Good Cardiovascular News from the SGLT2 Inhibitor Class?

SOURCE: Zinman B, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-2128.

Current FDA regulations require that new pharmacologic agents to treat diabetes must demonstrate cardiovascular safety in addition to glucose lowering. The rationale for this stipulation is that some very early clinical trials with sulfonylureas in type 2 diabetes (T2DM) suggested a negative effect on cardiovascular outcomes, and successive clinical trials have failed to demonstrate statistically significant improvements in cardiovascular outcomes, despite excellent glucose control. Indeed, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial suggested a potential worsening of cardiovascular outcomes and mortality in tightly controlled T2DM patients (A1c < 6.5).

The cardiovascular safety trial for empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, is known as the EMPA-REG trial. Investigators randomized T2DM patients (n = 7020) to empagliflozin or placebo for 3 years. At the conclusion of the trial, the primary outcome (a composite of death from cardiovascular cases, nonfatal myocardial infarction, and nonfatal stroke) was 14% better in the treatment group than placebo (absolute risk reduction 1.7%).

While these results were the source of much celebration when presented at the European Association for the Study of Diabetes meeting in Stockholm, Sweden, in September 2015, there are reasons for pause. First, clinical trials with two other SGLT2 inhibitors (dapagliflozin, canagliflozin), which work by essentially comparable mechanisms, have not yet completed their cardiovascular safety trials. On the other hand, the cardiovascular outcomes from trial data thus far accrued with both of these other agents does not suggest cardiovascular risk reduction. Until FDA-mandated cardiovascular risk trials are completed with each of the agents of this class, whether individual agents might provide particular cardiovascular benefits or not will remain speculative. Second, it is difficult to reconcile how a trial that did not show a reduction in fatal or nonfatal myocardial infarction and did not show a reduction in fatal or nonfatal stroke achieved a reduction in cardiovascular mortality. Isn’t the combination of stroke + myocardial infarction the primary constituent of cardiovascular mortality? For the time being, physicians will have to defer to the statistical wisdom of clinical trial data experts to decipher this intuitively self-contradictory result. While some physicians may want to celebrate the possible discovery of a pharmacologic treatment for T2DM associated with improved cardiovascular outcomes, I am not there yet.

Spironolactone Best Add-on for Resistant Hypertension

SOURCE: Williams B, et al. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): A randomised, double-blind, crossover trial. Lancet 2015;386:2059-2068.

Resistant hypertension (r-HTN) is currently defined as persistence of uncontrolled blood pressure (BP) despite full therapeutic doses of three antihypertensive medications, one of which is a diuretic. As evidenced by clinical trial data, the prevalence of r-HTN is generally in the 15-18% range. While it is appropriate to seek a secondary cause for r-HTN (e.g., sleep apnea, aldosteronism, etc.), an underlying correctable cause is not identified in most cases, so additional medications must be added to attain BP goals.

While essentially any medication not already present in the three-medication regimen could be considered as an add-on, several clinical trials point to the utility of aldosterone antagonists such as spironolactone and eplerenone, demonstrating considerable success in controlling otherwise resistant hypertension. But is aldosterone antagonism the best way to go?

Williams et al reported results of their double-blind, placebo-controlled, crossover trial in adults with r-HTN. Study subjects (n = 285) were randomized to one of four treatment arms: spironolactone, doxazosin, bisoprolol, or placebo added to their current three-drug regimen. Treatment periods lasted 12 weeks.

Spironolactone provided statistically significant greater reductions in BP than the other two active agents; adverse effects and withdrawal were similar among the three active treatment arms. Spironolactone is an inexpensive and effective way to address r-HTN.

Vitamin D: Conclusions from an NIH Conference

SOURCE: Taylor CL, et al. Questions about Vitamin D for primary care practice: Input from an NIH conference. Am J Med 2015;128:1167-1170.

Clinicians continue to have well-founded uncertainties about how to best capture potential benefits of vitamin D. Although there is no doubt that vitamin D deficiency impairs skeletal health, the optimum application of vitamin D supplementation for otherwise healthy persons is ill-defined.

Fairly strong evidence supports vitamin D supplementation in frail seniors to prevent falls. Beyond that, there is little definitive evidence on which to rely. Observational studies indicate that low vitamin D status is associated with risk for cardiovascular disease, cancer, diabetes, and other important disorders, but whether this relationship is causal is not yet known, and whether correction of such a causal relationship (if established) will improve outcomes remains to be determined.

The NIH conference confirmed that 25(OH) vitamin D remains the preferred metric, while acknowledging that consensus does not exist to specifically define optimum vitamin D levels or a specific threshold indicative of deficiency. Equally confounding is the acknowledgement that methods for measuring 25(OH) vitamin D are not standardized and may vary from laboratory to laboratory by as much as 20%.

Currently recommended supplemental doses of vitamin D (400-1000 IU/d) are generally considered safe, but concern for toxicity was expressed in reference to mega-dosing (10,000-50,000 IU/d).