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Trials That Matter: The Effect of a Fixed-Dose Combination of an Angiotensin-Converting Enzyme Inhibitor and a Diuretic on the Complications of Type 2 Diabetes

George L. Bakris, MD; and Michael Berkwits, MD, MSCE, Deputy Editor
[+] Article, Author, and Disclosure Information

From the University of Chicago, Chicago IL 60637, and the American College of Physicians, Philadelphia, PA 19106.

Potential Financial Conflicts of Interest:Consultancies: G.L. Bakris (Merck, Boehringer-Ingelheim, GlaxoSmithKline, Novartis, Abbott Laboratories, Forest Pharmaceuticals).

Grants received: G.L. Bakris (National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases, GlaxoSmithKline, Forest Pharmaceuticals).

Grants pending: G.L. Bakris (National Institutes of Health Alternative Medicine Institute). Royalties: G.L. Bakris (Dr. Bakris is the editor of many textbooks on hypertension).

Corresponding Author: Michael Berkwits, MD, MSCE, American College of Physicians, 190 N. Independence Mall West, Philadelphia, PA 19106.

Current Author Addresses: Dr. Bakris: University of Chicago, 924 East 57th Street, Suite 104, Chicago, IL 60637.

Dr. Berkwits: American College of Physicians, 190 N. Independence Mall West, Philadelphia, PA 19106.

Ann Intern Med. 2008;148(5):400-401. doi:10.7326/0003-4819-148-5-200803040-00012
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Providers who care for patients with type 2 diabetes often focus on lowering levels of glucose and hemoglobin A1c. Strict control of these glycemic measures reduces the incidence of microvascular complications of the disease, such as retinopathy and nephropathy, but has little effect on macrovascular complications, such as myocardial infarction and stroke, from which most patients with type 2 diabetes ultimately die. Prevention of these macrovascular complications requires equal attention to lowering blood pressure and lipid levels. Diabetes care would be simplified enormously if physicians had a treatment that could safely reduce both kinds of complications.

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The ACCORD study
Posted on March 11, 2008
Arcot Dwarakanathan
Associate Professor
Conflict of Interest: None Declared

Dear Sir:

While the observation by Dr. Barris in the ACCORD study regarding BP control is important, I would like to bring your attention to the glucose control part of the study.

Several clinical studies, both in type 1 and type 2 diabetes mellitus, have confirmed the relationship between elevated blood glucose levels and microvascular complications. These studies also support beneficial effect of improved glucose control in reducing microvascular complications. However, the impact of improved glucose control on macrovascular disease, especially cardiovascular events is not so clear. In fact, some recent published reports indicate that improvement in glucose control (hemoglobin A1c) does not always translate to a reduction in cardiovascular endpoints. (1,2,3) The most disturbing news is the decision of the NHLBI overseeing committee to stop the glucose control part of the ACCORD study after 4 years. The blood pressure and lipid lowering part of the study are still continuing. In this NHLBI-sponsored study, approximately 10,000 patings (average age 62 years) with cardiovascular disease or at least two risk factors for cardiovascular disease were randomized to intensive glucose control versus standard treatment. While the intensive group reached an average hemoglobin A1c of 6.4%versus 7.5% in the standard group, there were 54 more deaths in the intensively treated group (257 versus 203 deaths). We do not have microvascular disease data. Some possible explanations to this adverse outcome are:

1. Relatively rapid lowering blood glucose (very similar to observations with rapid lowering of blood pressure) may be detrimental to the patients with underlying cardiovascular disease.

2. Treatment regimen that were used in the intensively treated group may be at work. For example, the intensively treated patients may have been treated with medications like TZD's more often.

3. Undetected hypoglycemic episodes with the resultant epinephrine surges could be rather dangerous in these patients. In this context, very aggressive use of rapid acting insulin preparations will have to be looked for in the intensively treated group.

Although, there are many questions raised by the study, we should at least come to certain conclusions and recommendations at this time.

1. In the vast majority of the patients with diabetes, improving blood glucose level will decrease microvascular complications in the long run.

2. In the patients with known cardiovascular disease, we should avoid rapid and aggressive lowering of blood glucose levels. In this context, how low is too low and how fast is too fast is yet to be determined and certainly should be individualized.

3. Frequent blood glucose monitoring even in type 2 patients will uncover previously undetected hypoglycemic episodes and these will have to be diligently avoided. While lowering the hemoglobin A1c can be a surrogate marker for lowering microvascular disease, the relationship to cardiovascular disease is not only unclear, but has been questioned.

4. The picture becomes even more complicated when we hear that another similar, the ADVANCE, has not found any increase in death or cardiovascular events in the aggressively treated group of patients.

The ADVANCE study involved 11,140 patients and they reached the A1c of 6.4% in the intensively treated group very similar to the final A1c in the ACCORD group, while their standard treatment regimen reached A1c of 7% compared to 7.5% in the ACCORD patients. This study has been closed and the data has been locked up. Therefore, we are unable to obtain further information from the study and further details will be avaqilable in the future. In the meantime, we all have to pay attention and be cautious about aggressively lowering the blood glucose levels in older patients with cardiovascular disease or in patients with increased cardiovascular risk.


1. National Heart, Lung and Blood Institute. ACCORD telebriefing prepared remarks. Feb 6, 2008.

2. JAMA. 2007 Sept 12;298 (10):1189-95.

3. N. Engl J Med. 2007 Jun 14; 356(24): 2457-71. Epub 2007 May 21

Conflict of Interest:

None declared

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