Phase 3 N=66 Randomized Single-blind Treatment

Dapagliflozin and Metformin,Alone and in Combination, in Overweight/Obese Prior GDM Women

Diabetes Prevention in Women After GDM Who Are at High-risk

Bottom Line

View on ClinicalTrials.gov: NCT02338193 ↗

Enrolled (actual)

Serious AEs

0.0%

Results posted

Apr 2019

Primary outcome: Primary: Change in Body Weight — -21.5; -12.5; -4.4 kilograms — p=<0.032

Study Design & Population

Study type: Interventional
Phase: Phase 3
Interventions: DAPA/MET XR (Drug); DAPA (Drug); MET XR (Drug)
Age: Adult · 18+ yrs
Sex: Female
Sponsor: Woman's
Primary completion: Feb 2019

Outcome Measures

Outcome	Result	p-value
PRIMARY Change in Body Weight	-21.5; -12.5; -4.4	<0.032 sig
SECONDARY Change in Percent Body Weight	-4.9; -3.2; -1.1	<0.05 sig
SECONDARY Body Mass Index (BMI)	33; 33.7; 31	<0.01 sig
SECONDARY Waist Circumference (WC)	95.6; 95; 91.7	<0.012 sig
SECONDARY Waist- to -Hip Ratio (WHR; Measure of Central Adiposity)	0.81; 0.80; 0.83	0.007 sig
SECONDARY Waist-to-height Ratio (WHtR)	0.58; 0.57; 0.56	0.023 sig
SECONDARY Diastolic Blood Pressure (DBP)	79; 77.8; 79	>0.05
SECONDARY Systolic Blood Pressure (SBP)	125; 124; 119.6	>0.05
SECONDARY Liver Enzymes	1.13; 1.12; 1.18	<0.001 sig
SECONDARY Total Cholesterol Levels (CHOL)	196; 168; 178	<0.001 sig
SECONDARY Triglyceride (TRG) Levels	119; 89.8; 212	<0.004 sig
SECONDARY Fasting Blood Glucose (FBG)	89; 91; 87	<0.02 sig
SECONDARY Mean Blood Glucose (MBG) During an OGTT	109.5; 110.1; 112.5	<0.012 sig
SECONDARY Fasting Insulin Sensitivity (HOMA-IR)	2.6; 2.4; 1.8	>0.05
SECONDARY Matsuda Sensitivity Index (SI OGTT)	6.0; 6.3; 5.42	<0.028 sig
SECONDARY First Phase Insulin Secretion (IGI/HOMA-IR)	1.7; 1.1; 0.77	<.03 sig

Summary

Women with a history of gestational diabetes (GDM) are at substantially increased risk of type 2 diabetes mellitus (T2DM). Compared with the general population, these women are more likely to be overweight or obese. Moreover, weight gain after GDM is significantly associated with T2DM, independent of baseline body weight. Weight gain, particularly increased central adiposity after delivery, is strongly associated with deterioration of β-cell compensation for insulin resistance. Taken together, our findings and other studies support increased abdominal fat as the strongest factor associated with declining B-cell compensation for insulin resistance in prior GDM women at high risk for T2DM. Dapagliflozin is a novel highly selective SGLT2 inhibitor that improves glycemic control by reducing renal glucose reabsorption leading to urinary glucose excretion. Its efficacy and safety has been studied in multiple randomized controlled trials including an add-on to metformin compared with a placebo. To the extent that glucotoxicity contributes to the demise in β-cell function in subjects with impaired glucose, SGLT2 inhibitors also may prove useful in the treatment of "prediabetes." An additional secondary benefit of SGLT2 inhibition is the elimination of calories in the form of glucose. The loss of glucose with attendant caloric loss contributes to weight loss; in addition, improvements in β cell function have been seen. Weight loss seen with SGLT2 inhibitors is similar to that seen with glucagon-like peptide 1 analogs, and may be more acceptable because they are oral agents. A consistent finding in all dapagliflozin studies has been a reduction in blood pressure. The investigators hypothesize that combination dapagliflozin -metformin treatment over a 24-week period will have a greater positive impact on body weight, anthropometric measurements and glycemic and cardiometabolic parameters than dapagliflozin or metformin monotherapy in overweight/obese at-risk women with a history of GDM.

Eligibility Criteria

Inclusion Criteria

• Overweight/obese (BMI >25) females 18 years to 45 years of age, who experienced gestational diabetes (GDM) during recent (within 12 months) pregnancy
postpartum metabolic abnormalities determined by a 75 g oral glucose tolerance test (Inclusive of prior GDM women with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or both (IFG/IGT) postpartum)
Completed lactation
Using adequate contraception during study period unless sterilized
Written consent for participation in the study

Exclusion Criteria

Cholestasis during the past pregnancy
Any hepatic diseases in the past (viral hepatitis, toxic hepatic damage, jaundice of unknown etiology), gallstones, abnormal liver function tests or renal impairment (elevated serum creatinine levels or abnormal creatinine clearance
Presence of significant systemic disease, heart problems including congestive heart failure, history of pancreatitis, or diabetes mellitus (Type 1 or 2)
Renal impairment (e.g., serum creatinine levels ≥1.4 mg/dL for women, or eGFR 400 mg %)
Untreated or poorly controlled hypertension (sitting blood pressure >160/95mm Hg)
Prior history of a malignant disease requiring chemotherapy
Known hypersensitivity or contraindications to use of insulin sensitizers such as metformin or thiazolidinediones
History of hypersensitivity reaction to dapagliflozin or other SGLT2 inhibitors (e.g. anaphylaxis, angioedema, exfoliative skin conditions)
Current use of metformin, thiazolidinediones, GLP-1 receptor agonists, DPP-4 inhibitors, SGLT2 inhibitors or weight loss medications (prescription or OTC)
Uncontrolled thyroid disease (documented normal TSH) or hyperprolactinemia
Liver enzymes (serum alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST] ) levels exceeding more than twice normal lab values
Use of drugs known to exacerbate glucose tolerance
History of diabetes or prior use of medications to treat diabetes except GDM
Currently lactating
Eating disorders (anorexia, bulimia) or gastrointestinal disorders
Suspected pregnancy (documented negative serum pregnancy test within 72 hours before first dose of study drug), desiring pregnancy in next 6 months, breastfeeding, or known pregnancy in last 2 months
Active or prior history of substance abuse (smoke or tobacco use within past 3 years) or significant intake of alcohol or history of alcoholism
Patient not willing to use adequate contraception during study period and up to 4 weeks after last dose of study drug (unless sterilized).
Debilitating psychiatric disorder such as psychosis or neurological condition that might confound outcome variables
Inability or refusal to comply with protocol
Not currently participating or having participated in an experimental drug study in previous three months

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Data sourced from ClinicalTrials.gov (NCT02338193). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.