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Liraglutide: Promise of the Incretin Class
Source: Nauck M, et al. 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 (about 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 injectible member of the incretin class, exenatide.
Low-glycemic Index Diet in Type 2 Diabetics
Source: Jenkins DJ, et al. 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.
Glucose Control and Macrovascular Disease
Source: Duckworth W, et al. 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 blood pressure control to reduce CV endpoints in Type 2 diabetics.
Risks Associated with the Morning BP Surge
Source: Kario K, White WB. J Am Soc Hypertens 2008;2:397-402.
Ambulatory monitoring of blood pressure (BP) has demonstrated a pattern of BP change typified by an overnight reduction in BP of 10-20% and a "morning surge" in BP beginning closely around the time of awakening. Even in patients with hypertension, morning surge in BP is seen. And it's not only BP that surges in the morning: Blood coagulability, plaque vulnerability, platelet aggregability, and blood viscosity also increase at this time. Because CV events (MI, stroke, arrhythmia) also cluster disproportionately around this circadian phenomenon, experts have opined that modulation of the morning BP surge might provide benefits in clinical outcomes.
The relationship between the morning BP surge and CV risk is strengthened by the observation that it correlates with arterial wall stiffness, left ventricular hypertrophy, and carotid intima-media thickness.
Office blood pressure is typically measured several hours after the morning surge. Encouraging more widespread use of at-home BP self-monitoring is a reasonable first step to obtain more information about morning BP. Since we have not yet learned which, if any, antihypertensives might hold special benefits on morning BP, and we do not have a major clinical trial confirming risk reduction through morning BP control, we lack sufficient evidence to mandate control of morning BP surge as a specific entity at this time.
Simplifying Dosing for Actinic Keratoses
Source: Zeichner JA, et al. J Am Acad Dermatol 2009;60:59-62.
Actinic keratoses (AK) are at best precancerous skin lesions, and at worst (a belief held by many leaders in the skin cancer field) skin carcinoma in situ. In either case, the combination of cosmetic burden, troublesome symptoms, and association with squamous cell cancer motivates their destruction. Although it is commonplace to utilize simple local destructive measures (e.g., cryotherapy) to destroy an individual lesion, it is becoming increasingly clear that field therapy (i.e., treating an entire region to include both evident and subclinical AK lesions) provides a better and more lasting service to the patient.
Imiquimod is an immune system up-regulator that has shown excellent efficacy in eradication of AK. As with all other topical agents employed for this purpose, local adverse effects and complexity of dosing regimen are limitations for some patients. Typical dose regimens for imiquimod rely upon 2-3 times weekly application of 5% cream for 8-16 weeks. Less frequent dosing, if effective, would reduce cost, enhance compliance, and possibly be better tolerated.
In this small study (n = 20), subjects applied imiquimod 5% cream once weekly for 16 weeks to half of the face, and placebo to the other half. At 16 weeks, 47% of imiquimod recipients showed marked improvement or better. In contrast to 2-3 times weekly dosing regimens, local adverse effects were essentially absent.
Total clearance rates with more frequent dosing are much higher, but so are intolerance and adverse effect rates. The authors suggest that these favorable results should be stimulus for larger, longer-duration studies.
Aerobic and Resistance Training Effects in PAD
Source: McDermott MM, et al. JAMA 2009;301:165-174.
The presence of peripheral arterial disease (PAD), confirmed by an ankle-brachial index of < 0.95, is often manifest by limitation in ability to walk, pain with walking, and limitation in performance of normal daily activities. For most patients, smoking cessation is the most important intervention. Pharmacotherapy is of limited value. Exercise training has been suggested as a method to improve oxygen utilization by the tissues and functional ability.
McDermott et al studied PAD patients (n = 156) who were randomized to aerobic training (treadmill), resistance training (weight training), or control. The treadmill group exercised 3 times weekly, beginning at a 2 mph walking speed for 15 minutes, working up to 40 minutes (with increases in treadmill speed and grade as tolerated). The resistance training group exercised 3 times weekly with knee extensions, leg presses, and leg curls. Both groups were followed for 6 months. The primary outcome was distance on the 6-minute walk.
Treadmill exercise improved the primary endpoint, but the control and resistance training groups did not significantly differ. Treadmill exercise also improved distant vascular health, as demonstrated by improvements in brachial artery flow-mediated dilation (no improvement was seen in the control or resistance training groups).