Prevention of diabetes: The long-term outlook

Source: Diabetes Prevention Program Research Group; et al. Lancet 2009;374:1677-1686.

Numerous randomized clinical trials show that a variety of interventions can prevent the development of type 2 diabetes (DM2) in subjects with prediabetes (i.e., impaired glucose tolerance, defined as a 2-hour post-load glucose of 140-199 mg/dL). Lifestyle interventions (i.e., intensive diet and exercise programs) are generally at least as effective as pharmacotherapy (e.g., metformin, rosiglitazone, orlistat). Some experts quibble with the term "prevent," preferring instead to indicate that our prediabetes interventions simply "delay" diabetes. Since persons at high risk for DM2 are likely to remain in a high-risk group indefinitely, the long-term picture of interventions to prevent DM2 is important.

The Diabetes Prevention Program (DPP) was one of the largest diabetes prevention trials ever performed. At 2.8 years, incidence of DM2 was reduced 58% with lifestyle, and 31% with metformin (compared to placebo). A recent report by the Diabetes Prevention Program Research Group provides a window of insight into data 10 years from the date of randomization.

Compared to placebo, subjects in the lifestyle intervention group had a 34% reduction in new onset DM2; the metformin group had an 18% risk reduction.

Follow-up of subjects enrolled in the DPP indicates a long-term risk reduction in development of DM2 attained with lifestyle or metformin intervention. Whether you call it prevention or delay, less DM2 at 10 years is a good thing.

Does it matter how we lower LDL?

Source: Taylor AJ, et al. N Engl J Med 2009;361:2113-2122.

Based upon a presumed direct relationship between LDL lowering and reduction in CV events for persons with vasculopathy, many clinicians enthusiastically embraced the combination of ezetimibe (EZT) and statins, especially when therapeutic LDL goals were difficult to attain with a statin alone. After the ENHANCE trial, which questioned the ability of EZT to effectively regress carotid atherosclerosis, clinicians began to rethink the issue, fueled additionally by disappointing data from trials of torceptrapib, an HDL-raising drug, which not only did not reduce CV events, but actually worsened CV risk, and was subsequently withdrawn from consideration for FDA approval.

A single clinical trial, the Coronary Drug Project, showed CV risk reduction with niacin in long-term follow-up. Because of adverse effects that limit more universal use of niacin, agents that were much better tolerated (like EZT) appeared to be a more suitable choice.

A clinical trial was performed to evaluate the comparative efficacy of extended-release niacin with EZT in persons with known coronary disease or with a CHD risk equivalent (e.g., DM). All subjects were already on a statin and had achieved an LDL < 100 mg/dL. Over 14 months, the performance of niacin to regress carotid intima-media thickness was significantly greater than EZT. Indeed, the incidence of CV events was significantly lower in the niacin group also (1% vs 5%).

Although EZT is effective in reducing LDL, it has not been shown to have a favorable effect upon CV or vascular surrogate endpoints; hence, its use must be reconsidered.

Identifying risk factors for falls in seniors

Source: Leveille SG, et al. JAMA 2009;302:2214-2221.

Among older adults, falls remain in the top 10 causes of death. Risk factors for falls include vitamin D status, cognitive status, physical decline, and mobility impairment. The epidemiologic magnitude of fall risk has motivated the search for other risk factors.

Leveille et al studied a population of community-dwelling senior citizens (age > 70 years) in the greater Boston area. Each participant (n = 749) was assessed for chronic pain, and reassessed on a monthly basis for 18 months. During this interval, subjects reported 1029 falls.

Subjects were stratified into pain scores by tertile. Most pain syndromes were associated with disorders like osteoarthritis, and included individuals with a single painful area as well as multiple symptomatic sites.

There was a linear relationship between pain scores and risk for falls. Subjects with two or more painful sites had approximately 20% greater risk of falls when compared to persons without pain. Although one might think that analgesic use prompted by joint pain might explain a greater incidence of falls, such a relationship was not demonstrable in this population.

Why pain is associated with falls is uncertain. Perhaps pain leads to deconditioning, leading to falls. There is also some support for cognitive effects of chronic pain that might lead to lesser executive alacrity, impairing the ability to respond to precipitants of a fall. It remains to be shown whether superior pain control will reduce fall risk.

Resistance vs aerobic exercise and COPD

Source: O'Shea S, et al. Chest 2009;136:1269-1283.

COPD is currently the 4th most common cause of death in the United States. Other than smoking cessation, only oxygen therapy in late-stage disease has been shown to modify disease. Pharmacotherapy provides improvements in symptoms and pulmonary function tests, but has not been shown to alter disease progression.

Physical deconditioning is commonplace in COPD. Indeed, the pathologic phenomenon seen in COPD of dynamic hyperinflation — an even greater diminution in ability to utilize expiratory reserve during exercise than at rest — helps explain why COPD patients may lack enthusiasm for aerobic exercise. Resistance exercise trials indicate that COPD patients can improve muscle strength, but whether such improvements translate into incremental symptomatic benefit or ability to participate in activities of daily living is uncertain.

O'Shea et al performed a meta-analysis of 18 controlled trials employing progressive resistance exercises for COPD patients. The data show some benefits of resistance exercise in ability to rise from a sitting position and climb stairs; however, trials comparing aerobic training vs resistance training indicated more favorable outcomes for activities like cycling, and that resistance training added to aerobic training provides little if any additional benefit. Finally, studies that indicated resistance training benefits for activities of daily living were ranked as having higher risk of bias. More studies specifically addressing the effects of resistance training upon functionality in COPD are needed.

Breast cancer outcomes and soy intake

Source: Shu XO, et al. JAMA 2009;302:2437-2443.

Estrogen (EST) is felt to play a role in the development of breast cancer (BCA), and modulation of estrogen is utilized as a treatment for BCA. Soy foods contain a large amount of phytoestrogens, which impact natural estrogen receptors. Soy components have also been shown to possess anticancer effects. Ultimately, whether dietary soy affects important outcomes like survival or progression of disease among subjects with cancers that may be estrogen-sensitive — like BCA — is critical to ascertain.

Shu et al studied data from the Shanghai Breast Cancer Survival Study, which provides a population of Chinese breast cancer survivors (n = 5042). After approximately 4 years of follow-up, the relationship between soy intake and BCA recurrence, overall mortality, and BCA-related deaths was evaluated. There was a consistent, linear, and inverse relationship between soy intake and mortality and BCA recurrence. When compared with persons in the lowest quartile of soy intake, those in the highest quartile enjoyed a 29% lower relative risk of mortality, and a 32% lower risk of BCA recurrence.

The relationship between soy intake and favorable outcomes was not altered by estrogen receptor-positive or -negative status or tamoxifen use.

Average soy intake in U.S. women (1-6 mg/day) is markedly less than Chinese women (47 mg/d). Whether incremental dietary soy increases in the U.S. population will translate into risk reduction has not been determined.

Oxygen therapy for cluster headache

Source: Cohen A, et al. JAMA 2009;302:2451-2457.

The pain of cluster headache (CLUS) is among the most severe of any clinical syndrome. The advent of triptans, especially sumatriptan injection, has restructured the landscape of CLUS management, since SQ sumatriptan has been shown to provide effective CLUS pain relief within 15 minutes. Unfortunately, since some patients with CLUS have multiple attacks per day, for multiple days, triptan dosing limitations preclude use in these high-frequency sufferers. Additionally, CLUS patients with CAD are unable to use triptans.

Another first-line CLUS treatment is high-flow oxygen (OXY). Advantageous aspects of oxygen treatment include its low adverse-effect profile, ability to be combined with other treatments, and applicability for multiple attacks within a short time frame. Despite commonplace clinical use, trial data on OXY are quite limited.

Cohen et al performed a randomized placebo-controlled study to compare 100% oxygen vs room air (both delivered at 12 L/min for 15 minutes). Study participants (n = 109) were followed for 5 years, with instructions to treat at least 4 attacks of CLUS with either OXY or placebo (room air). All subjects received indistinguishable separate tanks of 100% oxygen and room air, and were instructed to alternate tanks for sequential CLUS episodes in their home.

The primary endpoint of the study was percent of individuals pain-free at 15 minutes. OXY was much superior to air (78% vs 20% pain free). Randomized, placebo-controlled confirmation of our clinical practice supports continued appropriateness of OXY for CLUS.