Limited meta-analysis suggests SGLT2 inhibitors improve cardiovascular outcomes in patients with T2DM + atherosclerosis

Reference

Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet 2019;393(10166):31-39.

Synopsis

Thee authors searched PubMed and EMBASE for published randomized trials of SGLT2 inhibitors (canagliflozin [Invokana], dapagliflozin [Farxiga], and empagliflozin [Jardiance]) that reported cardiovascular outcomes. The authors don't describe the mechanics of article selection. The authors used the Cochrane Collaboration Risk of Bias tool to assess the risk of bias among the included trials. They included 3 trial and 6 secondary analyses (caution: secondary analyses are generally better at generating hypotheses than testing them) with 34,322 patients with type 2 diabetes, 60% of whom had known atherosclerotic disease at the time of enrollment. One study provided no definition of atherosclerosis risk factors; 2 studies included smoking, hypertension, and dyslipidemia as risk factors, but each varied in the age thresholds and only one included duration of diabetes. It's not surprising then that the proportion of patients with multiple risk factors also varied: 0% for empagliflozin, 34% for canagliflozin, and 54% for dapagliflozin. Additionally, the included trials varied markedly in the proportion of patients with heart failure or renal involvement at baseline. The three trials were at low risk of bias, a common finding among industry-sponsored studies. Although the authors don't report the duration of each study, they provide event rates per 1000 patient-years. Approximately 10% of the patients experienced a MACE—a composite outcome of myocardial infarction, stroke, or cardiovascular death—75% of which occurred in patients with known atherosclerosis. Patients who took SGLT2 inhibitors had slightly fewer MACEs than patients taking a placebo, but this effect was only seen in patients with known atherosclerosis at baseline (36 vs 42 MACEs per 1000-patient years, respectively; number needed to treat [NNT] = ~167 per year). The authors report data on additional outcomes, but these largely came from the secondary analyses. These analyses show that SGLT2 inhibitors are associated with fewer composite events, such as hospitalizations for heart failure plus cardiovascular death, or decreased glomerular filtration rate, end-stage renal disease, or renal death. The only harms reported in this study were an increase in amputations in the canagliflozin trial (number needed to treat to harm [NNTH] = ~3000 per year) and ketoacidosis in all 3 of the studies (NNTH = ~2500 per year). We know from other studies of proprietary products that data are often suppressed, so red flags need to go up when a study only includes published data and makes no attempt to find unpublished studies. For example, a very cursory snoop at Clinicaltrials.gov reveals 30 completed clinical trials that show data for just ONE of these agents. Although this study received no funding, the paper lists a rather impressive number of "interests" among the authors. It may be true that this class of drugs truly is effective in improving clinically relevant outcomes, but I would love to see an independent, conflict-free, patient-level meta-analysis of ALL relevant studies.