Dapagliflozin and Metformin,Alone and in Combination, in Overweight/Obese Prior GDM Women
| Status: | Active, not recruiting |
|---|---|
| Conditions: | Obesity Weight Loss, Diabetes |
| Therapuetic Areas: | Endocrinology |
| Healthy: | No |
| Age Range: | 18 - 45 |
| Updated: | 3/10/2019 |
| Start Date: | September 22, 2015 |
| End Date: | April 30, 2019 |
A Randomized Study Evaluating Dapagliflozin and Metformin, Alone and in Combination, in Overweight Women With a Recent History of Gestational Diabetes Mellitus: Effects on Anthropometric Measurements and Cardiometabolic Abnormalities
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.
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.
Following written consent, all study patients will undergo the following clinical, metabolic
and laboratory evaluations before and during treatment. To ensure that patients remain
unidentified, all study subjects will be assigned an individual study identifier which
includes the study acronym, patient initials, and unique number. All blood samples will be
obtained and results identified and reported using this unique study identifier. A full
physical examination will be performed and vital signs (blood pressure, respiration and
temperature) determined. Trained personnel using standardized protocols at the baseline and
follow-up examination will obtain anthropometric measurements and blood specimens. Absolute
body weight, height, waist and hip circumference, body fat distribution (waist/hip {WHR}) and
waist/height ratio ({WHtR}) and blood pressure (BP) will be determined. Body weight will be
measured to the nearest 0.1 kg using a calibrated digital scale with participants in light
clothing and no shoes. Height will be measured to the nearest centimeter. The total body
adiposity (total fatness), defined as the accumulation of body fat without regard to regional
distribution, will be expressed as BMI and calculated as weight (kg)/ height (m) 2. The
circumference measurements will be taken in the upright position using a 15-mm width flexible
metric tape held close to the body but not tight enough to indent the skin. Waist
circumference (WC) will be measured at the narrowest level midway between the lowest ribs and
the iliac crest and hip circumference measured at the widest level over the buttocks while
the subjects are standing and breathing normally. The WHR and WHtR will be calculated for
measure of body fat distribution.
All patients will randomly be assigned to one of 3 medication treatment groups--
dapagliflozin-metformin (DAP-MET; 5 mg DAP/ MET 1000 mg BID), metformin XR (MET 1000 mg BID)
or dapagliflozin (DAP 10 mg QD); all subjects will be allocated to one of these 3 groups
based on computer-generated random numbers using a block randomization method. Oral glucose
tolerance tests (OGTTs) with glucose (G) and insulin (I) measured at 0, 30, 60, and 120 after
glucose load to assess diabetes, fasting (FBG) and mean blood glucose (MBG) concentrations,
insulin resistance and pancreatic ß-cell function will be performed prior to randomization
and at 20-24 weeks after full doses of study medications are reached. Mean blood glucose
(MBG) concentrations will be calculated by summing glucose values obtained at 0,30,60 and 120
minutes during the OGTT and dividing by 4. At the initial lab evaluation, creatinine and
calculated eGFR, TSH, and ß-hCG will be determined for study inclusion. Baseline blood
samples will also be analyzed for lipid profiles and liver enzymes.
All patients will receive the same counseling concerning the benefits of lifestyle
modification through diet and exercise. The patients will be also encouraged to increase
daily exercise (such as walking, using stairs), although this will not be formally assessed.
The participants will receive further encouragement to adhere to the regime during follow-up
phone calls. Side effects of the treatment and reason for any withdrawals from the study will
be recorded.
and laboratory evaluations before and during treatment. To ensure that patients remain
unidentified, all study subjects will be assigned an individual study identifier which
includes the study acronym, patient initials, and unique number. All blood samples will be
obtained and results identified and reported using this unique study identifier. A full
physical examination will be performed and vital signs (blood pressure, respiration and
temperature) determined. Trained personnel using standardized protocols at the baseline and
follow-up examination will obtain anthropometric measurements and blood specimens. Absolute
body weight, height, waist and hip circumference, body fat distribution (waist/hip {WHR}) and
waist/height ratio ({WHtR}) and blood pressure (BP) will be determined. Body weight will be
measured to the nearest 0.1 kg using a calibrated digital scale with participants in light
clothing and no shoes. Height will be measured to the nearest centimeter. The total body
adiposity (total fatness), defined as the accumulation of body fat without regard to regional
distribution, will be expressed as BMI and calculated as weight (kg)/ height (m) 2. The
circumference measurements will be taken in the upright position using a 15-mm width flexible
metric tape held close to the body but not tight enough to indent the skin. Waist
circumference (WC) will be measured at the narrowest level midway between the lowest ribs and
the iliac crest and hip circumference measured at the widest level over the buttocks while
the subjects are standing and breathing normally. The WHR and WHtR will be calculated for
measure of body fat distribution.
All patients will randomly be assigned to one of 3 medication treatment groups--
dapagliflozin-metformin (DAP-MET; 5 mg DAP/ MET 1000 mg BID), metformin XR (MET 1000 mg BID)
or dapagliflozin (DAP 10 mg QD); all subjects will be allocated to one of these 3 groups
based on computer-generated random numbers using a block randomization method. Oral glucose
tolerance tests (OGTTs) with glucose (G) and insulin (I) measured at 0, 30, 60, and 120 after
glucose load to assess diabetes, fasting (FBG) and mean blood glucose (MBG) concentrations,
insulin resistance and pancreatic ß-cell function will be performed prior to randomization
and at 20-24 weeks after full doses of study medications are reached. Mean blood glucose
(MBG) concentrations will be calculated by summing glucose values obtained at 0,30,60 and 120
minutes during the OGTT and dividing by 4. At the initial lab evaluation, creatinine and
calculated eGFR, TSH, and ß-hCG will be determined for study inclusion. Baseline blood
samples will also be analyzed for lipid profiles and liver enzymes.
All patients will receive the same counseling concerning the benefits of lifestyle
modification through diet and exercise. The patients will be also encouraged to increase
daily exercise (such as walking, using stairs), although this will not be formally assessed.
The participants will receive further encouragement to adhere to the regime during follow-up
phone calls. Side effects of the treatment and reason for any withdrawals from the study will
be recorded.
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 <60)
- Significantly elevated triglyceride levels (fasting triglyceride > 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 AST and/or ALT ) 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
We found this trial at
1
site
Baton Rouge, Louisiana 70815
Principal Investigator: Karen Elkind-Hirsch, Ph.D.
Phone: 225-231-5278
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