Gabriel Kim

Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: a randomised, double-blind, placebo-controlled, phase 3 trial

BACKGROUND We aimed to investigate the efficacy and tolerability of empagliflozin, an oral, potent, and selective inhibitor of sodium-glucose co-transporter 2, in patients with type 2 diabetes who had not received drug treatment in the preceding 12 weeks. METHODS In our multicentre, randomised, placebo-controlled, phase 3 trial, we enrolled adults (aged ≥18 years) who had not received oral or injected anti-diabetes treatment in the previous 12 weeks. Eligible patients had HbA1c concentrations of 7-10%. We randomly allocated patients (1:1:1:1) with a computer-generated random sequence, stratified by region, HbA1c, and estimated glomerular filtration rate at screening, to placebo, empagliflozin 10 mg, empagliflozin 25 mg, or sitagliptin 100 mg once daily for 24 weeks. Patients and investigators were masked to treatment assignment. The primary endpoint was change from baseline in HbA1c at week 24 by ANCOVA in all randomly allocated patients who were treated with at least one dose of study drug and had a baseline HbA1c value. This study is completed and registered with ClinicalTrials.gov, number NCT01177813. FINDINGS Between Aug 12, 2010, and March 19, 2012, we randomly allocated 228 patients to receive placebo, 224 to receive empagliflozin 10 mg, 224 to receive empagliflozin 25 mg, and 223 to receive sitagliptin. Compared with placebo, adjusted mean differences in change from baseline HbA1c at week 24 were -0·74% (95% CI -0·88 to -0·59; p<0·0001) for empagliflozin 10 mg, -0·85% (-0·99 to -0·71; p<0·0001) for empagliflozin 25 mg, and -0·73% (-0·88 to -0·59; p<0·0001) for sitagliptin. 140 (61%) patients in the placebo group reported adverse events (four [2%] severe and six [3%] serious), as did 123 (55%) patients in the empagliflozin 10 mg group (eight [4%] severe and eight [4%] serious), 135 (60%) patients in the empagliflozin 25 mg group (seven [3%] severe and five [2%] serious), and 119 (53%) patients in the sitagliptin group (five [2%] severe and six [3%] serious). INTERPRETATION Empagliflozin provides a tolerable and efficacious strategy to reduce HbA1c in patients with type 2 diabetes who had not previously received drug treatment. FUNDING Boehringer Ingelheim and Eli Lilly.

Improved Glucose Control With Weight Loss, Lower Insulin Doses, and No Increased Hypoglycemia With Empagliflozin Added to Titrated Multiple Daily Injections of Insulin in Obese Inadequately Controlled Type 2 Diabetes

OBJECTIVE We investigated the efficacy and safety of the sodium glucose cotransporter 2 inhibitor, empagliflozin, added to multiple daily injections of insulin (MDI insulin) in obese patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS Patients inadequately controlled on MDI insulin ± metformin (mean HbA1c 8.3% [67 mmol/mol]; BMI 34.8 kg/m2; insulin dose 92 international units/day) were randomized and treated with once-daily empagliflozin 10 mg (n = 186), empagliflozin 25 mg (n = 189), or placebo (n = 188) for 52 weeks. Insulin dose was to remain stable in weeks 1–18, adjusted to meet glucose targets in weeks 19–40, then stable in weeks 41–52. The primary end point was change from baseline in HbA1c at week 18. Secondary end points were changes from baseline in insulin dose, weight, and HbA1c at week 52. RESULTS Adjusted mean ± SE changes from baseline in HbA1c were −0.50 ± 0.05% (−5.5 ± 0.5 mmol/mol) for placebo versus −0.94 ± 0.05% (−10.3 ± 0.5 mmol/mol) and −1.02 ± 0.05% (−11.1 ± 0.5 mmol/mol) for empagliflozin 10 mg and empagliflozin 25 mg, respectively, at week 18 (both P < 0.001). At week 52, further reductions with insulin titration resulted in changes from baseline in HbA1c of −0.81 ± 0.08% (−8.9 ± 0.9 mmol/mol), −1.18 ± 0.08% (−12.9 ± 0.9 mmol/mol), and −1.27 ± 0.08% (−13.9 ± 0.9 mmol/mol) with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively, and final HbA1c of 7.5% (58 mmol/mol), 7.2% (55 mmol/mol), and 7.1% (54 mmol/mol), respectively. More patients attained HbA1c <7% (<53 mmol/mol) with empagliflozin (31–42%) versus placebo (21%; both P < 0.01). Empagliflozin 10 mg and empagliflozin 25 mg reduced insulin doses (−9 to −11 international units/day) and weight (−2.4 to −2.5 kg) versus placebo (all P < 0.01) at week 52. CONCLUSIONS In obese, difficult-to-treat patients with T2DM inadequately controlled on high MDI insulin doses, empagliflozin improved glycemic control and reduced weight without increasing the risk of hypoglycemia and with lower insulin requirements.

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.

Empagliflozin as Add-on Therapy to Pioglitazone With or Without Metformin in Patients With Type 2 Diabetes Mellitus

PURPOSE To investigate the long-term efficacy and safety of empagliflozin as add-on therapy to pioglitazone with or without metformin in patients with type 2 diabetes mellitus. METHODS Of 498 patients randomized to empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily for 24 weeks in the EMPA-REG PIO™ study, 305 (61.2%) were treated in a double-blind extension trial for ≥52 weeks (total duration ≥76 weeks). Exploratory end points at week 76 included changes from baseline in glycosylated hemoglobin (HbA1c), weight, and blood pressure assessed using ANCOVA in patients who received ≥1 dose of study drug and had a baseline HbA1c measurement in the initial study. FINDINGS Compared with placebo, adjusted mean (95% CI) changes from baseline in HbA1c level at week 76 were -0.59% (-0.79% to -0.40%; P < 0.001) for empagliflozin 10 mg (-6.5 [-8.6 to -4.4] mmol/mol) and -0.69% (-0.88% to -0.50%; P < 0.001) for empagliflozin 25 mg (-7.5 [-9.6 to -5.4] mmol/mol). Compared with placebo, adjusted mean (95% CI) changes from baseline in weight at week 76 were -2.0 kg (-2.7 to -1.2 kg; P < 0.001) and -1.7 kg (-2.4 -1.0 kg; P < 0.001) for empagliflozin 10 mg and 25 mg, respectively. Compared with placebo, only empagliflozin 25 mg led to significant reductions in systolic blood pressure (adjusted mean [95% CI] change: -3.7 mmHg [-6.1 to -1.3 mmHg]; P = 0.003) and diastolic blood pressure (adjusted mean [95% CI] change: -2.2 mmHg [-3.7 to -0.7 mmHg]; P = 0.004). Sensitivity analyses were consistent with these results for HbA1c level, fasting plasma glucose concentration, and weight, but revealed no significant difference between empagliflozin and placebo in change from baseline in systolic or diastolic blood pressure at week 76. Confirmed hypoglycemic adverse events (glucose ≤3.9 mmol/L and/or requiring assistance) were reported in 4.2%, 1.8%, and 3.0% of patients treated with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively; 1 patient each taking placebo and empagliflozin 25 mg required assistance. Adverse events consistent with urinary tract infection were reported in 26.7%, 22.4%, and 22.0% of patients treated with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. Adverse events consistent with genital infection were reported in 3.0%, 10.3%, and 4.2% of patients treated with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. IMPLICATIONS Empagliflozin 10 mg or 25 mg as add-on therapy to pioglitazone with or without metformin for 76 weeks was well tolerated and led to sustained reductions in HbA1c and weight compared with placebo in patients with type 2 diabetes. ClinicalTrials.gov identifier: NCT01210001.

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

This study investigated the long-term efficacy and safety of empagliflozin as add-on to metformin plus sulphonylurea in patients with type 2 diabetes mellitus (T2DM). Of 666 patients treated with empagliflozin 10 mg, empagliflozin 25 mg or placebo once daily for 24 weeks, 472 patients (70.9%) were treated in a double-blind extension trial for ≥52 weeks. Pre-specified exploratory endpoints included changes from baseline in HbA(1c), weight and blood pressure at week 76. At week 76, adjusted mean differences versus placebo in change from baseline in HbA(1c) were -0.7% (-8 mmol/mol) with empagliflozin 10 mg or 25 mg (both p<0.001), in weight were -1.8 kg and -1.6 kg with empagliflozin 10 mg and 25 mg, respectively (both p<0.001), and in systolic blood pressure (SBP) were -2.2 mmHg with empagliflozin 10 mg (p=0.021) and -2.1 mmHg with empagliflozin 25 mg (p=0.029). Sensitivity analyses provided consistent results for HbA1c and weight, but showed no significant difference between empagliflozin and placebo in change from baseline in SBP. Adverse events (AEs) were reported in 81.7%, 82.0% and 81.3% of patients on empagliflozin 10 mg, 25 mg and placebo, respectively. Confirmed hypoglycaemic AEs (glucose ≤3.9 mmol/l and/or requiring assistance) were reported in 23.7%, 19.4% and 15.6% of patients on empagliflozin 10 mg, 25 mg and placebo, respectively; one patient each on empagliflozin 10mg and placebo required assistance. In conclusion, empagliflozin as add-on to metformin plus sulphonylurea for 76 weeks was well tolerated and led to sustained reductions in HbA1c and weight versus placebo. CLINICALTRIALS.GOV: NCT01289990.

Cardiovascular safety of empagliflozin in patients with type 2 diabetes: a meta-analysis of data from randomized placebo-controlled trials.

To assess the effect of empagliflozin on cardiovascular (CV) risk in patients with type 2 diabetes (T2DM) through a meta‐analysis of data from eight placebo‐controlled trials.