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By Louis Kuritzky, MD, Clinical Assistant Professor, University of Florida, Gainesville. Dr. Kuritzky is an advisor for Endo, Kowa, Pricara, and Takeda.Long-Term CV Effects of Intensive Glucose Lowering: The ACCORD Study
Source: Gerstein HC, et al. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med 2011;364:818-828.
The action to control cardiovascu-lar risk in diabetes (ACCORD) study is really three studies in one, providing information about blood pressure, glucose, and triglyceride treatment in high-risk diabetic patients. Probably the most unsettling component of ACCORD was the early termination of the comparison of tight glucose control (attainment of an A1c < 6) with standard control (A1c 7-7.9) due to an unanticipated INCREASE in mortality associated with tight control. The glucose control arm of ACCORD was designed to go on for 5 years, but intensive glucose control was stopped at 3.5 years. Though various explanations for these results have been offered, none is wholly satisfying.
Once the increased mortality of tight control was appreciated, ALL study subjects were switched to the standard control regimen and followed to the 5-year mark. This most recent publication details outcomes of persons who originally were treated with tight control, and then were switched to standard control for the next 17 months.
Just as had been seen in the initial results of ACCORD, the group that had been assigned to tight control (even though now they had been receiving more relaxed control, and their A1c had risen 7.2%) continued to experience a statistically significant 19% greater risk for death. During Phase 2 of ACCORD, the frequency of hypoglycemia was the same between the standard control group and the group that had changed from tight to standard control; hence, although the greater frequency of hypoglycemia seen in tight control had received some focus as a culprit in inducing greater mortality, this follow-up suggests that is not the case. Why tight control is associated with increased mortality remains unknown.
Cysteine as a Biomarker for Sleep Apnea
Source: Cintra F, et al. Cysteine: A potential biomarker for obstructive sleep apnea. Chest 2011;139:246-252.
Obstructive sleep apnea (OSA) is consistently associated with cardiovascular misadventure: An increased risk for hypertension, tachycardia, cardiac arrhythmia, myocardial infarction, and stroke has been noted. OSA seems to reset the sympathetic nervous system to a higher level of activity, thus explaining some of these adversities. Tools to identify OSA are somewhat cumbersome and expensive. Were biomarkers available to identify OSA, clinicians could better reserve expensive confirmatory testing for persons with higher pre-test likelihood of disease.
Animal studies have found that sleep deprivation and hypoxia produce elevations in cysteine (CYS). Cintra et al measured CYS levels in subjects undergoing sleep studies (n = 75) and a group of matched controls (n = 75). A non-obese OSA subgroup was included to ascertain whether obesity has an impact on CYS.
CYS levels were significantly higher (15%-17%) in OSA subjects than controls (P < 0.01), whether obese or lean. A 6-month period of CPAP treatment resulted in a reduction of CYS levels. No pathogenetic role of CYS is known, but if further studies confirm the relationship between CYS and OSA, it may serve as a reasonable screening tool for selecting those who might benefit from sleep studies.
Steroid or Steroid Plus Long-Acting Beta Agonist for Mild Persistent Asthma
Source: Postma DS, et al. Comparison of the effect of low-dose ciclesonide and fixed-dose fluticasone propionate and salmeterol combination on long-term asthma control. Chest 2011;139:311-318.
The largest body of asthmatics is classified as mild persistent asthma, defined as daytime symptoms more than once weekly but not daily, nocturnal symptoms less than once weekly, and essentially normal lung function between exacerbations. At this stage, long-term controller medications inhaled corticosteroids (ICS) or leukotriene inhibitors (LKT) are suggested, reserving combination inhaled corticosteroid/long-acting beta agonist (ICS/LABA) for refractory cases or patients who progress to moderate persistent asthma and beyond. LABA monotherapy is no longer considered appropriate for asthma patients at any stage of disease.
Ciclesonide (CIC) is a novel ICS with at least two favorable attributes: once daily dosing, and minimal hypothalamic pituitary axis perturbation at typical clinical doses. This clinical trial compared low-dose CIC with low-dose fluticasone/salmeterol in patients with mild persistent asthma (n = 657). The two co-primary endpoints were time to first severe asthma exacerbation and number of poorly controlled asthma days.
CIC alone was not superior to placebo in time to first severe asthma exacerbation, but ICS/LABA was. Other aspects of asthma control were comparable between the two regimens. Although ICS alone is advocated as appropriate initial treatment for mild persistent asthma, this comparison trial suggests that ICS/LABA provides at least one aspect of superiority.