Empagliflozin as add-on to metformin plus sulphonylurea in patients with type 2 diabetes

Haering, Hans-Ulrich; Merker, Ludwig; Christiansen, Anita Vedel; Roux, Flavien; Salsali, Afshin; Kim, Gabriel; Meinicke, Thomas; Woerle, Hans J.; Broedl, Uli C.

doi:10.1016/j.diabres.2015.05.044

Cited by 69 publications

(37 citation statements)

References 18 publications

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“…Weight loss with empagliflozin treatment is consistent with data from phase III trials (6)(7)(8)(9)(10)(11)(12) and is likely due, primarily, to the loss of calories via the increased urinary glucose excretion associated with empagliflozin (17), whereas linagliptin is considered to be weight neutral (5,18). Weight loss or avoiding weight gain is important to patients (19), with weight gain associated with decreased treatment satisfaction and health-related quality of life (20).…”

Section: Discussionsupporting

confidence: 57%

“…However, this study did not control for changes in the use of antihypertensive drugs, which may have impacted the effects observed on BP. Statistically significant reductions in SBP were demonstrated in phase III trials with empagliflozin as monotherapy or add-on therapy (6)(7)(8)(9)(10)(11). Empagliflozin reduces BP via mechanisms that may include diuretic effects, weight loss, and improved glycemic control (21), whereas linagliptin has no effect on BP (22).…”

Section: Discussionmentioning

confidence: 99%

“…In phase III trials, empagliflozin as monotherapy or add-on to existing therapy was associated with clinically relevant improvements in glycemic control and weight at week 24, which were sustained until week 76, as well as reductions in blood pressure (BP) (6)(7)(8)(9)(10)(11)(12). Empagliflozin was well tolerated and associated with a low risk of hypoglycemia (6)(7)(8)(9)(10)(11)(12). Furthermore, patients with type 2 diabetes at high cardiovascular risk who received empagliflozin in the EMPA-REG OUTCOME trial had a lower rate of the primary composite cardiovascular outcome (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) and of death from any cause, compared with placebo (13).…”

mentioning

confidence: 99%

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Empagliflozin as Add-on Therapy in Patients With Type 2 Diabetes Inadequately Controlled With Linagliptin and Metformin: A 24-Week Randomized, Double-Blind, Parallel-Group Trial

et al. 2016

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OBJECTIVETo evaluate the efficacy and safety of empagliflozin versus placebo as add-on therapy in patients with type 2 diabetes and inadequate glycemic control with linagliptin and metformin. RESEARCH DESIGN AND METHODSPatients with HbA 1c ‡8.0% and £10.5% ( ‡64 and £91 mmol/mol) while receiving stable-dose metformin received open-label linagliptin 5 mg (n = 606) for 16 weeks. Subsequently, those with HbA 1c ‡7.0 and £10.5% ( ‡53 and £91 mmol/mol) were randomized to receive double-blind, double-dummy treatment with empagliflozin 10 mg (n = 112), empagliflozin 25 mg (n = 111), or placebo (n = 110) for 24 weeks; all patients continued treatment with metformin and linagliptin 5 mg. The primary end point was the change from baseline in HbA 1c after 24 weeks of double-blind treatment. RESULTSAt week 24, empagliflozin significantly reduced HbA 1c (mean baseline 7.96-7.97% [63-64 mmol/mol]) versus placebo; the adjusted mean differences in the change from baseline with empagliflozin 10 and 25 mg versus placebo were 20.79% (95% CI -1.02, -0.55) (28.63 mmol/mol [-11.20, -6.07 mmol/mol]) and 20.70% (95% CI -0.93, -0.46) (27.61 mmol/mol [-10.18, -5.05 mmol/mol]), respectively (both P < 0.001). Fasting plasma glucose and weight were significantly reduced in both empagliflozin groups versus placebo (P < 0.001 for all comparisons). More patients receiving placebo than empagliflozin 10 and 25 mg reported adverse events during double-blind treatment (68.2%, 55.4%, and 51.8%, respectively). CONCLUSIONSEmpagliflozin treatment for 24 weeks improved glycemic control and weight versus placebo as an add-on to linagliptin 5 mg and metformin and was well tolerated.

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Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Empagliflozin as Add-on Therapy in Patients With Type 2 Diabetes Inadequately Controlled With Linagliptin and Metformin: A 24-Week Randomized, Double-Blind, Parallel-Group Trial

et al. 2016

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“…1), totalling 15,309 unique participants [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21]. Four SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin and ipragliflozin) were evaluated.…”

Section: Resultsmentioning

confidence: 99%

Elevated serum magnesium associated with SGLT2 inhibitor use in type 2 diabetes patients: a meta-analysis of randomised controlled trials

et al. 2016

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Aims/hypothesis By analysing available evidence from randomised controlled trials (RCTs), we aimed to examine whether and to what extent sodium-glucose cotransporter 2 (SGLT2) inhibitors affect serum electrolyte levels in type 2 diabetes patients. Methods We searched PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL) a nd ClinicalTrials.gov up to 24 May 2016 for published RCTs of SGLT2 inhibitors that reported changes in serum electrolyte levels. Weighted mean differences (WMD) between each SGLT2 inhibitor and placebo were calculated using a randomeffects model. Dose-dependent relationships for each SGLT2 inhibitor were evaluated using meta-regression analysis.Results Eighteen eligible RCTs, including 15,309 patients and four SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin and ipragliflozin) were evaluated. In patients without chronic kidney disease, each SGLT2 inhibitor significantly increased serum magnesium levels compared with placebo (canagliflozin: WMD 0.06 mmol/l for 100 mg and 0.09 mmol/l for 300 mg; dapagliflozin: WMD 0.1 mmol/l for 10 mg; empagliflozin: WMD 0.04 mmol/l for 10 mg and 0.07 mmol/l for 25 mg; and ipragliflozin: WMD 0.05 mmol/l for 50 mg). Canagliflozin increased serum magnesium in a linear dose-dependent manner (p = 0.10). Serum phosphate was significantly increased by dapagliflozin. Serum sodium appeared to significantly differ by SGLT2 inhibitor type. No significant changes in serum calcium and potassium were observed. Findings were robust after including trials involving patients with chronic kidney disease. Conclusions/interpretation SGLT2 inhibitors marginally increased serum magnesium levels in type 2 diabetes patients indicating a drug class effect. Further investigations are required to examine the clinical significance of elevated magnesium levels in individuals with type 2 diabetes.

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“…Moderate-quality evidence suggests that empagliflozin reduces all-cause mortality (7,11,40,44,46,47,(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61) and increases the rates of diabetes control without increasing the risk of serious adverse effects and hypoglycemia when compared with placebo in adults with type 2 diabetes ( Table 1) (50,51,70). The increase in rates of glycemic improvement starts at the dose of 10 mg/day (150 attributable events per 1,000 treated, Figure 1) and increases to 210 attributable events per 1,000 treated after the larger dose of empagliflozin (25 mg/day, Figure 1).…”

Section: Efficacymentioning

confidence: 99%

Comparative effectiveness and safety of empagliflozin on cardiovascular mortality and morbidity in adults with type 2 diabetes

Aronow¹,

Shamliyan²

2017

Ann. Transl. Med.

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Background: Based on a single placebo-controlled randomized clinical trial, empagliflozin is licensed to reduce cardiovascular death in diabetes and comorbid cardiovascular disease. Methods:We examined the comparative effectiveness of empagliflozin on mortality and cardiovascular morbidity in type 2 diabetes. We conducted random-effects direct frequentist meta-analyses of aggregate data and appraised the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. Our search in PubMed, EMBASE, the Cochrane Library, patients). Two network meta-analyses concluded that sodium-glucose cotransporter 2 (SGLT2) inhibitors, mostly due to empagliflozin, decrease all-cause and cardiovascular mortality but increase the risk of nonfatal stroke, genital infection, and volume depletion. Conclusions:We conclude that empagliflozin reduces all-cause and cardiovascular mortality in patients with established cardiovascular disease and type 2 diabetes. Sparse direct evidence suggests no difference in mortality between empagliflozin and metformin, glimepiride, linagliptin, or sitagliptin. Long-term comparative safety needs to be established.

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Empagliflozin as add-on to metformin plus sulphonylurea in patients with type 2 diabetes

Cited by 69 publications

References 18 publications

Empagliflozin as Add-on Therapy in Patients With Type 2 Diabetes Inadequately Controlled With Linagliptin and Metformin: A 24-Week Randomized, Double-Blind, Parallel-Group Trial

Empagliflozin as Add-on Therapy in Patients With Type 2 Diabetes Inadequately Controlled With Linagliptin and Metformin: A 24-Week Randomized, Double-Blind, Parallel-Group Trial

Elevated serum magnesium associated with SGLT2 inhibitor use in type 2 diabetes patients: a meta-analysis of randomised controlled trials

Comparative effectiveness and safety of empagliflozin on cardiovascular mortality and morbidity in adults with type 2 diabetes

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