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Empagliflozin Reduces Blood Pressure in Patients With Type 2 Diabetes and Hypertension

OBJECTIVE To investigate the efficacy, safety, and tolerability of empagliflozin in patients with type 2 diabetes and hypertension. RESEARCH DESIGN AND METHODS Patients (N = 825) with type 2 diabetes and hypertension (mean seated systolic blood pressure [SBP] 130–159 mmHg and diastolic blood pressure [DBP] 80–99 mmHg) were randomized (double blind) to 10 mg or 25 mg empagliflozin or placebo once daily for 12 weeks. RESULTS At week 12, adjusted mean difference versus placebo in change from baseline in mean 24-h SBP (ambulatory blood pressure monitoring [ABPM]) was −3.44 mmHg (95% CI −4.78, −2.09) with 10 mg empagliflozin and −4.16 mmHg (−5.50, −2.83) with 25 mg empagliflozin (both P < 0.001). At week 12, adjusted mean difference versus placebo in change from baseline in mean 24-h DBP (ABPM) was −1.36 mmHg (95% CI −2.15, −0.56) with 10 mg empagliflozin and −1.72 mmHg (95% CI −2.51, −0.93) with 25 mg empagliflozin (both P < 0.001). Changes in office BP were consistent with ABPM. Adjusted mean difference versus placebo in change from baseline in HbA1c at week 12 was −0.62% (95% CI −0.72, −0.52) (−6.8 mmol/mol [95% CI −7.9, −5.7]) with 10 mg empagliflozin and −0.65% (95% CI −0.75, −0.55) (−7.1 mmol/mol [95% CI −8.2, −6.0]) with 25 mg empagliflozin (both P < 0.001). Empagliflozin was well tolerated. One patient on placebo and one patient on 10 mg empagliflozin reported events consistent with volume depletion. CONCLUSIONS Empagliflozin was associated with significant and clinically meaningful reductions in BP and HbA1c versus placebo and was well tolerated in patients with type 2 diabetes and hypertension.

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

BACKGROUND Metformin is the recommended first-line pharmacotherapy for patients with type 2 diabetes. There is no consensus on the optimum second-line pharmacotherapy. We compared the efficacy and safety of the sodium glucose cotransporter 2 inhibitor empagliflozin and the sulfonylurea glimepiride as add-on to metformin in patients with type 2 diabetes. METHODS In this double-blind phase 3 trial, patients (aged ≥18 years) with type 2 diabetes and HbA1c concentrations of 7-10%, despite metformin treatment and diet and exercise counselling, were randomly assigned in a 1:1 ratio with a computer-generated random sequence, stratified by HbA1c, estimated glomerular filtration rate (eGFR), and region, to empagliflozin (25 mg once daily, orally) or glimepiride (1-4 mg once daily, orally) as add-on to metformin for 104 weeks. Patients and investigators were masked to treatment assignment. The primary endpoint was change from baseline in HbA1c levels at weeks 52 and 104. Differences in the primary endpoint were first tested for non-inferiority (based on a margin of 0·3%). If non-inferiority was shown, differences in the primary endpoint at week 104 were then tested for superiority. Analysis was done on the full-analysis set-ie, patients who were treated with at least one dose of study drug and had a baseline HbA1c value. This study is registered with ClinicalTrials.gov, number NCT01167881. A 104-week extension is ongoing. FINDINGS Between August, 2010, and June, 2011, 1549 patients were randomly assigned to receive empagliflozin (n=769) or glimepiride (n=780); four patients in the empagliflozin group did not receive the assigned treatment. Empagliflozin was non-inferior to glimepiride at both timepoints. At week 104, adjusted mean difference in change from baseline in HbA1c with empagliflozin versus glimepiride was -0·11% (95% CI -0·19 to -0·02; p=0·0153 for superiority). Adverse events were reported in 661 (86%) patients treated with empagliflozin and 673 (86%) patients treated with glimepiride. Severe adverse events were reported in 72 (9%) patients in the empagliflozin group and 68 (9%) in the glimepiride group. Serious adverse events were reported in 119 (16%) patients in the empagliflozin group and 89 (11%) in the glimepiride group. Confirmed hypoglycaemic adverse events (plasma glucose ≤3·9 mmol/L or requiring assistance) at week 104 were reported in 19 (2%) patients treated with empagliflozin and 189 (24%) patients treated with glimepiride. INTERPRETATION Empagliflozin might be an effective and a well tolerated second-line treatment option for patients with type 2 diabetes who have not achieved good glycaemic control on metformin. FUNDING Boehringer Ingelheim and Eli Lilly.

Impact of empagliflozin added on to basal insulin in type 2 diabetes inadequately controlled on basal insulin: a 78‐week randomized, double‐blind, placebo‐controlled trial

To investigate the efficacy and tolerability of empagliflozin added to basal insulin‐treated type 2 diabetes.

Impact of Empagliflozin on Blood Pressure in Patients With Type 2 Diabetes Mellitus and Hypertension by Background Antihypertensive Medication

In the EMPA-REG BP trial, empagliflozin 10 mg and 25 mg once daily reduced glycohemoglobin, blood pressure (BP), and weight versus placebo in patients with type 2 diabetes mellitus and hypertension. Patients received placebo (n=271), empagliflozin 10 mg (n=276), or empagliflozin 25 mg (n=276) for 12 weeks (n=full analysis set). This present analysis investigated changes from baseline to week 12 in mean 24-hour systolic BP (SBP) and diastolic BP (DBP) in patients receiving 0, 1, or ≥2 antihypertensive medications and patients receiving/not receiving diuretics or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers. Compared with placebo, empagliflozin 10 mg and 25 mg reduced mean 24-hour SBP/DBP in patients receiving 0 (10 mg: −3.89/−2.58 mm Hg; 25 mg: −3.77/−2.45 mm Hg), 1 (10 mg: −4.74/−1.97 mm Hg; 25 mg: −4.27/−1.81 mm Hg), or ≥2 (10 mg: −2.36/−0.68 mm Hg; 25 mg: −4.17/−1.54 mm Hg) antihypertensives. The effect of empagliflozin was not significantly different between subgroups by number of antihypertensives for changes in SBP (interaction P value 0.448) or DBP (interaction P value 0.498). Empagliflozin reduced 24-hour mean SBP/DBP irrespective of diuretic or angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use, with no significant difference between subgroups by use/no use of diuretics (interaction P values 0.380 [systolic]; 0.240 [diastolic]) or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (interaction P values 0.900 [systolic]; 0.359 [diastolic]). In conclusion, in patients with type 2 diabetes mellitus and hypertension, empagliflozin for 12 weeks reduced SBP and DBP versus placebo, irrespective of the number of antihypertensives and use of diuretics or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers. Clinical Trial Registration—URL: https://clinicaltrials.gov. Unique identifier: NCT01370005.

Analysis of Fractures in Patients With Type 2 Diabetes Treated With Empagliflozin in Pooled Data From Placebo-Controlled Trials and a Head-to-Head Study Versus Glimepiride

OBJECTIVE To assess the effect of empagliflozin on bone fractures and bone mineral density in patients with type 2 diabetes in pooled placebo-controlled trial data and a head-to-head study versus glimepiride. RESEARCH DESIGN AND METHODS Pooled data were analyzed from patients who were randomized 1:1:1 to empagliflozin 10 mg, empagliflozin 25 mg, or placebo in phase I–III clinical trials. Data were also analyzed from the EMPA-REG H2H-SU trial in which patients received empagliflozin 25 mg or glimepiride as an add-on to metformin for 104 weeks with a 104-week extension. Bone fracture adverse events (AEs) were evaluated through a search of investigator-reported (nonadjudicated) events. RESULTS In the pooled analysis, bone fracture AEs were reported in 119 of 4,221 (2.8%), 105 of 4,196 (2.5%), and 123 of 4,203 (2.9%) patients in the empagliflozin 10 mg, empagliflozin 25 mg, and placebo groups, respectively (rates of 1.55, 1.36, and 1.69/100 patient-years, respectively). In the EMPA-REG H2H-SU trial, bone fracture AEs were reported in 31 of 765 (4.1%) patients receiving empagliflozin 25 mg and in 33 of 780 (4.2%) patients receiving glimepiride (rates of 1.28 and 1.40/100 patient-years, respectively). CONCLUSIONS Empagliflozin did not increase the risk of bone fracture compared with placebo in a pooled analysis of >12,000 patients or compared with glimepiride in a 4-year head-to-head study.

Safety and tolerability of empagliflozin in East Asian patients with type 2 diabetes: Pooled analysis of phase I-III clinical trials

We investigated the safety and tolerability of empagliflozin (EMPA) in East Asian patients with type 2 diabetes.

Correction to: Comparison of Adipose Distribution Indices with Gold Standard Body Composition Assessments in the EMPA-REG H2H SU Trial: A Body Composition Sub-Study (Diabetes Therapy, (2015), 6, 4, (635-642), 10.1007/s13300-015-0146-7)

In the original publication, disclosure statement for the author Ian J. Neeland was published incorrectly. The correct statement should read as “Ian J. Neeland received financial assistance for publishing/article processing fees from Boehringer Ingelheim”.