Cognitive Impairment Progression Blunted by Exercise

Source: Lautenschlager NT, et al. Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease: A randomized trial. JAMA 2008;300:1027-1037.

Clinical trials of pharmacotherapy to prevent progression of cognitive decline in those with mild cognitive impairment (MCI) have been disappointing; neither cholinesterase inhibitors (donepezil, rivastigmine, galantamine), vitamin E, nor COX-2 inhibitors has demonstrated any clinically meaningful benefit in placebo-controlled MCI trials.

Observational data are consistent that regular physical activity, even if started late in life, is associated with reduced risk of dementia. Whether exercise might prevent progression in persons with MCI was the subject of this first randomized trial to address the issue.

Subjects (n = 170) with MCI between the ages of 50-77 (mean age, 68.6 years) were randomized to receive either 50-min sessions of moderate-intensity exercise (e.g., brisk walking, ballroom dancing, and swimming) three times weekly vs control (general education about health, including physical activity, diet, alcohol, and stress management). All educational materials were also provided to the intervention group. All participants (control and intervention) wore a pedometer and provided diaries of daily total number of steps. Physical activity and cognitive function were assessed at 6, 12, and 18 months after randomization.

At each assessment point, cognitive scores for the intervention group were better than the control group. The intervention group averaged approximately 6000 more steps/week than the control group. Exercise, averaging as little as 21 min/day, reduces cognitive decline in persons with MCI.

Incidentalomas in the Knee

Source: Englund M, et al. Incidental meniscal findings on knee MRI in middle-aged and elderly persons. N Engl J Med 2008;359:1108-1115.

One of the primary things that has stood in the way of definitive diagnosis of acute low back pain is the extraordinarily high rate of false-positive findings seen on plain films, CT, or MRI. Indeed some studies suggest that as many as half of healthy, asymptomatic individuals studied by MRI of the lumbar spine have findings consistent with disk pathology.

Little is known about the frequency of incidental findings seen upon MRI of the knee, since studies generally investigate symptomatic individuals; subsequent radio-graphic findings, if they correlate with symptomatology, have been taken to support a causal relationship.

Englund et al performed an MRI of the right knee in 991 randomly selected adult subjects ages 50-90 in Massachusetts. Excluded subjects included those with rheumatoid arthritis, knee replacement, terminal illness, or non-ambulatory status.

The incidence of meniscal tears seen ranged from 19% in the youngest women (ages 50-59) to 56% in senior men (ages 70-90). Among the group with radiographic changes of osteoarthritis, the frequency of meniscal tears in symptomatic and asymptomatic individuals was similar (63% vs 60%, respectively). Overall, the majority of persons (60%) with meniscus tears confirmed by MRI had no symptoms referable to the knee.

It appears that as with back MRI, incidental findings of pathology are frequent, and call into question an ironclad attribution of knee symptoms to positive findings on MRI.

Hormone Replacement and Skin Health in Menopausal Women

Source: Phillips TJ, et al. Does hormone therapy improve age-related skin changes in postmenopausal women? J Am Acad Dermatol 2008;59:397-404.

As little as a decade ago, menopausal status alone was the ticket of admission to advocate hormone replacement therapy (HRT). The "story line" went that HRT prevented cognitive decline, improved symptoms, enhanced cardiovascular health, and preserved cutaneous health, i.e., reduced age-related wrinkles, dryness, and laxity. Unfortunately, HRT has failed to live up to numerous of its hopeful claims.

To study the effects of HRT on menopausal women's skin, 485 subjects were randomly assigned to placebo or two different HRT doses in double-blind fashion. Dermatologists evaluated skin wrinkling, laxity, and texture (as did the patients) over a 48-week interval. The mean age of the women was 54 years.

At study end, there were no statistically significant differences in any primary endpoint of the trial. When the data were analyzed for impact of baseline levels of estradiol, race, or age, no meaningful differences were found. During the trial, all study groups enjoyed some skin improvements attributable to daily application of moisturizing cream and sunscreen, but HRT added nothing to this. Claims that HRT provides reduced risk of age-related skin changes are not supported by this trial.

Reconfirmation of the Death of Homocysteine

Source: Ebbing M, et al. Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: A randomized controlled trial. JAMA 2008;300:795-804.

Homocysteine (HCYS) has all the trappings of a first-rate cardiovascular risk factor: as strong an association with CVD endpoints as cholesterol, ease of identification, and simplicity of modulation. Trouble is, trials to date have been unable to show that reductions of homocysteine provide meaningful benefits to patients. Indeed, one recent commentary following a large double-blind interventional trial of HCYS for cardiovascular endpoints began with "The homocysteine hypothesis is dead … ."

Apparently as undaunted as Mark Twain ("The reports of my death are greatly exaggerated …"), Ebbing et al tested HCYS reduction through B vitamins after coronary angiography. The primary endpoint of the study was all-cause mortality, non-fatal stroke and MI, and hospitalization for unstable angina (composite).

The trial (n = 3096) was designed to follow patients for 4 years, but was stopped at 38 months due to information from another trial that had reported a possible negative effect of B vitamin intervention. B vitamins did reduce HCYS by approximately 30%, but failed to have any impact (positive or negative) upon endpoints. The HCYS hypothesis is still dead.

Pramlintide as a Weight-Loss Adjunct

Source: Smith SR, et al. Sustained weight loss following 12-month pramlintide treatment as an adjunct to lifestyle intervention in obesity. Diabetes Care 2008;3:1816-1823.

Something that neither mother nor medical school taught us was that more than one hormone is secreted from the beta cells of the pancreas in response to rising glucose. In conjunction with insulin, the hormone amylin is released. Pramlintide is a synthetic form of amylin. The physiologic effects of amylin include slowed gastric emptying (thereby slowing the rate of glucose delivery to the intestine), suppression of glucagon, and centrally mediated satiety. For addressing obesity, there is great conceptual appeal to an agent that improves satiety.

Smith et al performed a double-blind, placebo-controlled trial of various doses of subcutaneous pramlintide (bid to tid) in obese, nondiabetic subjects, who were also receiving intensive lifestyle (diet/exercise) intervention. The initial 4-month double-blind phase was followed by a 4-month single-blind extension (for those who completed the initial phase without protocol violation).

Weight loss was dose-proportional: At 360 mg twice daily the placebo-corrected weight loss was 3.3 kg at month 4 and 7.2 kg at month 12. No safety concerns were seen. Nausea, which is also the most common adverse event seen in diabetic subjects, was mostly mild to moderate, and improved over time. Nausea is not the mechanism of action, since weight reduction was similar in those who did and did not experience nausea. These initial data are encouraging that pramlintide may find a role in enhancing weight loss when used in conjunction with lifestyle intervention.

Undiagnosed Diabetes in Obese Americans

Source: Wee CC, et al. Obesity and undiagnosed diabetes in the U.S. Diabetes Care 2008;31:1813-1815.

No clinician is surprised to see that diabetes often goes undiagnosed. Patients can persist with modest symptoms, or even asymptomatically, for protracted periods during the early stages of type 2 diabetes. The fact that literally half of type 2 diabetics have one or more of the traditional complications of diabetes (neuropathy, nephropathy, retinopathy, dermopathy) at the time of clinical diagnosis attests to the fact that diagnosis lags substantially behind disease onset.

Most type 2 diabetics are obese, and obesity provides an environment that promotes insulin resistance, a cardinal dysfunction in early diabetes and pre-diabetes. Hence, scrutiny of obese subjects provides a window of observation into a population felt to be at greater risk for developing diabetes. On the one hand, the clinician might think that the presence of obesity would prompt greater vigilance for diabetes; on the other hand, there is evidence that compared to the non-obese, obese individuals experience delays in receiving preventive care.

From the 1999-2004 NHANES data, it was determined that 9.8% of the population had diabetes (defined as FBG > 126 mg/dL). Slightly more than one-fourth (28.1%) of persons with FBG > 126 mg/dL had not been diagnosed with diabetes. When parsed into BMI categories, normal weight individuals were actually less likely to have undiagnosed diabetes than overweight or obese persons (22.2% vs 32.5% vs 27.4%, respectively). Because more than one-half of undiagnosed diabetes is seen in overweight and obese individuals, enhanced vigilance is appropriate.