Finding ACCORD in the Management of Type 2 Diabetes?

Pharmacology Watch

In this issue: Examining the three arms of the ACCORD trial; and FDA Actions: clopidogrel, dexlansoprazole, and tamsulosin.

ACCORD and type 2 diabetes

Every once in a while a medical study comes along that turns medical dogma on its ear. The Multiple Risk Factor Intervention Trial (MRFIT), published in 1982, was such a study, so was the Women's Health Initiative (WHI), published in 2002. Both studies challenged conventional wisdom and changed practice. MRFIT caused us to take a hard look at risk factor intervention especially hypertensive treatment, while WHI established that combination hormone therapy in postmenopausal women should no longer be routinely recommended because of the risk of breast cancer and heart disease.

The Action to Control Cardiovascular Risk in Diabetics (ACCORD) trial, published in March in the New England Journal of Medicine, is also such a study, and is destined to change medical practice in the treatment of type 2 diabetes. ACCORD looked at three aspects of care in type 2 diabetes, the first was the effects of intensive glucose lowering, the second was the effect of intensive blood pressure control, and the third was the effect of combination lipid therapy.

The intensive glucose lowering study was published early in 2008 when it was found that the intensive therapy group (targeting hemoglobin A1c < 6.0%) reported a higher mortality than the standard therapy group (targeting A1c 7.0%-7.9%). At the same time, intensive therapy did not significantly reduce major cardiovascular events (N Engl J Med 2008;358:2545-2559).

The second and third wings of the ACCORD trial were published on-line March 14, and the results were similarly discouraging for aggressive care. A total of 4733 participants with type 2 diabetes were enrolled in the intensive blood pressure control wing and were randomized to intensive therapy, targeting a systolic pressure < 120 mmHg, or standard therapy targeting a systolic blood pressure < 140 mmHg. The primary composite outcome was nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. After a mean follow-up of 4.7 years, mean target blood pressures were met in both groups. The annual rate of the primary outcome was 1.87% in the intensive therapy group and 2.09% in the standard therapy group (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.73-1.06; P = 0.20). The annual rates of death from any cause were 1.28% in the intensive therapy group and 1.19% in the standard therapy group (HR, 1.07; 95% CI, 0.85-1.35; P = 0.55). There was a slightly reduced risk of stroke in the intensive therapy group (0.32% vs 0.53%; P = 0.01); however, serious adverse events were more than double in the intensive therapy group. The authors conclude that in patients with type 2 diabetes targeting systolic blood pressure < 120 mm Hg as compared to < 140 mm Hg did not reduce the rate of the composite outcome of fatal and nonfatal major cardiovascular events (N Engl J Med published on-line March 14, 2010). While these results are somewhat surprising, they may not change the general recommendation for more aggressive blood pressure management in type 2 diabetes to systolic blood pressure ≤ 130/80 mm Hg, which is consistent with most current guidelines (including JNC VII).

In the third wing of ACCORD, 5518 patients with type 2 diabetes who were being treated with the statin simvastatin were randomized also to receive fenofibrate or placebo. The primary outcome was first occurrence of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. After a mean follow-up of 4.7 years, the annual rate of primary outcome was 2.2% in the fenofibrate group and 2.4% in the placebo group (HR 0.92; 95% CI, 0.79-1.08; P = 0.32). There were also no significant differences between the two study groups with respect to any secondary outcomes or death rate. Subgroup analysis suggested slightly higher benefit for men vs women and perhaps a benefit for those with high baseline triglycerides (> 204 mg/dL) and low HDL (≤ 34 mg/dL). The authors conclude that the combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal myocardial infarction, or nonfatal stroke compared with simvastatin alone (N Engl J Med published on-line March 14, 2010). This study does not in any way diminish the known benefit from aggressive statin therapy in type 2 diabetics, but does suggest that targeted treatment of triglycerides with fenofibrate is of no value. The FDA is reviewing the ACCORD data, but as of this time they have "made no new conclusions or recommendations regarding the use of simvastatin or other statin drugs and fenofibrate."

Do statins increase the risk of type 2 diabetes? It has been suggested that lipophilic statins may cause unfavorable metabolic side effects such as reduction of insulin secretion and worsening of insulin resistance. In a small single-blind, placebo-controlled parallel study, 40 to 44 patients were randomized to receive placebo, or atorvastatin 10, 20, 40, and 80 mg during a 2-month period. While atorvastatin significantly reduced LDL and apolipoprotein B levels, the drug was also associated with significantly increased fasting plasma insulin levels, as well as hemoglobin A1c levels (mean changes in fasting insulin levels, 25%, 42%, 31%, and 45%, respectively, for increasing dose; A1c increases of 2%, 5%, 5%, and 5%, respectively; P < 0.05 by paired t-test). Atorvastatin also decreased insulin sensitivity in a dose-responsive fashion. The authors conclude that atorvastatin resulted in significant increases in fasting insulin, hemoglobin A1c consistent with increased insulin resistance (J Am Coll Cardiol 2010;55:1209-1216). Previous studies have shown similar results with lipophilic statins including atorvastatin, rosuvastatin, and simvastatin, while pravastatin seems to reduce the risk of diabetes.

FDA Actions

The FDA has issued a warning to health care providers regarding the antiplatelet drug clopidogrel (Plavix®). It is recently been found that up to 14% of the population did not metabolize the drug effectively and may not fully convert the drug to its active form. Clopidogrel is dependent on CYP2C19 and those that genetically lack the enzyme may not convert the drug to its active form. Recent studies have suggested that reduced CYP2C19 activity was associated with higher risk for cardiovascular outcomes. A test is available to identify genetic differences in CYP2C19 function and the FDA is recommending that health care professionals consider use of other antiplatelet medications or use alternative dosing if patients are poor metabolizers. The manufacturer of Plavix is being asked to add a black box warning to the drug labeling to this effect. Previously, it was discovered that some proton pump inhibitors including omeprazole may also inhibit metabolism to the active drug. Meanwhile Eli Lilly's prasugrel (Effient®), a direct competitor to clopidogrel, is not affected by CYP genetic variants.

The FDA has approved Takeda Pharmaceutical's request to change the name of its proton pump inhibitor dexlansoprazole from Kapidex® to Dexilant™. The change is being made due to several dispensing errors that occurred between Kapidex and the prostate cancer drug Casodex® (bicalutamide) and the analgesic Kadian® (morphine).

The FDA has approved a generic version of Boeringer Ingelheim's tamsulosin (Flomax®) for the treatment of benign prostatic hyperplasia in men. Generic tamsulosin should be available later in 2010.

This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5468. E-mail: