Background
Sulfonylureas in the treatment of T2DM
Empagliflozin, an SGLT2 inhibitor
Empagliflozin versus glimepiride: a 4-year phase III trial
Methods
Patients
Inclusion criteria | Exclusion criteria |
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Adult (aged ≥18 years) male or female patients with T2DM with insufficient glycemic control with diet, exercise and metformin IR* (≥1500 mg/day or maximum tolerated dose, or maximum dose according to local label, with dose unchanged for 12 weeks prior to randomization) | Blood glucose level >240 mg/dL (13.3 mmol/L) after an overnight fast during placebo run-in, confirmed by a 2nd measurement |
HbA1c ≥7% and ≤10% at screening | Use of any anti-diabetes drugs other than metformin IR ≤12 weeks prior to randomization |
BMI ≤45 kg/m2 at screening | Bariatric surgery within 2 years; treatment with anti-obesity drugs within 3 months of screening; any treatment leading to unstable body weight |
Female patients: post-menopausal, or pre-menopausal and using appropriate contraception; not pregnant/breastfeeding | eGFR <60 mL/min/1.73 m2 (MDRD) during screening or placebo run-in |
Indication of liver disease (ALT, AST or alkaline phosphatase >3 x ULN) during screening or placebo run-in | |
History of cancer within 5 years (except basal cell carcinoma) | |
Acute coronary syndrome, stroke or transient ischemic attack within 3 months of informed consent | |
Disorders causing unstable red blood cells; treatment with systemic steroids; change in dose of thyroid hormones within 6 weeks of screening; any uncontrolled endocrine condition (except T2DM) | |
Alcohol or drug abuse within 3 months of informed consent | |
Taking an investigational drug ≤ 30 days prior to receiving study drug |
Study design
Endpoints
HbA1c | At screening, randomization, after 4, 12, 28, 40, 52, 65, 78, 91, 104, 117, 130, 143, 156, 169, 182, 195 and 208 weeks of treatment |
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Body weight | At screening, randomization, after 12, 28, 52, 78, 104, 130, 156, 182 and 208 weeks of treatment, and follow-up (4 weeks after treatment discontinuation) |
Blood pressure | At screening, start of placebo run-in, randomization, after 4, 8, 12, 16, 28, 40, 52, 65, 78, 91, 104, 117, 130, 143, 156, 169, 182, 195 and 208 weeks of treatment, and follow-up (4 weeks after treatment discontinuation) |
List of study efficacy endpoints
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Change from baseline in HbA1c after 52 and 104 weeks of treatment
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Change from baseline in body weight after 52 and 104 weeks of treatment
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Occurrence of confirmed hypoglycemic AEs† during 52 and 104 weeks of treatment
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Change from baseline in SBP and DBP after 52 and 104 weeks of treatment
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Glucose control
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HbA1c <7.0% or <6.5% after 52, 104 and 208 weeks of treatment
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HbA1c lowering by ≥0.5% after 52, 104 and 208 weeks of treatment
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Change from baseline in HbA1c after 208 weeks of treatment
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Coefficient of durability for HbA1c response‡
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Change from baseline in FPG after 52, 104 and 208 weeks of treatment
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Change from baseline in MDG (8-point) after 52, 104 and 208 weeks of treatment (sub-study)
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Change from baseline in 2-h PPG after 52, 104 and 208 weeks of treatment and follow-up (4 weeks after treatment discontinuation) (sub-study)
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Biomarkers of insulin secretion and resistance after 104 and 208 weeks of treatment and (in the MTT sub-study) follow-up (4 weeks after treatment discontinuation)
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Confirmed hypoglycemic AEs† during 208 weeks of treatment
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Weight loss
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Change from baseline in body weight of >2% and >5% after 52, 104 and 208 weeks of treatment
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Change from baseline in body weight after 208 weeks of treatment and follow-up (4 weeks after treatment discontinuation)
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Change from baseline in waist circumference after 52, 104 and 208 weeks of treatment and follow-up (4 weeks after treatment discontinuation)
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Changes from baseline in trunk fat, limb fat, fat-free mass and total fat mass (using DXA scan) after 52, 104 and 208 weeks of treatment (sub-study)
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Changes from baseline in bone mineral density and T-scores (using DXA scan) after 52, 104 and 208 weeks of treatment (sub-study)Changes from baseline in abdominal VAT, abdominal SAT and VAT/SAT ratio (using MRI) after 52, 104 and 208 weeks of treatment (sub-study)
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Blood pressure
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Proportion of patients with BP <130/80 mmHg after 52, 104 and 208 weeks of treatment
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Change from baseline in SBP and DBP after 208 weeks of treatment and follow-up (4 weeks after treatment discontinuation)
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Composite endpoints
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HbA1c <7.0% or HbA1c reduction ≥1.0%, no confirmed hypoglycemic AEs, and weight loss >2% after 52, 104 and 208 weeks of treatment
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HbA1c <6.5% or HbA1c reduction ≥1.0%, no confirmed hypoglycemic AEs, and weight loss >2% after 52, 104 and 208 weeks of treatment
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Lipid profile
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Change from baseline in lipid profile after 52, 104 and 208 weeks of treatment and follow-up (4 weeks after treatment discontinuation)
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†Blood glucose ≤70 mg/dL and/or assistance required.
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‡Calculated as slope of least-squares regression line including all measurements from week 28 to last available measurement.
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Legend: HbA 1c glycosylated hemoglobin, AEs adverse events, SBP systolic blood pressure, DBP diastolic blood pressure, FPG fasting plasma glucose, MDG mean daily glucose, PPG post-prandial glucose, MTT meal tolerance test, DXA Dual Energy X-ray Absorptiometry, VAT visceral adipose tissue, SAT subcutaneous adipose tissue, MRI magnetic resonance imaging, BP: blood pressure.
Statistical analysis
Analysis | Testing hierarchy for 52-week analysis (interim analysis) | Testing hierarchy for 104-week analysis (main analysis) | |
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1 | Primary | Non-inferiority in change from baseline in HbA1c | Non-inferiority in change from baseline in HbA1c |
2 | Secondary | Superiority in change from baseline in body weight | Superiority in change from baseline in body weight |
3 | Superiority in incidence of confirmed hypoglycemic AEs | Superiority in incidence of confirmed hypoglycemic AEs | |
4 | Superiority in change from baseline in SBP | Superiority in change from baseline in HbA1c | |
5 | Superiority in change from baseline in DBP | Superiority in change from baseline in SBP | |
6 | Superiority in change from baseline in DBP |
Results
Gender, n (%) | |
Male | 854 (55.3) |
Race, n (%) | |
Caucasian | 1017 (65.8) |
Asian | 507 (32.8) |
Black/African-American | 20 (1.3) |
Hawaiian/Pacific Islander | 1 (0.1) |
Ethnicity, n (%) | |
Non-Hispanic/Latino | 1233 (79.8) |
Hispanic/Latino | 312 (20.2) |
Region, n (%) | |
Europe/South Africa | 639 (41.4) |
Asia | 434 (28.1) |
Latin America | 276 (17.9) |
North America | 196 (12.7) |
Age (years), mean (SD) | 55.9 (10.4) |
Time (years) since diagnosis of T2DM, n (%) | |
≤1 | 172 (11.1) |
>1 to 5 | 677 (43.8) |
>5 to 10 | 425 (27.5) |
>10 | 271 (17.5) |
Body weight (kg), mean (SD) | 82.8 (19.2) |
Body mass index (kg/m2), mean (SD) | 30.1 (5.3) |
Body mass index (kg/m2), n (%) | |
<25 | 243 (15.7) |
25 to <30 | 587 (38.0) |
30 to <35 | 434 (28.1) |
≥35 | 281 (18.2) |
Waist circumference (cm), mean (SD) | |
Male | 104.1 (13.0) |
Female | 98.8 (12.8) |
HbA1c (%), mean (SD) | 7.9 (0.8) |
HbA1c (%), n (%) | |
<8.5 | 1173 (75.9) |
≥8.5 | 372 (24.1) |
Fasting plasma glucose (mg/dL), mean (SD) | 149.9 (33.9)a |
HOMA-IR (mU/L x mmol/L), mean (SD) | 6.03 (5.31)b |
HOMA-B (mU/mmol), mean (SD) | 77.0 (79.0)c |
Cardiovascular medications, n (%) | 1174 (76.0) |
Antihypertensive agents | 933 (60.4) |
Lipid lowering agents | 805 (52.1) |
Acetylsalicylic acid | 498 (32.2) |
Systolic blood pressure (mmHg), mean (SD) | 133.5 (15.9) |
Diastolic blood pressure (mmHg), mean (SD) | 79.5 (9.4) |
Blood pressure controlled (<130/80 mmHg), n (%) | |
Yes | 486 (31.5) |
No | 1059 (68.5) |
Serum lipids (mmol/L), mean (SD) | |
Total cholesterold | 4.49 (1.01) |
HDL-cholesterole | 1.25 (0.31) |
LDL-cholesterolf | 2.42 (0.86) |
Triglyceridese | 1.86 (1.29) |
Markers of renal function and damage | |
eGFR (mL/min/1.73 m2) according to MDRD, mean (SD) | 88.0 (17.3) |
eGFR (mL/min/1.73 m2) according to MDRD, n (%) | |
≥90 (normal renal function) | 633 (41.0) |
60 to <90 (mild renal impairment) | 877 (56.8) |
30 to <60 (moderate renal impairment) | 35 (2.3) |
Urine albumin/creatinine ratio (mg/g), mean (SD) | 40.22 (135.59) |
Urine albumin/creatinine ratio (mg/g), n (%) | |
<30 (normal) | 1221 (79.0) |
30 to <300 (microalbuminuria) | 289 (18.7) |
≥300 (macroalbuminuria) | 35 (2.3) |