Association between circulating GDF-15 and cardio-renal outcomes and effect of canagliflozin: results from the CANVAS trial

Background Studies have suggested that sodium glucose co-transporter 2 inhibitors exert anti-inflammatory effects. We examined the association of baseline growth differentiation factor-15 (GDF-15), a marker of inflammation and cellular injury, with cardiovascular events, hospitalization for heart failure (HF), and kidney outcomes in patients with type 2 diabetes in the CANVAS (Canagliflozin Cardiovascular Assessment Study) and determined the effect of the sodium glucose co-transporter 2 inhibitor canagliflozin on circulating GDF-15. Methods and Results The CANVAS trial randomized 4330 people with type 2 diabetes at high cardiovascular risk to canagliflozin or placebo. The association between baseline GDF-15 and cardiovascular (non-fatal myocardial infarction, non-fatal stroke, cardiovascular death), HF, and kidney (40% estimated glomerular filtration rate decline, end-stage kidney disease, renal death) outcomes was assessed using multivariable adjusted Cox regression models. During median follow-up of 6.1 years (N=3549 participants with available samples), 555 cardiovascular, 129 HF, and 137 kidney outcomes occurred. Each doubling in baseline GDF-15 was significantly associated with a higher risk of cardiovascular (hazard ratio [HR], 1.2; 95% CI, 1.0‒1.3), HF (HR, 1.5; 95% CI, 1.2‒2.0) and kidney (HR, 1.5; 95% CI, 1.2‒2.0) outcomes. Baseline GDF-15 did not modify canagliflozin's effect on cardiovascular, HF, and kidney outcomes. Canaglifozin treatment modestly lowered GDF-15 compared with placebo; however, GDF-15 did not mediate the protective effect of canagliflozin on cardiovascular, HF, or kidney outcomes. Conclusions In patients with type 2 diabetes at high cardiovascular risk, higher GDF-15 levels were associated with a higher risk of cardiovascular, HF, and kidney outcomes. Canagliflozin modestly lowered GDF-15, but GDF-15 reduction did not mediate the protective effect of canagliflozin

Different eGFR decline thresholds and renal effects of cnagliflozin: data from the CANVAS program

BACKGROUND: Traditionally, clinical trials evaluating effects of a new therapy with creatinine-based renal end points use doubling of serum creatinine (equivalent to a 57% eGFR reduction), requiring large sample sizes. METHODS: To assess whether eGFR declines <57% could detect canagliflozin's effects on renal outcomes, we conducted a post hoc study comparing effects of canagliflozin versus placebo on composite renal outcomes using sustained 57%, 50%, 40%, or 30% eGFR reductions in conjunction with ESKD and renal death. Because canagliflozin causes an acute reversible hemodynamic decline in eGFR, we made estimates using all eGFR values as well as estimates that excluded early measures of eGFR influenced by the acute hemodynamic effect. RESULTS: Among the 10,142 participants, 93 (0.9%), 161 (1.6%), 352 (3.5%), and 800 (7.9%) participants recorded renal outcomes on the basis of 57%, 50%, 40%, or 30% eGFR reduction, respectively, during a mean follow-up of 188 weeks. Compared with a 57% eGFR reduction (risk ratio [RR], 0.51; 95% confidence interval [95% CI], 0.34 to 0.77), the effect sizes were progressively attenuated when using 50% (RR, 0.61; 95% CI, 0.45 to 0.83), 40% (RR, 0.70; 95% CI, 0.57 to 0.86), or 30% (RR, 0.81; 95% CI, 0.71 to 0.93) eGFR reductions. In analyses that controlled for the acute hemodynamic fall in eGFR, effect sizes were comparable, regardless of whether a 57%, 50%, 40%, or 30% eGFR reduction was used. Estimated sample sizes for studies on the basis of lesser eGFR reductions were much reduced by controlling for this early hemodynamic effect. CONCLUSIONS: Declines in eGFR <57% may provide robust estimates of canagliflozin's effects on renal outcomes if the analysis controls for the drug's acute hemodynamic effect. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: CANagliflozin cardioVascular Assessment Study (CANVAS), NCT01032629 and CANVAS-R, NCT01989754

Patients' perceptions of subcutaneous insulin in the OPTIMIZE study: A multicenter follow-up study

Background: The Optimizing Control in Diabetes (OPTIMIZE) survey was conducted to understand the patients' perspective to achieving good glycemic control and to determine how patients' perceptions of insulin may affect their decisions to initiate or intensify their insulin therapy. Methods: A total of 1,444 subjects with type 2 diabetes, at least 25% of whom were currently using insulin, were recruited from an online patient database and via physicians. Results: Duration of diabetes was ≥2 years in 1,243 (86%) respondents. Two-thirds (975 [67%]) of respondents were not using insulin, of whom 111 (11%) were using diet and exercise alone and 864 (89%) were receiving oral agents, and 469 (32%) were using subcutaneous (SC) insulin. Overall, 823 of 1,444 (57%; 95% confidence interval [CI], 54% to 60%) individuals were not aware of their most recent hemoglobin A1c (HbA1c) test results or declined to answer. Of those using SC insulin, 120 of 175 (69%; 95% CI, 61% to 75%) reported HbA 1c levels ≥7%. This was unrelated to whether they used pens or syringes. The majority of respondents "wished there was another way to take insulin" whether they were using insulin (371 of 469 [79%]; 95% CI, 75% to 83%) or not (782 of 975 [80%]; 95% CI, 78% to 83%). When patients not currently using insulin were questioned how they felt about requiring SC insulin in the future, 445 of 975 (46%; 95% CI, 42% to 49%) indicated they would avoid it if at all possible. The majority (71%) cited injection-related factors as the main reason for their apprehension. Conclusions: In this survey, the majority of patients reported that they wished there was another way to take SC insulin regardless of whether they were currently using SC insulin or not. Improving patients' perceptions and acceptance of insulin could encourage earlier insulin use and assist in achieving and maintaining long-term appropriate glycemic control. © Mary Ann Liebert, Inc. 2008