Clinical Briefs By Louis Kuritzky, MD
Clinical Briefs
By Louis Kuritzky, MD, Clinical Assistant Professor, University of Florida, Gainesville. Dr. Kuritzky is a consultant for GlaxoSmithKline and is on the speaker's bureau of GlaxoSmithKline, 3M, Wyeth-Ayerst, Pfizer, Novartis, Bristol-Myers Squibb, AstraZeneca, Jones Pharma, and Boehringer Ingelheim.
Glucose Control and Macrovascular Disease
Source: Duckworth W, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009;360:129-139.
Most clinicians maintain a fairly glucose-centric view of diabetes. That is, we have made the assumption that the most visible derangement in diabetes, hyperglycemia, is the culprit producing vascular disease. The next intuitive step is that if glucose is pathogenetic in the development of vascular disease, then glucose modulation should reduce it. Despite consistent favorable clinical trial data confirming the benefits of glucose control upon microvascular disease (retinopathy, nephropathy, neuropathy), no clinical trial (except a single trial with acarbose) has shown reduction in macrovascular risk (myocardial infarction or stroke).
The VA Diabetes Trial (VADT) follows close on the heels of the ACCORD and ADVANCE trials, which not only failed to show reductions in macrovascular disease, but in one trial (ACCORD) demonstrated increased mortality in persons with very tightly controlled diabetes.
The VADT enrolled almost 2000 veterans with Type 2 diabetes and randomly assigned them to standard vs intensive therapy. Since almost half had already sustained a CV event, other tools to reduce CV risk were already widely employed in both groups.
At the 5.6 year endpoint of the trial, the intensive therapy group attained a substantially lower A1c than the standard therapy group: 6.9% vs 8.4%. Disappointingly, there was no discernible reduction in CV risk or microvascular endpoints in this group. There was a reassuring contrast between VADT and ACCORD: No increase in mortality with tight control was seen, despite a greater incidence of hypoglycemia. Clinicians will have to rely upon diet, exercise, smoking cessation, lipid modulation, and BP control to reduce CV endpoints in Type 2 diabetics.
Low-Glycemic Index Diet in Type 2 Diabetics
Source: Jenkins DJ, et al. Effect of a low-glycemic index or a high-cereal fiber diet on type 2 diabetes. JAMA 2008;300:2742-2753.
The knowledge that not all carbohydrate sources provide a similar rate of glucose rise has been captured with the glycemic index metric; high-glycemic index foods (e.g., bread, potatoes, simple sugars) produce very prompt glucose rise compared with low-glycemic index items (e.g., beans, complex carbohydrate sources like cruciferous vegetables). In Type 2 diabetics, in whom first-phase insulin secretion (that component of insulin secretion intended to respond to prompt glucose rise) is lost, low-glycemic index foods are intuitively preferred. Unfortunately, confirming meaningful benefits from consumption of a low-glycemic index diet has been difficult.
In this trial, Jenkins et al studied Type 2 diabetics (n = 210) assigned to 6 months of a low-glycemic index diet or a high-cereal fiber diet. Both diets achieved A1c reduction, but the low-glycemic index diet was superior (0.5% vs 0.18%). An additional favorable effect of the low-glycemic index diet was a modest HDL increase.
Whether patients can and will sustain a low-glycemic index diet, and whether such A1c reductions will reduce diabetes-related endpoints, remains to be determined. In the meantime, there is no suspicion of any detrimental effect of the low-glycemic index diet: Most short and intermediate term data suggest salutary effects.
Liraglutide: Promise of the Incretin Class
Source: Nauck M, et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes. Diabetes Care 2009;32:84-90.
Glucagon-like peptide-1 (GLP) is a recently "rediscovered" endogenous hormone of the incretin class. GLP has diverse favorable metabolic effects that modulate excess glucose excursions, including enhancement of glucose-dependent insulin secretion, slowing of gastric emptying, blunting of glucagon, and increased satiety. "Natural" GLP has a fleeting (2-minutes or less) half-life, precluding its utility as a pharmacotherapeutic tool. Recently, we have captured some of the valuable activity of the incretins by employing agents that block the degradation enzyme of GLP, DPP-4. Subcutaneous liraglutide (LIR) is a synthetic GLP analogue with a half-life of 13 hours, allowing once-daily dosing.
Nauck et al performed a double-blind, controlled trial of LIR vs glimepiride or placebo added to maximum-dose metformin in more than 1000 Type 2 diabetics. Subjects were followed for approximately 6 months.
At the end of treatment, A1c reductions (~ 1%) were similar for 2 different doses of LIR or glimepiride. Important differences, however, included changes in body weight and incidence of hypoglycemia. For instance, minor hypoglycemia was seen in only about 3% of LIR subjects, but 17% of glimepiride subjects. LIR was associated with modest weight loss (average 2.3 kg) compared to a 1 kg weight gain in glimepiride subjects. The most common adverse effect noted with LIR was nausea (11-19%), which has been commonly reported with another injectable member of the incretin class, exenatide.
Most clinicians maintain a fairly glucose-centric view of diabetes. That is, we have made the assumption that the most visible derangement in diabetes, hyperglycemia, is the culprit producing vascular disease.Subscribe Now for Access
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