefit from maintenance of near-euglycemia.
Additionally, patients with alcoholism or other serious substance abuse, and patients with severe uncontrolled mental illness may be unable to effectively participate in the care of their diabetes, placing them at high risk for severe hypoglycemic reactions if near-normal glucose levels are targeted. Finally, patients with hypoglycemia unawareness (ie, lack adrenergic warning signs of hypoglycemia) or those with recurrent episodes of severe hypoglycemia (ie, hypoglycemia requiring treatment by another person) should also have high target levels at least temporarily.
Although ED clinicians rarely start new therapy for diabetes, being acquainted with the drugs used and their adverse effects and contraindications is useful. The AHRQ has reviewed the adverse effects associated with oral diabetes medications and assessed the relative risks of such effects with particular medications. For descriptions of insulins, see Diabetes Mellitus, Type 1 - A Review.

Sulfonylurea Agents

These agents reduce serum glucose concentrations by increasing insulin secretion from pancreatic beta cells in patients with residual beta cell function. All are well absorbed; half-life and duration of action vary. These agents are classified as first generation (acetohexamide, chlorpropamide, tolazamide, tolbutamide; not described below), second generation (glipizide, glyburide), and third generation (glimepiride). All may cause hypoglycemia.

Glipizide (Glucotrol, Glucotrol XL)

Second-generation sulfonylurea; stimulates insulin release from pancreatic beta cells.


5 mg/d PO initially in untreated patients with symptomatic hyperglycemia; not to exceed 40 mg/d PO; daily doses >20 mg given in divided doses bid; Glucotrol XL not to exceed 20 mg/d PO
Start at 2.5 mg/d PO for elderly patients and patients with hepatic or renal disease; may start at higher doses in patients with severe hyperglycemia or symptoms, if home glucose monitoring and close follow-up can be arranged


Not established


Numerous possible, few clinically significant; sulfonamides may enhance hypoglycemic effect


Documented hypersensitivity; DKA; type 1 diabetes mellitus


C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus


Caution in hepatic or renal impairment; cardiovascular disorders may occur; other risk factors are older age, malnutrition, and irregular eating (if prolonged or recurrent, consider admission); may cause rash, nausea, vomiting, leukopenia, agranulocytosis, aplastic anemia (rare), intrahepatic cholestasis (rare), disulfiramlike reaction, flushing, headache, and SIADH causing hyponatremia

Glyburide (DiaBeta, Micronase, PresTab, Glynase)

Second-generation sulfonylurea agent; increases insulin secretion from pancreatic beta cells.


5 mg/d PO initially in untreated, symptomatic patients; not to exceed 20 mg/d PO
Start 2.5 mg/d PO for elderly patients and patients with hepatic or renal disease; may start at <20 mg/d in patients with severe hyperglycemia or symptoms, if home glucose monitoring and close follow-up can be arranged
Dosing for Glynase (micronized formulation) differs: 3 mg/d PO initially; not to exceed 12 mg/d


Not established


Numerous possible, few clinically significant; sulfonamides may enhance hypoglycemic effect


Documented hypersensitivity; DKA; type 1 diabetes mellitus


C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus


Caution in hepatic or renal impairment; cardiovascular disorders may occur; other risk factors are older age, malnutrition, and irregular eating (if prolonged or recurrent, consider admission); may cause rash, nausea, vomiting, leukopenia, agranulocytosis, aplastic anemia (rare), intrahepatic cholestasis (rare), disulfiramlike reaction, flushing, headache, and SIADH causing hyponatremia

Glimepiride (Amaryl)

Third-generation sulfonylurea; increases insulin secretion from pancreatic beta cells.


Usual starting dose is 1-2 mg PO qd with breakfast; usual maintenance dose is 1-4 mg PO qd; maximum dose is 8 mg PO qd


Not established


NSAIDs, sulfonamides, chloramphenicol, probenecid, warfarin, MAOIs, beta-blockers, and miconazole produce increased hypoglycemic effects; thiazides, hydantoins, oral contraceptives, corticosteroids, phenothiazines, thyroid estrogen, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid produce decreased hypoglycemic effects; increases alcohol-related disulfiram reactions; increases warfarin effects


Documented hypersensitivity, diabetic ketoacidosis


C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus


Caution in patients predisposed to hypoglycemia, such as patients with liver disease, renal disease, and elderly patients


These agents are short-acting insulin secretagogues. They act on the ATP-dependent potassium channels in pancreatic beta cells, allowing opening of calcium channels and increased insulin release.

Repaglinide (Prandin)

Stimulates insulin release from pancreatic beta cells.


0.5-4 mg PO ac; may dose bid/qid preprandial, not to exceed 16 mg/d


Not established


CYP3A4 inhibitors (eg, clarithromycin, ketoconazole, miconazole, erythromycin) decrease metabolism, increasing serum levels and effects; thiazides, diuretics, corticosteroids, estrogens, oral contraceptives, nicotinic acid, CCBs, phenothiazines, and thyroid products, may lower glycemic control; toxicity increased with highly protein-bound drugs (eg, NSAIDs, sulfonamides, anticoagulants, hydantoins, salicylates, phenylbutazone)


Documented hypersensitivity; DKA; type 1 diabetes mellitus


C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus


Hypoglycemia, especially if carbohydrate not eaten after drug; caution in hepatic impairment

Nateglinide (Starlix)

Short-acting insulin secretagogue. Action is dependent upon functional beta-cells in pancreatic islets. Stimulates pancreatic insulin secretion within 20 min of oral administration.


120 mg PO tid ac; may decrease to 60 mg PO tid ac


Not established


Metabolized by cytochrome P450 isozyme CYP2C9 (70%) and CYP3A4 (30%); may inhibit CYP2C9; inhibitors of CYP2C9 (eg, NSAIDs, fluvoxamine, cimetidine) may decrease elimination; inducers of CYP2C9 (eg, carbamazepine, phenobarbital, phenytoin) may enhance elimination; coadministration with NSAIDs, salicylates, MAOIs, and non-selective beta-blocking agents may potentiate hypoglycemic effects; thiazides, corticosteroids, thyroid products, and sympathomimetics may reduce hypoglycemic effects


Documented hypersensitivity; diabetic ketoacidosis


C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus


Reduce dose in hepatic impairment; may cause hypoglycemia (monitor glucose level); may cause GI distress; hypersensitivity reactions have been reported


These agents increase sensitivity of insulin by decreasing hepatic gluconeogenesis (primary effect) and increasing peripheral insulin sensitivity (secondary effect). They do not increase insulin levels or cause weight gain. Alone, they rarely cause hypoglycemia.

Absorbed from intestine (bioavailability 50-60%). Not bound to plasma proteins, not metabolized; rapidly eliminated by kidneys. Levels increase markedly in renal insufficiency. Accumulates in intestine; may decrease local glucose absorption (may explain GI effects). At high levels (eg, in renal failure), accumulates in mitochondria; inhibits oxidative phosphorylation and causes lactic acidosis (potentiated by alcohol). This side effect is rare.

Metformin (Glucophage)

Monotherapy or with sulfonylurea, thiazolidinediones, or insulin. Take with food to minimize adverse GI effects.
Available in immediate-release and extended-release formulations as well as in combination with other antidiabetic drugs.


Metformin immediate release: 500 or 850 mg/d PO with dinner; increase less than q2wk to desired effect (1 g PO bid), GI effects prevent increase, or 2550 mg/d


Not established


Numerous possible, few (if any) clinically significant


Serum creatinine level >1.5 mg/dL (men) or >1.4 mg/dL (women); hepatic dysfunction; acute or chronic acidosis; local or systemic tissue hypoxia; excessive alcohol intake; drug therapy for CHF


B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals


Fatal lactic acidosis if given with contraindication (rare without contraindication); discontinue before IV contrast enhancement, do not restart until creatinine level normal; withhold in acute hypoxia; check renal function regularly and discontinue if abnormal; adverse effects (including GI, especially diarrhea [30%]), may cause discontinuation (5%)


Thiazolidinedione derivatives improve glycemic control by improving insulin sensitivity. These drugs are selective agonists for peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Activation of PPAR-gamma receptors regulates insulin-responsive gene transcription involved in glucose production, transport, and utilization, thereby reducing blood glucose concentrations and hyperinsulinemia. Must be taken about 12-16 weeks to achieve maximal effect. These agents are used as monotherapy or with sulfonylurea, metformin, meglitinide, or insulin.
The US Food and Drug Administration issued an alert to patients and health care professionals on May 21, 2007, of rosiglitazone potentially causing an increased risk of myocardial infarction (MI) and heart-related deaths following the online publication of a meta-analysis (See rosiglitazone).
In the RECORD trial, cardiovascular outcomes were assessed after adding rosiglitazone to metformin or sulfonylurea regimens for type 2 diabetes mellitus.4 The study was a multicenter, open-label trial that included 4447 patients with mean HbA1c of 7.9%. Follow-up of the 2 combinations took place over 5-7 years. No difference was observed between the 2 groups for cardiovascular death, myocardial infarction, and stroke. Sixty-one patients who received rosiglitazone experienced heart failure that caused either hospital admission or death compared with 29 patients in the active control group (hazard ratio [HR] 2.10, 1.35-3.27 risk difference per 1000 person-years 2.6, 2.2-4.1).
Noncardiovascular adverse effects included increased upper and distal lower limb fracture rates, particularly in women. At 5 years, mean HbA1c was lower in the rosiglitazone group compared with the active control group. Results of the RECORD study found that use of rosiglitazone for type 2 diabetes mellitus increases risk of heart failure. Additionally, the risk for select fractures is increased, particularly in women. 
Troglitazone (Rezulin), another thiazolidinedione, was voluntarily withdrawn from the market by the manufacturer on March 21, 2000, following concerns about its hepatic toxicity.

Pioglitazone (Actos)

Insulin sensitizer; decreases hepatic glucose output and increases insulin-dependent glucose use in skeletal muscle and possibly liver and adipose tissue.


15 or 30 mg PO qd; may increase prn; not to exceed 45 mg/d; maximal effect may not be achieved for up to 12 wk


Not established


With insulin or oral hypoglycemics (eg, sulfonylureas) may increase risk of hypoglycemia


Documented hypersensitivity; active liver disease, ALT level >2.5 times upper limits of normal; DKA; type 1 diabetes mellitus; congestive heart failure


C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus


Caution in patients with edema; may worsen macular edema; may decrease hemoglobin, hematocrit, and WBC counts (dilution); effects on lipids neutral or beneficial (decreased triglyceride, increased HDL levels); may increase risk for distal fractures in women

Rosiglitazone (Avandia)

Insulin sensitizer; major effect in stimulating glucose uptake in skeletal muscle and adipose tissue. Lowers plasma insulin levels. Used to treat type 2 diabetes mellitus with insulin resistance.


4-8 mg/d PO or divided bid


Not established


With insulin or oral hypoglycemics (eg, sulfonylureas) may increase risk of hypoglycemia


Documented hypersensitivity; active liver disease, ALT level >2.5 times upper limits of normal; DKA; type 1 diabetes mellitus; congestive heart failure


C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus


Caution in edema; may worsen macular edema; may decrease hemoglobin, hematocrit, and WBC counts (dilution); may increase HDL cholesterol, neutral effect on triglycerides; may increase risk for distal fractures in women
The US Food and Drug Administration issued an alert to patients and health care professionals on May 21, 2007, of rosiglitazone potentially causing an increased risk of myocardial infarction (MI) and heart-related deaths following the online publication of a meta-analysis. A large-scale phase III trial (RECORD) is currently underway that is specifically designed to study cardiovascular outcomes of rosiglitazone.
For more information, see FDA's Safety Alert on Avandia. The online published meta-analysis entitled "Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes" can be viewed at The New England Journal of Medicine. Additionally, responses to the controversy can be viewed at the Heartwire news ( from WebMD) including the following articles: (1) Rosiglitazone increases MI and CV death in meta-analysis, (2) The rosiglitazone aftermath: Legitimate concerns or hype? and (3) RECORD interim analysis of rosiglitazone safety: No clear-cut answers. Also see, the FDA's Information for Health Care Professionals updated August 14, 2007.

Dipeptidyl Peptidase IV (DPP-4) Inhibitors

These agents block the action of DPP-4, which is known to degrade glucagon-like peptide 1 (GLP-1), thereby increasing its concentrations. The levels of GLP-1 achieved enhance glucose-dependent insulin secretion and suppress elevated glucagon secretion.

Sitagliptin (Januvia)

Indicated for monotherapy or combined with metformin or a thiazolidinedione.


100 mg PO qd
CrCl >30 to <50 mL/min: 50 mg PO qd
CrCl <30 mL/min: 25 mg PO qd


Not established


Data limited; caution with other drugs that decrease glucose levels


Documented hypersensitivity


B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals


Common adverse effects include upper respiratory tract infection, nasopharyngitis, and headache; assess renal function before initiating therapy and periodically thereafter; decrease dose with moderate or severe renal insufficiency

Saxagliptin (Onglyza)

Dipeptidyl peptidase IV (DPP-4) inhibitors. Blocks the enzyme DPP-4, which is known to degrade incretin hormones. Increases concentrations of active intact incretin hormones (GLP-1 and GIP). The hormones stimulate insulin release in response to increased blood glucose levels following meals. This action enhances glycemic control. Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.


2.5-5 mg PO qd
CrCl <50 mL/min: 2.5 mg PO qd
Coadministration with strong CYP450 3A4/5 inhibitors: 2.5 mg PO qd


<18 years: Not established


Coadministration with strong CYP3A4/5 inhibitors (eg, ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin) significantly increases serum concentration (do not exceed 2.5 mg/d with concurrent use of these drugs); concurrent use with CYP3A4/5 inducers (eg, rifampin) significantly decreases exposure, but not active metabolite AUC (dose adjustment not needed); coadministration with sulfonylureas increases risk of hypoglycemia (decrease dose of sulfonylurea); coadministration with thiazolidinedione (eg, rosiglitazone, pioglitazone) increases risk for peripheral edema


Documented hypersensitivity


B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals


Common adverse effects include upper respiratory tract infection, urinary tract infection, and headache; may cause peripheral edema (especially when coadministered with thiazolidinedione); hypoglycemia reported more often when coadministered with sulfonylurea; may cause hypersensitivity-related events (eg, urticaria, facial edema)

Incretin Mimetics

These agents mimic human incretin (glucagon-like peptide 1 [GLP-1]) and thereby enhances glucose-dependent insulin secretion, suppresses elevated glucagon secretion, delays gastric emptying, and promotes satiety. These agents may cause weight loss.

Exenatide (Byetta)

Indicated as adjunctive therapy to improve glycemic control in patients with type 2 diabetes mellitus who are taking metformin or a sulfonylurea, but have not achieved adequate glycemic control.
Available as 5-mcg and 10-mcg fixed-dose prefilled pens.


5 mcg SC bid within 1 h ac in morning and evening; based on response, may increase to 10 mcg SC bid after 1 mo


Not established


Data limited; may decrease absorption of orally administered drugs (take drugs requiring rapid absorption, eg, oral contraceptives, antibiotics, at least 1 h before exenatide); may prolong INR in patients taking warfarin


Documented hypersensitivity


C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus


Administer in thigh, abdomen, or upper arm; may cause hypoglycemia, nausea, vomiting, diarrhea, jittery feeling, dizziness, headache, or dyspepsia; may develop antibodies to protein contents; mild-to-moderate nausea is common (in 30%), generally self-limited, typically resolving within 2 wk of therapy

Amylin Analogs

These agents have endogenous amylin effects; they delay gastric emptying, decrease postprandial glucagon release, and modulate appetite.

Pramlintide acetate (Symlin)

Synthetic analogue of human amylin, hormone made in beta cells. Slows gastric emptying, suppresses postprandial glucagon secretion, and regulates food intake (centrally mediated appetite modulation). Indicated to treat type 1 or 2 diabetes mellitus, in conjunction with prandial and basal insulin. Given before meals in patients who have not achieved desired glucose control despite optimal insulin therapy. Helps lower glucose levels after meals, lowers fluctuation during day, and improves long-term control (A 1C ) as compared with insulin alone. Lowers insulin use and body weight.


Dose for type 1 and type 2 diabetes differs
Treatment of patients with type 2 diabetes: 60 mcg SC ac initially; titrate up (if no significant nausea for >3 d) to maintenance dose of 120 mcg; premeal insulin dose is decreased by 50% when pramlintide is started, but the basal insulin dose is usually unchanged; after target dose of pramlintide is achieved, optimize insulin dose to maintain glycemic control


Not established


May delay absorption of concomitant oral drug (administer other drug 1 h before or 2 h after)


Documented hypersensitivity to pramlintide, components, or metacresol; gastroparesis; hypoglycemia unawareness; drugs that slow gastric emptying (eg, anticholinergics, eg, atropine) or that slow intestinal nutrient absorption (eg, alpha-glucosidase)


C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus


Increases risk of insulin-induced severe hypoglycemia, especially with type 1 diabetes mellitus or gastroparesis, rare in patients with type 2 diabetes mellitus; common adverse effects are GI complaints, especially nausea (decreased when dose increased gradually); always use separate insulin syringe to measure and administer, do not mix in same syringe (insulin alters pharmacokinetics); redness, swelling, or itching at injection site; do not administer without major meal (>250 cal or 30 g carbohydrates)

Alpha-glucosidase Inhibitors

These agents inhibit action of alpha-glucosidase (carbohydrate digestion), delaying and attenuating postprandial blood glucose peaks. Undigested sugars are delivered to the colon, where they are converted into short-chain fatty acids, methane, carbon dioxide, and hydrogen.

Alpha-glucosidase inhibitors (AGIs) do not increase insulin levels or inhibit lactase; their major effect is to lower postprandial glucose levels (lesser effect on fasting levels). They do not cause weight gain and may restore ovulation in anovulation due to insulin resistance. AGIs are not commonly used in the United States, but they are more commonly used in other countries.

Alone, AGIs do not cause hypoglycemia. Less than 2% is absorbed as active drug. They are used as monotherapy or with sulfonylurea, TZD, metformin, or insulin. Take with food to minimize GI effects.

Acarbose (Precose)

Delays hydrolysis of ingested complex carbohydrates and disaccharides and absorption of glucose. Inhibits metabolism of sucrose to glucose and fructose.


25 mg PO tid ac initially with first bite of food; adjust q4-8wk based on 1-h postprandial glucose levels and tolerance; may increase dose prn, not to exceed 100 mg PO tid


Not established


Hypoglycemia with insulin or sulfonylurea agents (give glucose as dextrose, as absorption of long-chain carbohydrates is delayed); may decrease absorption and bioavailability of digoxin, propranolol, and ranitidine; digestive enzymes (eg, amylase, pancreatin) may reduce effects


Documented hypersensitivity; DKA; cirrhosis; IBD; colonic ulceration; serum creatinine level >2 mg/dL; elevated liver enzyme levels; partial or predisposition to intestinal obstruction


B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals


GI effects (eg, flatulence, diarrhea, abdominal discomfort) common, especially with metformin (17% discontinue); systemic accumulation at high doses and in renal dysfunction, with possible drug-induced hepatitis

Miglitol (Glyset)

Delays glucose absorption in small intestine; diminishes postprandial hyperglycemia.


25 mg PO tid ac initially with first bite of food; increase to 50 mg tid after 4-8 wk; may increase prn; not to exceed 100 mg PO tid


Not established


Hypoglycemia with insulin or sulfonylurea agents (give glucose as dextrose, as absorption of long-chain carbohydrates is delayed); may decrease absorption and bioavailability of digoxin, propranolol, and ranitidine; digestive enzymes (eg, amylase, pancreatin) may reduce effects


Documented hypersensitivity; DKA; colonic ulceration; partial or predisposition to intestinal obstruction; IBD


B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals


May cause GI symptoms; not recommended in significant renal dysfunction


Further Inpatient Care
  • Inpatient care generally is warranted only for the management of major acute complications such as severe recurrent hypoglycemia, major infections, or HHS.
Further Outpatient Care
  • Although a few of the complications require hospitalization, type 2 diabetes mellitus can usually be managed on an outpatient basis.
  • Moderation in diet, weight loss, and exercise are all important deterrents of type 2 diabetes mellitus. The ADA suggests that metformin can be used to help prevent the progression of prediabetes to diabetes.
  • Risk for vascular complications and cardiovascular mortality in patients with diabetes mellitus is increased by poor glucose control. Loimaala et al evaluated the efficacy of a long-term exercise training program on metabolic control and arterial stiffness in patients with type 2 diabetes mellitus. The study showed that long-term endurance and strength training was effective and resulted in improved metabolic control of diabetes mellitus compared with standard treatment; however, significant cardiovascular risk reduction and conduit arterial elasticity did not improve.5
  • The complications of diabetes include hypoglycemia and hyperglycemia, increased risk of infections, microvascular complications (ie, retinopathy, nephropathy), neuropathic complications, and macrovascular disease.
  • Diabetes is the major cause of blindness in adults aged 20-74 years.
  • Diabetes is the leading cause of nontraumatic lower-extremity amputation and ESRD.
  • For a detailed discussion of complications, see Emergency Department Care.
  • Patients with diabetes have a lifelong challenge to achieve and maintain blood glucose levels as close to the reference range as possible. With appropriate glycemic control, the risk of microvascular and neuropathic complications is decreased markedly. In addition, if hypertension and hyperlipidemia are treated aggressively, the risk of macrovascular complications decreases as well.
  • These benefits are weighed against the risk of hypoglycemia and the short-term costs of providing high-quality preventive care. Studies have shown cost savings due to a reduction in acute diabetes-related complications within 1-3 years after starting effective preventive care.
  • With each healthcare system encounter, patients with diabetes should be educated about and encouraged to follow an appropriate treatment plan. Providers must ensure that the care for each patient with diabetes includes all necessary laboratory tests, examinations (eg, foot and neurologic examinations), and referrals to specialists (eg, ophthalmologist, podiatrist).
Patient Education
  • For excellent patient education resources, see eMedicine's Diabetes Center. Also, visit eMedicine's patient education article Diabetes.


Medicolegal Pitfalls
  • Overtreatment or undertreatment of hypoglycemia such as premature discharge of a patient who develops hypoglycemia due to long-acting insulin
    • After an episode of severe hypoglycemia, patients should be discharged home with a prescription for glucagon.
    • If the hypoglycemia resulted in a loss of consciousness while driving, patients with diabetes should be educated about how to drive safely with their condition. In many states, a loss of consciousness while driving must be reported to the state department of motor vehicles, though if a patient has a monitored treatment plan for their diabetes, this notification may not be required.
  • Failure to treat the blood glucose levels of patients with wounds or active infections when levels are greater than 200 mg/dL
  • Underestimation of the severity of diabetic retinopathy on funduscopic examination because of a failure to dilate the pupils or the failure to urgently refer any patient with lesions near the macula to an ophthalmologist
  • Failure to provide adequate hydration to patients with mild diabetic nephropathy before contrast material is given may precipitate acute renal failure
  • Failure to examine the patient's feet and failure to detect small ulcers or underestimating their seriousness
  • Failure to consider myocardial ischemia in patients with nonspecific symptoms
Special Concerns
  • Pregnancy
    • MNT is the treatment of choice for GDM. If diet fails, the treatment is insulin.
    • In the past, oral antidiabetic agents were considered contraindicated in pregnancy. Glyburide is safe and effective in the treatment of GDM. Evidence suggests that metformin may be safe and effective in pregnancy as well. Studies are underway to assess their role in pregnant patients with increased insulin resistance.
    • Because patient education and ongoing glycemic control are essential to optimize fetal outcomes, consultation and specific follow-up are imperative.
  • Childhood diabetes: Although the predominant form of diabetes in children is type 1, type 2 diabetes also may occur in children.


  1. [Best Evidence] Kooy A, de Jager J, Lehert P, Bets D, Wulffelé MG, Donker AJ, et al. Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch Intern Med. Mar 23 2009;169(6):616-25. [Medline].

  2. Agency for Healthcare Research and Quality. Comparative Effectiveness and Safety of Oral Diabetes Medications for Adults With Type 2 Diabetes. AHRQ: Agency for Healthcare Research and Quality. Available at Accessed January 27, 2009.

  3. US Food and Drug Administration. Early Communication About Safety of Lantus (insulin Glargine). July 1, 2009. [Full Text].

  4. [Best Evidence] Home PD, Pocock SJ, Beck-Nielsen H, Curtis PS, Gomis R, Hanefeld M, et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet. Jun 20 2009;373(9681):2125-35. [Medline].

  5. [Best Evidence] Loimaala A, Groundstroem K, Rinne M, Nenonen A, Huhtala H, Parkkari J, et al. Effect of long-term endurance and strength training on metabolic control and arterial elasticity in patients with type 2 diabetes mellitus. Am J Cardiol. Apr 1 2009;103(7):972-7. [Medline].

  6. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. Jan 2007;30 Suppl 1:S42-7. [Medline]. [Full Text].

  7. American Diabetes Association. Standards of medical care in diabetes--2007. Diabetes Care. Jan 2007;30 Suppl 1:S4-S41. [Medline]. [Full Text].

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