Empagliflozin compared with glimepiride in metformin‐treated patients with type 2 diabetes: 208‐week data from a masked randomized controlled trial

Ridderstråle, Martin; Rosenstock, Julio; Andersen, Kim Francis; Woerle, Hans J.; Salsali, Afshin

doi:10.1111/dom.13457

Cited by 40 publications

(35 citation statements)

References 22 publications

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“…The proportion of participants with confirmed hypoglycaemia was somewhat higher with empagliflozin than with placebo; however, no severe hypoglycaemic events requiring assistance were reported. Participants with T2D are at an increased risk of UTIs and genital infections, and some studies have indicated that SGLT2 inhibitors may be associated with events consistent with UTIs, genital infections and volume depletion . In this trial, the frequency of events consistent with UTIs did not differ between empagliflozin and placebo, whereas the proportion of participants with events consistent with genital tract infections was higher with empagliflozin than placebo.…”

Section: Discussionmentioning

confidence: 55%

“…Participants with T2D are at an increased risk of UTIs and genital infections, 24,25 and some studies have indicated that SGLT2 inhibitors may be associated with events consistent with UTIs, genital infections and volume depletion. [26][27][28] In this trial, the frequency of events consistent with UTIs did not differ between empagliflozin and placebo, whereas the proportion of participants with events consistent with genital tract infections was higher with empagliflozin than placebo. Finally, there may be an increased risk of developing diabetic or euglycaemic ketoacidosis with SGLT2 inhibitor treatment, 29,30 as SGLT2 inhibitors increase glucagon levels and ketone body formation, while clearing glucose via renal excretion.…”

Section: Discussionmentioning

confidence: 58%

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Efficacy and safety of empagliflozin as add‐on to insulin in Japanese patients with type 2 diabetes: A randomized, double‐blind, placebo‐controlled trial

Sone

Kaneko

Shiki

et al. 2019

Diabetes Obesity Metabolism

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Aim To assess the efficacy and safety of empagliflozin as add‐on to insulin in Japanese patients with type 2 diabetes (T2D). Materials and methods This multicentre, double‐blind, parallel‐group study randomized Japanese patients with T2D insufficiently controlled with insulin (1:1:1) to empagliflozin 10 mg (n=89), empagliflozin 25 mg (n=90) or placebo (n=90) for 52 weeks. The primary endpoint was change from baseline in glycated haemoglobin (HbA1c) at 16 weeks. Results At 16 weeks, empagliflozin 10 mg and 25 mg significantly decreased HbA1c: adjusted mean difference −0.92% (95% confidence interval [CI] −1.11, −0.73) and −1.00% (95% CI −1.18, −0.82; both P<0.0001) compared with placebo. This difference was maintained up to 52 weeks: adjusted mean difference at 52 weeks −0.90% (95% CI −1.09, −0.70) and −0.96% (95% CI −1.15, −0.77; both P<0.0001). At 52 weeks, significant improvements in fasting plasma glucose (adjusted mean difference −27.62 mg/dL [95% CI −36.15, −19.08] and −31.99 mg/dL [95% CI −40.35, −23.62]) and in body weight (−1.78 kg [95% CI −2.46, −1.10] and −1.92 kg [95% CI −2.58, −1.25]) were also seen with empagliflozin 10 mg and 25 mg compared with placebo (all P<0.0001). At 52 weeks, the frequency of adverse events (AEs) and serious AEs was similar in the three treatment groups; confirmed hypoglycaemia was reported slightly more in participants in the empagliflozin 10 mg and 25 mg groups (23.3% and 22.2% vs 14.4%). All hypoglycaemic events were mild in severity; no episodes required assistance. Conclusions In Japanese patients with insufficiently controlled T2D, adding empagliflozin 10 mg or 25 mg to insulin treatment was associated with clinically meaningful reductions in HbA1c at 16 weeks and was generally well tolerated.

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Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 58%

Efficacy and safety of empagliflozin as add‐on to insulin in Japanese patients with type 2 diabetes: A randomized, double‐blind, placebo‐controlled trial

Sone

Kaneko

Shiki

et al. 2019

Diabetes Obesity Metabolism

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“…A total of 27 trials fulfilling the inclusion criteria was identified (Figure S1 and Table S1). The retrieved trials comprised 27 744 and 20 441 patients in SGLT‐2 inhibitor and comparator groups, respectively, with a mean duration of treatment of 84 weeks. Mean age, duration of diabetes, baseline HbA1c and BMI of enrolled patients at baseline were 59.0, 8.3 years, 8.0% and 30.9 Kg/m 2 , respectively.…”

Section: Resultsmentioning

confidence: 99%

Sodium‐glucose co‐transporter‐2 (SGLT‐2) inhibitors and cancer: A meta‐analysis of randomized controlled trials

Dicembrini

Nreu

Mannucci

et al. 2019

Diabetes Obesity Metabolism

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Aim: The aim of this meta-analysis of randomized trials was to assess the effects of SGLT-2i on the overall incidence of malignancies and on different types of cancer, summerizing the results of trials with a duration of at least 1 year. This was done in light of the effect of SGLT-2 inhibitors (SGLT-2is) that has been highlighted by some studies, showing an increased incidence of bladder cancer, particularly with use of empagliflozin.Materials and methods: A Medline and Embase search for "Canaglifozin", "Dapaglifozin", "Empaglifozin", "Ertuglifozin", "Ipraglifozin", Tofoglifozin" or "Luseoglifozin" was performed, identifying randomized trials with a duration of more than 52 weeks up to 1 December 2018 that compared SGLT-2is with placebo or active comparators. The outcomes considered were all types of cancer and several site-specific cancers (ie, breast, pulmonary, gastrointestinal, hepatic, pancreatic, skin, prostate and bladder). Mantel-Haenszel odds ratios with 95% Confidence Intervals (MH-OR, 95% CI) were calculated for all outcomes.Results: A total of 27 trials fulfilled the inclusion criteria. Retrieved trials had enrolled 27 744 and 20 441 patients in SGLT-2 inhibitor and comparator groups, respectively.No difference was observed in the incidence of all malignancies between patients allocated to ). The incidence of bladder cancer, and of any other type of cancer, was not significantly increased by treatment with any SGLT-2i.Conclusions: Available data from randomized trials do not suggest a detrimental effect of SGLT-2is on the incidence of malignancies in general, or in bladder cancer in particular. K E Y W O R D Smalignancies, meta-analysis, SGLT-2 inhibitors, type 2 diabetes

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“…A 4‐year head‐to‐head study (EMPA‐REG H2H‐SU), conducted in T2D patients inadequately controlled on metformin alone (baseline HbA1c 7%‐10%), looked specifically at the relationship between hypoglycemia and fracture risk, comparing the SGLT2 inhibitor empagliflozin (25 mg) vs glimepiride (1‐4 mg), as add‐on to metformin. Hypoglycemic events occurred in 28% of patients on glimepiride vs only 3% on empagliflozin; however, bone fracture occurrence was similar across the groups (4.1% in empagliflozin group; 4.2% in glimepiride group) . In the ACCORD BONE study, intensive glycemic control with any SU was not associated with a higher risk of falls or fracture, in spite of more hypoglycemic episodes .…”

Section: Drugs and Bonementioning

confidence: 88%

“…239,240 Recently, it was reported that the activation of the NLRP3 inflammasome in human mesenchymal stem cells, a major pathway involved in β-cell failure and multiple complications of T2D, also impairs osteogenic differentiation and promotes adipocyte differentiation. 246 Therefore, new SU molecules have been designed to target both the KATP channels and NLRP3 activation, 247 262 ; however, bone fracture occurrence was similar across the groups (4.1% in empagliflozin group; 4.2% in glimepiride group). 263 In the ACCORD BONE study, intensive glycemic control with any SU was not associated with a higher risk of falls or fracture, in spite of more hypoglycemic episodes.…”

Section: Skeletal Effects: In Vitromentioning

confidence: 99%

Diabetes pharmacotherapy and effects on the musculoskeletal system

Kalaitzoglou

Fowlkes

Popescu

et al. 2018

Diabetes Metabolism Res

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Summary Persons with type 1 or type 2 diabetes have a significantly higher fracture risk than age‐matched persons without diabetes, attributed to disease‐specific deficits in the microarchitecture and material properties of bone tissue. Therefore, independent effects of diabetes drugs on skeletal integrity are vitally important. Studies of incretin‐based therapies have shown divergent effects of different agents on fracture risk, including detrimental, beneficial, and neutral effects. The sulfonylurea class of drugs, owing to its hypoglycemic potential, is thought to amplify the risk of fall‐related fractures, particularly in the elderly. Other agents such as the biguanides may, in fact, be osteo‐anabolic. In contrast, despite similarly expected anabolic properties of insulin, data suggests that insulin pharmacotherapy itself, particularly in type 2 diabetes, may be a risk factor for fracture, negatively associated with determinants of bone quality and bone strength. Finally, sodium‐dependent glucose co‐transporter 2 inhibitors have been associated with an increased risk of atypical fractures in select populations, and possibly with an increase in lower extremity amputation with specific SGLT2I drugs. The role of skeletal muscle, as a potential mediator and determinant of bone quality, is also a relevant area of exploration. Currently, data regarding the impact of glucose lowering medications on diabetes‐related muscle atrophy is more limited, although preclinical studies suggest that various hypoglycemic agents may have either aggravating (sulfonylureas, glinides) or repairing (thiazolidinediones, biguanides, incretins) effects on skeletal muscle atrophy, thereby influencing bone quality. Hence, the therapeutic efficacy of each hypoglycemic agent must also be evaluated in light of its impact, alone or in combination, on musculoskeletal health, when determining an individualized treatment approach. Moreover, the effect of newer medications (potentially seeking expanded clinical indication into the pediatric age range) on the growing skeleton is largely unknown. Herein, we review the available literature regarding effects of diabetes pharmacotherapy, by drug class and/or by clinical indication, on the musculoskeletal health of persons with diabetes.

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Empagliflozin compared with glimepiride in metformin‐treated patients with type 2 diabetes: 208‐week data from a masked randomized controlled trial

Abstract: In patients with type 2 diabetes, empagliflozin 25 mg as add-on to metformin for 208 weeks reduced HbA1c with a significantly lower risk of hypoglycaemia and a significantly smaller proportion of patients receiving rescue therapy compared with glimepiride.

Cited by 40 publications

References 22 publications

Efficacy and safety of empagliflozin as add‐on to insulin in Japanese patients with type 2 diabetes: A randomized, double‐blind, placebo‐controlled trial

Efficacy and safety of empagliflozin as add‐on to insulin in Japanese patients with type 2 diabetes: A randomized, double‐blind, placebo‐controlled trial

Sodium‐glucose co‐transporter‐2 (SGLT‐2) inhibitors and cancer: A meta‐analysis of randomized controlled trials

Diabetes pharmacotherapy and effects on the musculoskeletal system

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