Egon Pfarr

Empagliflozin and Assessment of Lower-Limb Amputations in the EMPA-REG OUTCOME Trial

Sodium–glucose cotransporter 2 (SGLT2) inhibitors are oral glucose-lowering agents indicated for the treatment of type 2 diabetes. In the CANagliflozin cardioVascular Assessment Study (CANVAS) Program, the SGLT2 inhibitor canagliflozin was associated with an increased risk for lower-limb amputation (LLA) (including minor and major amputation) versus placebo (hazard ratio [HR] 1.97 [95% CI 1.41, 2.75]) in patients with type 2 diabetes and high cardiovascular risk (1). In the EMPA-REG OUTCOME trial in patients with type 2 diabetes and established cardiovascular disease (2), the proportion of patients with LLA was similar between those treated with empagliflozin and placebo (3). We report further analyses of LLA in the EMPA-REG OUTCOME trial. Any hospital admission during the EMPA-REG OUTCOME trial was to be reported as a serious adverse event. Investigators were asked to provide a detailed narrative with additional medical information for each serious adverse event. From the EMPA-REG OUTCOME trial database, we identified LLA via a systematic search of serious adverse event narratives, from events reported as adverse events, and from those reported as a “medical procedure” under “concomitant therapy” in electronic case report forms or in investigator comments describing adverse events. All cases identified were medically reviewed to confirm an LLA event. Time to first LLA was analyzed using a …

Pooled analysis of Phase III trials indicate contrasting influences of renal function on blood pressure, body weight, and HbA1c reductions with empagliflozin

Sodium glucose cotransporter 2 (SGLT2) inhibitors reduce HbA1c, blood pressure, and weight in patients with type 2 diabetes. To investigate the effect of renal function on reductions in these parameters with the SGLT2 inhibitor empagliflozin, we assessed subgroups by baseline estimated glomerular filtration rate (eGFR; Modification of Diet in Renal Disease) in pooled data from five 24-week trials of 2286 patients with type 2 diabetes randomized to empagliflozin or placebo. Reductions in HbA1c with empagliflozin versus placebo significantly diminished with decreasing baseline eGFR. Reductions in systolic blood pressure (SBP) with empagliflozin were maintained in patients with lower eGFR. The mean placebo-corrected changes from baseline in systolic blood pressure at week 24 with empagliflozin were -3.2 (95% confidence interval -4.9,-1.5) mmHg, -4.0 (-5.4, -2.6) mmHg, -5.5 (-7.6, -3.4) mmHg, and -6.6 (-11.4, -1.8) mmHg in patients with an eGFR of 90 or more, 60 to 89, 30 to 59, and under 30 ml/min/1.73m2, respectively. Similar trends were observed for diastolic blood pressure. Weight loss with empagliflozin versus placebo tended to be attenuated in patients with a lower eGFR. Results were consistent in a 12-week ambulatory blood pressure monitoring trial in 823 patients with type 2 diabetes and hypertension. Thus, unlike HbA1c reductions, systolic blood pressure and weight reductions with empagliflozin are generally preserved in patients with chronic kidney disease.

Efficacy and safety of empagliflozin in Japanese patients with type 2 diabetes mellitus: A sub-analysis by body mass index and age of pooled data from three clinical trials

AIMS To investigate the efficacy and safety of empagliflozin in subgroups based on body mass index (BMI) and age, using a pooled data set from Japanese patients with type 2 diabetes mellitus (T2DM). METHODS Pooled data from 1403 patients treated with empagliflozin at 10mg/day or 25mg/day in three clinical studies (≥52week treatment) were stratified by baseline BMI (<22, 22 to <25 and ≥25kg/m2) and baseline age (<50, 50 to <65 and ≥65years). RESULTS Empagliflozin at 10mg/day and 25mg/day reduced mean glycated hemoglobin (HbA1c) (-0.77 to -0.87% and -0.76 to -0.97%, respectively), mean fasting plasma glucose (FPG) (-20.79 to -27.06mg/dL and -26.08 to -29.60mg/dL) and mean body weight (-3.4 to -4.7% and -3.7 to -4.7%) in all subgroups of baseline BMI and age, regardless of age and degree of obesity. Adverse events were observed in approximately 70-80% patients in BMI and age subgroups of both empagliflozin groups. No hypoglycemia requiring assistance was observed. Neither UTI nor genital infection rates differed markedly among the BMI and age subgroups. Volume depletion was increased in patients ≥65years of age as compared to younger patients. CONCLUSIONS Empagliflozin was well tolerated and improved HbA1c, FPG and body weight in all BMI and age subgroups of Japanese patients with T2DM, regardless of age and degree of obesity. Empagliflozin is considered to be effective and well tolerated for treating a wide range of Japanese patients with T2DM. TRIAL REGISTRATION Study 1 (NCT01193218), Study 2 (NCT01289990) and Study 3 (NCT01368081).

Cardiovascular Safety of Empagliflozin Versus Dipeptidyl Peptidase-4 (DPP-4) Inhibitors in Type 2 Diabetes: Systematic Literature Review and Indirect Comparisons

IntroductionClinical trials conducted in patients with type 2 diabetes (T2DM) treated with glucose-lowering drugs and examining cardiovascular-related outcomes have yielded mixed results. In this work, we aimed to assess the relative treatment effects of empagliflozin versus sitagliptin and saxagliptin (dipeptidyl peptidase-4 (DPP-4) inhibitors) on cardiovascular-related outcomes in patients with T2DM.MethodsWe conducted a systematic literature review to identify clinical trials assessing cardiovascular-related outcomes for sitagliptin-, saxagliptin-, and empagliflozin-treated patients with T2DM. A network meta-analysis of indirect treatment comparisons was conducted in a Bayesian framework. Hazard ratios (HR) and 95% credible intervals (CrI) were computed for six cardiovascular-related outcomes to estimate the relative efficacies of these agents.ResultsEmpagliflozin showed a statistically significant superiority over saxagliptin (HR 0.60; 95% CrI 0.46–0.80) and sitagliptin (HR 0.60; 95% CrI 0.46–0.79) to reduce the risk for cardiovascular-related mortality. For all-cause mortality, empagliflozin showed a statistically significant risk reduction compared to saxagliptin (HR 0.61; 95% CrI 0.49–0.76) and sitagliptin (HR 0.67; 95% CrI 0.54–0.83). A similar pattern was observed in the risk reduction for hospitalization due to heart failure, where empagliflozin was found to be statistically significantly superior to saxagliptin (HR 0.51; 95% CrI 0.37–0.70) and sitagliptin (HR 0.65; 95% CrI 0.47–0.90). Empagliflozin was not statistically significantly different to sitagliptin and saxagliptin with regard to the risk of a composite endpoint composed of death, stroke or myocardial infarction.ConclusionIn this indirect comparison to the DPP-4 inhibitors saxagliptin and sitagliptin, empagliflozin significantly lowered the risk of cardiovascular-related mortality, all-cause mortality and hospitalizations due to heart failure.FundingBoehringer Ingelheim GmbH.