Endpoints in diabetes cardiovascular outcome trials

Patel, Tejas; Tesfaldet, Bereket; Chowdhury, Iffat; Kettermann, Anna; Smith, James P.; Pucino, Frank; Almario, E. E. Navarro

doi:10.1016/s0140-6736(18)31184-x

Cited by 11 publications

(7 citation statements)

References 13 publications

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“…Approximately 31% of adjudicated heartfailure hospitalizations or urgent visits were not confirmed to be primary events (Table S8), leading to overestimation of the number of events. [47][48][49] Furthermore, hospitalization for reasons other than heart failure would remove patients from the risk of a primary end-point event, although fewer total hospitalizations in the sotagliflozin group than in the placebo group (1923 vs. 2094) spanning fewer total patient-years (104 vs. 119) suggest the absence of bias favoring sotagliflozin with respect to the primary end point. The SGLT1/2 inhibitor sotagliflozin resulted in a lower risk of the composite of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure than placebo among patients with diabetes mellitus and chronic kidney disease, with or without albuminuria.…”

Section: Discussionmentioning

confidence: 99%

Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease

et al. 2021

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BACKGROUNDThe efficacy and safety of sodium-glucose cotransporter 2 inhibitors such as sotagliflozin in preventing cardiovascular events in patients with diabetes with chronic kidney disease with or without albuminuria have not been well studied. METHODSWe conducted a multicenter, double-blind trial in which patients with type 2 diabetes mellitus (glycated hemoglobin level, ≥7%), chronic kidney disease (estimated glomerular filtration rate, 25 to 60 ml per minute per 1.73 m 2 of body-surface area), and risks for cardiovascular disease were randomly assigned in a 1:1 ratio to receive sotagliflozin or placebo. The primary end point was changed during the trial to the composite of the total number of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure. The trial ended early owing to loss of funding. RESULTSOf 19,188 patients screened, 10,584 were enrolled, with 5292 assigned to the sotagliflozin group and 5292 assigned to the placebo group, and followed for a median of 16 months. The rate of primary end-point events was 5.6 events per 100 patient-years in the sotagliflozin group and 7.5 events per 100 patient-years in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.63 to 0.88; P<0.001). The rate of deaths from cardiovascular causes per 100 patient-years was 2.2 with sotagliflozin and 2.4 with placebo (hazard ratio, 0.90; 95% CI, 0.73 to 1.12; P = 0.35). For the original coprimary end point of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, the hazard ratio was 0.84 (95% CI, 0.72 to 0.99); for the original coprimary end point of the first occurrence of death from cardiovascular causes or hospitalization for heart failure, the hazard ratio was 0.77 (95% CI, 0.66 to 0.91). Diarrhea, genital mycotic infections, volume depletion, and diabetic ketoacidosis were more common with sotagliflozin than with placebo. CONCLUSIONSIn patients with diabetes and chronic kidney disease, with or without albuminuria, sotagliflozin resulted in a lower risk of the composite of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure than placebo but was associated with adverse events. (Funded by Sanofi and Lexicon Pharmaceuticals; SCORED ClinicalTrials.gov number, NCT03315143.

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Section: Discussionmentioning

confidence: 99%

Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease

et al. 2021

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“…Major adverse cardiovascular events (MACE) 29 were evaluated as AEs by an adjudication committee consisting of a cardiologist and a neurosurgeon using four sets of preferred terms. The standardized MedDRA queries (SMQ) for MACE include the preferred terms for “Myocardial Infarction” and “Central Nervous System Hemorrhages and Cerebrovascular Accidents” 30 , and are further classified into “broad” and “narrow” sets 31 . We also used the “FDA custom MACE” term, a subset of SMQ MACE with greater specificity for myocardial infarction and ischemic stroke 32 , and the “Company custom MACE”, which was defined by the adjudication committee to specifically evaluate three‐point MACE (cardiac death, non‐fatal myocardial infarction, stroke), and includes heart failure, unstable angina, coronary revascularization and transient ischemic attack.…”

Section: Methodsmentioning

confidence: 99%

Safety and effectiveness of tofogliflozin in Japanese patients with type 2 diabetes mellitus treated in real‐world clinical practice: Results of a 36‐month post‐marketing surveillance study (J‐STEP/LT)

Utsunomiya

Koshida

Kakiuchi

et al. 2020

J of Diabetes Invest

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Aims/Introduction Tofogliflozin is a sodium–glucose cotransporter 2 (SGLT2) inhibitor that lowers plasma glucose levels by enhancing urinary glucose excretion. After its approval in Japan in 2014 for the treatment of type 2 diabetes mellitus, we carried out a 3‐year prospective observational post‐marketing surveillance study in Japanese patients (Japanese Study of Tofogliflozin with Type 2 Diabetes Mellitus Patients/Long Term [J‐STEP/LT]). Materials and Methods This surveillance was carried out between September 2014 and February 2019, and recorded safety in terms of adverse drug reactions (ADRs) and ADRs of special interest, and effectiveness in terms of changes in glycated hemoglobin and bodyweight from baseline to last observation carried forward. Results Of 6,897 patients with type 2 diabetes mellitus registered, 6,711 and 6,451 were analyzed for safety and effectiveness, respectively. ADRs were reported in 846 patients (12.61%), with serious ADRs in 101 patients (1.5%). ADRs of special interest included hypoglycemia (62 patients [0.9%]), polyuria/pollakiuria (90 [1.3%]), volume depletion‐related disorders (135 [2.0%]), urinary tract infections (91 [1.4%]), genital infections (117 [1.7%]) and skin diseases (53 [0.8%]). One case of diabetic ketoacidosis was reported. The mean ± standard deviation changes from baseline to last observation carried forward in glycated hemoglobin and bodyweight were −0.68 ± 1.34% (n = 6,158, P < 0.0001) and −3.13 ± 4.67 kg (n = 5,213, P < 0.0001), respectively. Conclusions J‐STEP/LT, a 3‐year, prospective, observational, post‐marketing study in Japan, found no unprecedented ADRs, and consistent reductions from baseline in glycated hemoglobin and bodyweight over the observation period. The present results provide further evidence regarding the safety and tolerability of tofogliflozin in Japanese patients with type 2 diabetes mellitus.

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“…Although the gold‐standard method used in CV outcomes trials for decades, the incremental precision of estimates of treatment effects and overall impact on top‐line trial results has been challenged . As others have reported, a reliable concordance was observed in estimates of major CV efficacy outcomes in contemporary CV outcome trials of antihyperglycaemic therapies between investigator‐reported adverse events, captured using Medical Dictionary of Regulatory Activities (MedDRA) preferred terms and Smart MedDRA Queries of outcomes, and results based on analyses of events confimed by central adjudication. These observations support the consideration to jettison central adjudication of primary CV outcome events in trials going forward, which would save significant trial costs, estimated between five and 50 million USD, and resource utilization, as also discussed in a recent report from the US Department of Health and Human Services concerning clinical trial costs and barriers for drug development…”

Section: Cardiovascular Outcome Trial Design Conduct and Analyses: Omentioning

confidence: 99%

FDA guidance on antihyperglyacemic therapies for type 2 diabetes: One decade later

McGuire

Johansen

Inzucchi

et al. 2019

Diabetes Obesity Metabolism

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In 2008, the US Food and Drug Administration (FDA) issued a guidance to industry statement concerning evaluation of the cardiovascular (CV) safety of new antihyperglycaemic therapies for type 2 diabetes. Fifteen CV outcome trials assessing three novel classes of antihyperglycaemic therapies, DPP‐4 inhibitors, GLP‐1 receptor agonists and SGLT‐2 inhibitors, were completed by the end of 2018 and several others are ongoing. In addition, one comparative insulin trial also has been completed. None of these trials reported an increase in risk for major adverse CV events (MACE), and six agents have demonstrated CV benefits. This experience has led to the first FDA‐approved indications for antihyperglycaemic medications to reduce the risk of CV death (empagliflozin) and to reduce the risk of MACE (liraglutide, canagliflozin), both indications specific to patients with established atherosclerotic cardiovascular disease (ASCVD). Because of the aggregate results from dedicated CV outcomes trials conducted in response to the FDA guidance statement, the contemporary paradigm for treatment of patients with type 2 diabetes has evolved substantially. However, the guidance has substantially increased the cost of developing new medications to address this important disease that afflicts hundreds of millions of adults worldwide, with reduction in quality of life as well as in life expectancy. The cost burden of drug development of medications proven effective that may directly impact cost to patients and to their insurers might be alleviated by modifications to the present guidance statement. These include areas of trial design, aspects of trial operation, expansion of composite outcomes to include broader component CV outcomes and continued evolution of analytic methodology. The guidance statement will benefit from consideration of a number of modifications to support continued innovation and, of course, the safety of marketed medications for type 2 diabetes. However, the requirement to assess each new antihyperglycaemic medication in at least one large‐scale standard randomized clinical outcomes trial should remain, so that clinicians can be reassured about the favourable efficacy/safety profiles of the medications they prescribe.

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Endpoints in diabetes cardiovascular outcome trials

Cited by 11 publications

References 13 publications

Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease

Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease

Safety and effectiveness of tofogliflozin in Japanese patients with type 2 diabetes mellitus treated in real‐world clinical practice: Results of a 36‐month post‐marketing surveillance study (J‐STEP/LT)

FDA guidance on antihyperglyacemic therapies for type 2 diabetes: One decade later

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