Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes: a 104-week randomised, active-controlled, double-blind, phase 3 trial

Ridderstråle, Martin; Andersen, Kim Francis; Zeller, Cordula; Kim, Gabriel; Woerle, Hans J.; Broedl, Uli C.

doi:10.1016/s2213-8587(14)70120-2

Cited by 318 publications

(307 citation statements)

References 27 publications

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“…11, 12, 22, 23, 24, 25, 26, 27, 28, 29, 30 For cardiovascular outcomes analysis, 3 RCTs11, 12, 22 and 2 observational studies23, 24 were included with 351 476 patients and median follow‐up of 3.1 years. Nine RCTs contributed to the analysis of long‐term noncardiovascular safety and efficacy of SGLT2 inhibitors, with a medium follow‐up of 2 years 11, 12, 22, 25, 26, 27, 28, 29, 30. All trials were carried out with patients who had type 2 DM.…”

Section: Resultsmentioning

confidence: 99%

Cardiovascular Safety, Long‐Term Noncardiovascular Safety, and Efficacy of Sodium–Glucose Cotransporter 2 Inhibitors in Patients With Type 2 Diabetes Mellitus: A Systemic Review and Meta‐Analysis With Trial Sequential Analysis

Zhang

Zhu

Chen

et al. 2018

JAHA

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BackgroundThe cardiovascular and long‐term noncardiovascular safety and efficacy of SGLT2 (sodium–glucose cotransporter 2) inhibitors have not been well documented.Methods and ResultsFor cardiovascular outcomes, we performed a meta‐analysis with trial sequential analysis of randomized controlled trials and adjusted observational studies, each with a minimum of 26 weeks and 2000 patient‐years of follow‐up. For long‐term noncardiovascular safety and efficacy outcome analyses, we included only randomized controlled trials with at least 2 years and 1000 patient‐years of follow‐up. Five studies with 351 476 patients were included in cardiovascular outcomes analysis. Meta‐analyses showed that SGLT2 inhibitors significantly reduced the risks of major adverse cardiac events (hazard ratio [HR]: 0.80; 95% confidence interval [CI], 0.69–0.92; P=0.002), all‐cause mortality (HR: 0.67; 95% CI, 0.54–0.84; P<0.001), cardiovascular mortality (HR: 0.77; 95% CI, 0.60–0.98; P=0.03), nonfatal myocardial infarction (HR: 0.86; 95% CI, 0.76–0.98; P=0.02), hospitalization for heart failure (HR: 0.62; 95% CI, 0.55–0.69; P<0.001), and progression of albuminuria (HR: 0.68; 95% CI, 0.58–0.81; P<0.001). No significant difference in nonfatal stroke was found. Analyses limited to randomized controlled trials showed similar findings. Trial sequential analysis provided firm evidence of a 20% reduction in major adverse cardiac events, all‐cause mortality, and hospitalization for heart failure with SGLT2 inhibitors, but evidence remains inconclusive for cardiovascular mortality. Nine randomized controlled trials contributed to long‐term noncardiovascular and efficacy analyses. SGLT2 inhibitors reduced incidence of hypoglycemia and acute kidney injury but increased the risks of urinary tract and genital infections.Conclusions SGLT2 inhibitors showed remarkable cardiovascular‐ and renal‐protective effects and good long‐term noncardiovascular safety with sustained efficacy.

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Section: Resultsmentioning

confidence: 99%

Cardiovascular Safety, Long‐Term Noncardiovascular Safety, and Efficacy of Sodium–Glucose Cotransporter 2 Inhibitors in Patients With Type 2 Diabetes Mellitus: A Systemic Review and Meta‐Analysis With Trial Sequential Analysis

Zhang

Zhu

Chen

et al. 2018

JAHA

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“…The majority of weight loss in patients with type 2 diabetes is attributable to a reduction in fat mass, including reductions in both trunk fat and limb fat and in both abdominal visceral and abdominal subcutaneous adipose tissue 23. Insulin treatment and intensification of insulin treatment often leads to weight gain in patients with type 1 diabetes, which can lead to delays in intensification of therapy and can affect patients' adherence to treatment 3.…”

Section: Discussionmentioning

confidence: 99%

Empagliflozin as adjunct to insulin in patients with type 1 diabetes: a 4‐week, randomized, placebo‐controlled trial (EASE‐1)

Pieber

Famulla

Eilbracht

et al. 2015

Diabetes Obesity Metabolism

157

165

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AimsTo investigate the pharmacodynamics, efficacy and safety of empagliflozin as adjunct to insulin in patients with type 1 diabetes.MethodsA total of 75 patients with glycated haemoglobin (HbA1c) concentrations of ≥7.5 to ≤10.5% (≥58 to ≤91 mmol/mol) were randomized to receive once‐daily empagliflozin 2.5 mg, empagliflozin 10 mg, empagliflozin 25 mg, or placebo as adjunct to insulin for 28 days. Insulin dose was to be kept as stable as possible for 7 days then adjusted, at the investigator's discretion, to achieve optimum glycaemic control. The primary exploratory endpoint was change from baseline in 24‐h urinary glucose excretion (UGE) on day 7.ResultsEmpagliflozin significantly increased 24‐h UGE versus placebo on days 7 and 28. On day 28, adjusted mean differences with empagliflozin versus placebo in changes from baseline in: HbA1c were −0.35 to −0.49% (−3.8 to −5.4 mmol/mol; all p < 0.05 vs. placebo); total daily insulin dose −0.07 to −0.09 U/kg (all p<0.05 vs placebo); and weight were −1.5 to −1.9 kg (all p < 0.001 vs. placebo). In the placebo, empagliflozin 2.5, 10 and 25 mg groups, respectively, adverse events were reported in 94.7, 89.5, 78.9 and 100.0% of patients, and the rate of symptomatic hypoglycaemic episodes with glucose ≤3.0 mmol/l not requiring assistance was 1.0, 0.4, 0.5 and 0.8 episodes per 30 days.ConclusionsIn patients with type 1 diabetes, empagliflozin for 28 days as adjunct to insulin increased UGE, improved HbA1c and reduced weight with lower insulin doses compared with placebo and without increasing hypoglycaemia.

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“…Per il trattamento con insulina in monoterapia o insulina combinata con gli altri antidiabetici orali è stata stimata un'incidenza annuale di eventi ipoglicemici severi pari a 2,44% nel caso di insulina basale e a 5,04% per l'insulina basal-bolus (17,18). Per i trattamenti con gli altri antidiabetici orali senza associazione a insulina, sulfaniluree o repaglinide, è stata assunta un'incidenza annuale di eventi ipoglicemici severi pari a zero (18)(19)(20). Il costo unitario per la gestione di un evento ipoglicemico severo è stato considerato pari a €1.911,18 sulla base di uno studio osservazionale italiano in cui sono stati analizzati 3516 eventi di ipoglicemia grave, di cui il 33,1% aveva richiesto ospedalizzazione (21).…”

Section: Dati Dell'analisiunclassified

Analisi di Impatto Sul Budget di Empagliflozin Nel Trattamento Dei Pazienti Con Diabete di tipo 2 e Malattia Cardiovascolare Accertata

Iannazzo

Maggioni

Mannucci

2017

Global & Regional Health Technology Assessment

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ORIGINAL RESEARCH ARTICLElivello di glucosio nel sangue nel DT2 porta nel tempo a gravi danni a cuore, vasi sanguigni, occhi, rene e nervi. Le cause del DT2 sono principalmente l'obesità e l'inattività fisica, e si prevede che nel 2030 la malattia diverrà la settima causa di morte nel mondo (3). Il DT2 viene trattato con dieta, attività fisica, farmaci antidiabetici e somministrazione di insulina, in funzione della progressione della malattia.Empagliflozin è un inibitore specifico e reversibile del cotrasportatore sodio-glucosio di tipo 2 (sodium-glucose cotransporter 2, SGLT2) che ha bassa affinità ma alta capacità di trasportare glucosio. Esso è altamente espresso nel tubulo prossimale renale ed è responsabile del 90% del riassorbimento di glucosio che avviene nel segmento contorto del tubulo prossimale del rene (il restante 10% è riassorbito dagli SGLT1 nel segmento rettilineo del tubulo prossimale). Questo meccanismo di riassorbimento del glucosio è alterato nel paziente con DT2. Il co-trasportatore SGLT2, infatti, è sovraespresso a livello renale nei pazienti con DT2 rispetto ai soggetti senza diabete, e anche la sua attività di riassorbimento del glucosio è aumentata. Questo determina nei pazienti con DT2 e iperglicemia un aumento della quantità di glucosio che

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Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes: a 104-week randomised, active-controlled, double-blind, phase 3 trial

Cited by 318 publications

References 27 publications

Cardiovascular Safety, Long‐Term Noncardiovascular Safety, and Efficacy of Sodium–Glucose Cotransporter 2 Inhibitors in Patients With Type 2 Diabetes Mellitus: A Systemic Review and Meta‐Analysis With Trial Sequential Analysis

Cardiovascular Safety, Long‐Term Noncardiovascular Safety, and Efficacy of Sodium–Glucose Cotransporter 2 Inhibitors in Patients With Type 2 Diabetes Mellitus: A Systemic Review and Meta‐Analysis With Trial Sequential Analysis

Empagliflozin as adjunct to insulin in patients with type 1 diabetes: a 4‐week, randomized, placebo‐controlled trial (EASE‐1)

Analisi di Impatto Sul Budget di Empagliflozin Nel Trattamento Dei Pazienti Con Diabete di tipo 2 e Malattia Cardiovascolare Accertata

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