Clinical Briefs in Primary Care
Microalbuminuria and venous thromboembolism
Source: Mahmoodi BK, et al. Microalbuminuria and risk of venous thromboembolism. JAMA 2009;301:1790-1797.
Current laboratory standards indicate that normal urinary albumin excretion (UAE) should not exceed 30 mg/24 hours in healthy persons. Acute stressors (e.g., fever, significant physical exertion, acute illness) can transiently induce UAE above these limits and require reevaluation. Sustained increases in UAE between 30-300 mg/24 hours are designated microalbuminuria, which is separated from macroalbuminuria (frank nephropathy) by prognostic distinctions: Microalbuminuria can often be halted or even reversed, whereas frank nephropathy typically progresses to end-stage renal disease (although it may be slowed with pharmacotherapy).
Numerous data sets have consistently shown a relationship between abnormal UAE and arterial vascular disease, specifically coronary artery disease and ischemic stroke. In essence, it appears that the same vasculopathy manifest in the glomerulus as increased UAE heralds vasculopathy elsewhere in the arterial vascular tree.
The Prevention of Renal and Vascular End-state Disease trial is an ongoing study of all adult residents of Groningen, Netherlands (n = 85,421). A cohort from this population (n = 8592) was followed for 8.6 years. Venous thromboembolism (pulmonary embolus and/or DVT) was twice as common in persons with microalbuminuria as without. Indeed, there was a linear relationship of increased DVT risk with increasing levels of albuminuria. This study expands the pathologic associations of increased UAE to the venous side of the circulation.
Rosuvastatin lowers DVT risk
Source: Glynn RJ, et al. A randomized trial of rosuvastatin in the prevention of venous thromboembolism. N Engl J Med 2009;360:1851-1861.
Clinicians attribute most, if not all, of the favorable outcomes in statin trials to LDL reduction. Some observational studies have suggested that statin use is associated with less venous thromboembolism (DVT), but observational data have been conflicting. The JUPITER trial, which demonstrated that rosuvastatin (ROV) reduced CV endpoints in persons with essentially normal LDL (< 130 mg/L) but elevated CRP (> 2.0 mg/L), also included a DVT endpoint.
The outcome measured was a composite of DVT or pulmonary embolus among 17,802 persons randomized to ROV or placebo and followed for up to 5 years (mean, 1.9 years).
The relative risk reduction in DVT was 43% (hazard ratio, 0.57). There was a trend toward favorable effects in persons with unprovoked DVT (i.e., absence of known precipitant factors), and a very strong 48% risk reduction in persons with provoked DVT (i.e., after trauma, in cancer patients, etc.). This risk reduction augments the already demonstrated benefits for CV endpoints. The mechanism(s) by which statins may benefit venous circulation are complex and incompletely understood. The consequences of DVT are significant; this additional benefit of statin therapy, in the absence of any signal of increased bleeding, is a welcome message.
Long-term safety of ramelteon for insomnia
Source: Richardson GS, et al. Safety and subjective sleep effects of ramelteon administration in adults and older adults with chronic primary insomnia. J Clin Psychiatry 2009;70:467-476.
A variety of highly effective agents for primary insomnia are currently available including benzodiazepines, benzodiazepine receptor agonists, and other classes. Agents that impact the benzodiazepine receptors (i.e., either benzodiazepines or benzodiazepine receptor agonists) are controlled substances and have occasional problematic issues such as misuse, diversion, cognitive clouding, and rebound upon withdrawal.
Ramelteon is a melanocortin receptor agonist (MT1 and MT2 receptors) that is not a controlled substance and has a clear safety profile, absent of next-day residual effects when used up to 5 weeks. To date, ramelteon has neither shown characteristics of substances of abuse, nor any street popularity as such.
Many literature resources suggest that soporific agents are best used over short-term periods (i.e., 2-3 weeks). Despite this assertion, many patients successfully use benzodiazepines and benzodiazepine receptor agonists for very long time periods without demonstrable toxicity. Nonetheless, concerns as mentioned above stimulate identification of safe agents for long-term use.
This large clinical trial (n = 1213) included a substantial subgroup of seniors (n = 248). Long-term administration of ramelteon (8 mg to seniors, 16 mg to younger adults) over 1 year was associated with improved sleep latency in both study groups, the efficacy of which did not diminish over time. Overall, there was excellent tolerability with no evidence of rebound. Ramelteon is a viable tool for long-term management of insomnia in adults.
Statins lower testo-sterone in diabetic men
Source: Stanworth RD, et al. Statin therapy is associated with lower total but not bioavailable or free testosterone in men with type 2 diabetes. Diabetes Care 2009;32:541-546.
Diabetic men have a disproportionate incidence of comorbid hypogonadism. The acknowledged association might even be underestimated, since many experts believe that low-normal (not subnormal) testosterone levels, in concert with prototypic symptoms of hypogonadism, merit consideration for testosterone supplementation.
There are few type 2 diabetics who do not qualify for statin therapy, since the presence of type 2 diabetes is considered a cardiovascular risk equivalent. Accordingly, most midlife type 2 diabetic males are appropriately receiving a statin. Because cholesterol is a building block of testosterone, and statin therapy impacts cholesterol production, it is sensible to look at whether statin therapy affects testosterone levels.
In a study of adult (mean age, 58 years) type 2 diabetic men (n = 250), measurements of total testosterone were compared in men on statins vs men not on statins. Patients on statins had lower total testosterone; however, the sex hormone binding globulin (the protein responsible for the bound, or unavailable, testosterone in plasma) levels were also lower, resulting in a net neutral effect on free testosterone. Since free testosterone is the component necessary for testosterone activity, these results are reassuring that statins should not cause decrements in testosterone activity. Clinicians should be reminded that reliance on total testosterone measurement is insufficient to assess testosterone status: Free testosterone assessment is also necessary.
Bariatric surgery for obese diabetic subjects
Source: Keating CL, et al. Cost-efficacy of surgically induced weight loss for the management of type 2 diabetes. Diabetes Care 2009;32:580-584.
Weight management issues continue to be problematic for persons with type 2 diabetes. Success attainable with exercise, diet, and pharmacotherapy has stark limitations. Surgical approaches provide prompt, dramatic results; indeed, the metabolic responses to gastric bypass surgical procedures occur more rapidly and intensively than can be attributed to simple weight loss.
Since management of diabetes and its consequences incurs a substantial burden on health care systems, it is conceivable that not only is a surgical approach metabolically beneficial, but it might also be cost-effective.
A randomized controlled trial in Australia of obese persons (n = 60) compared surgical therapy with conventional diabetes management (diet, exercise, and pharmacotherapy). The conventional treatment arm received much more intensive support than what would be seen in typical clinical practice, thus making the challenge for surgical intervention (laparoscopic adjustable gastric banding) to demonstrate superiority even more difficult.
In the first 6 months of this 2-year study, costs were 7-fold greater in the surgical group than conventional treatment; cost differentials progressively declined with time, such that costs were equal in both groups in the last 6 months of the trial. In these newly diagnosed diabetics, surgical treatment was associated with 18 additional cases of remission of diabetes, at a cost of AUD$16,600 (US$13,000) per case. These data support surgical therapy as a cost-effective intervention for obesity in type 2 diabetes.
CRP links sleep apnea and CV adversity
Source: Lui MM, et al. C-reactive protein is associated with obstructive sleep apnea independent of visceral obesity. Chest 2009;135:950-956.
The link between obstructive sleep apnea (OSA) and cardiovascular (CV) adversity is strong and consistent. The primary putative mechanism leading to adverse CV events is the hyperactivation of the sympathetic nervous system routinely identified in persons with OSA; higher levels of sympathetic tone appears to be the compensatory response to progressive increases in apnea and hypopnea. Confirming this association are the reductions in blood pressure, arrhythmia, and catecholamine levels seen with successful interventions such as CPAP.
Yet, there may be other etiologic factors. Lui et al studied non-obese men (n = 111) who had sleep apnea to investigate whether OSA—independent of visceral adiposity seen in obese individuals—is associated with increased levels of CRP.
The mean CRP level was significantly higher in persons with moderate-to-severe OSA than in men with no/mild OSA (1.32 vs 0.54). These data suggest that OSA is associated with higher levels of CRP, independent of visceral adiposity. Because the data were determined solely in men, a similar relationship cannot be presumed in women. Interestingly, a pediatric trial found reductions in CRP subsequent to tonsillectomy, but CRP results of OSA treatment in adults have been conflicting.
Microalbuminuria and venous thromboembolism; Rosuvastatin lowers DVT risk; Long-term safety of ramelteon for insomnia; Statins lower testo-sterone in diabetic men; Bariatric surgery for obese diabetic subjects; CRP links sleep apnea and CV adversity;Subscribe Now for Access
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