GLP-1, SGLT2 combination therapy provides largest weight loss for women with PCOS
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Combination therapy with a GLP-1 receptor agonist and an SGLT2 inhibitor may provide better weight-loss benefits than a single agent for women with polycystic ovary syndrome and obesity, according to study data.
In a randomized, single-blind, 24-week study, participants assigned to dual therapy of 2 mg weekly of the GLP-1 receptor agonist exenatide (Bydureon, AstraZeneca) and 10 mg daily of the SGLT2 inhibitor dapagliflozin (Farxiga, AstraZeneca) lost more weight than those taking either agent alone or those receiving dapagliflozin and metformin extended-release (Xigduo XL, AstraZeneca) or phentermine/topiramate extended-release (Qsymia, Vivus).
“Greater improvements in participants with exenatide plus dapagliflozin may be explained in part by their different, and potentially complementary, mechanisms of action and confirm other studies showing that combining these two agents may exert stronger beneficial effects than each drug alone,” Karen Elkind-Hirsch, MSc, PhD, HCLD, scientific director of research at Woman’s Hospital Research Center in Baton Rouge, Louisiana, told Healio. “These findings, together with the convenience of once‐daily oral dosing and once‐weekly injection, support the use of these medications in this prediabetic population.”
Elkind-Hirsch and colleagues recruited 119 premenopausal women aged 18 to 45 years with obesity and PCOS and without diabetes to participate in the study. Participants were randomly assigned to one of five therapies: exenatide alone, dapagliflozin alone, dual therapy of exenatide and dapagliflozin, combined dapagliflozin and metformin therapy, or the weight-loss medication phentermine/topiramate extended-release. Clinical, anthropometric and biochemical assessments were conducted at baseline, 12 weeks and 24 weeks.
The findings were published in The Journal of Clinical Endocrinology & Metabolism.
Combination therapy produces greater weight loss
All treatment groups had improvements in fasting glucose, mean glucose, insulin sensitivity and insulin secretion at 24 weeks. Participants receiving combination exenatide and dapagliflozin had a greater reduction in mean blood glucose compared with the dapagliflozin, dapagliflozin and metformin, and phentermine/topiramate extended-release groups (P < .03). Those receiving exenatide or exenatide and dapagliflozin had larger increases in insulin secretion compared with the other three treatment groups (P < .04).
All five treatment groups had reductions in absolute body weight and BMI at 24 weeks, but the exenatide and dapagliflozin group had greater weight loss than those receiving only dapagliflozin or dapagliflozin and metformin (P = .005). Mean weight loss was 6.9% for those receiving exenatide and dapagliflozin therapy and 8% for those receiving phentermine/topiramate extended-release compared with 1.5% for participants receiving only dapagliflozin and 1.7% for those on dapagliflozin and metformin (P < .001).
“Modest weight loss is well known to reduce the risk of future diabetes in individuals with prediabetes,” Elkind-Hirsch said. “Therefore, it cannot be excluded that the modest reduction in body weight contributed in part to the improvement in insulin sensitivity in all groups. While phentermine/topiramate extended-release resulted in consistent significant changes in BMI and waist circumference, only exenatide and dapagliflozin and exenatide alone resulted in significant improvements in insulin secretion as well as mean blood glucose over an oral glucose tolerance test. This finding confirms the beneficial effect of GLP-1 agonists on beta-cell function in this obese prediabetic population.”
Long-term studies needed
Cholesterol, HDL cholesterol, LDL cholesterol and triglycerides-to-HDL ratio did not differ between the two groups. Triglycerides were lower at 24 weeks for the exenatide and dapagliflozin groups compared with phentermine/topiramate extended-release (P < .05). Both systolic and diastolic blood pressure decreased in all treatments at 24 weeks. There were no serious adverse events reported during the trial.
Elkind-Hirsch said the findings are encouraging, but more studies are needed to better establish long-term safety and efficacy of GLP-1 receptor agonists for women with PCOS.
“Future studies should include in their design consideration of the significant number of women with this disorder and the relatively young age of this population,” Elkind-Hirsch said.
For more information:
Karen Elkind-Hirsch, MSc, PhD, HCLD, can be reached at karen.elkind-hirsch@womans.org.
Perspective
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Polycystic ovary syndrome is the most common endocrinopathy encountered in reproductive-aged women and a predisposing factor for type 2 diabetes. Obesity, on the other hand, is an epidemic that affects approximately two-fifths of U.S. adults, with a prevalence of 42.7% in 2017-2018. Lifestyle changes, including calorie-restricted diet and exercise; medications, including those affecting glucose metabolism and appetite; and bariatric surgery are the mainstays of treatment for obesity.
In this single-blind randomized controlled study, Elkind-Hirsch and colleagues examined the effects of the diabetes medications exenatide, dapagliflozin and metformin and appetite suppressants phentermine/topiramate, alone or in combination, on metabolic parameters and weight loss of women with obesity and PCOS and without diabetes. They found that the combination of exenatide and dapagliflozin was the most efficient strategy in reducing weight and total body fat. Considering different mechanism of actions for both medications, it is not surprising that they had favorable additive effects in improving insulin sensitivity and secretion and mean blood glucose levels, as well as in reducing weight.
The results of this study are promising in exploring new treatment strategies for women with obesity and PCOS and without diabetes. Looking to the future, there are two issues to consider. First, rebound weight loss is a major issue in all types of obesity treatments, including bariatric surgery. It would be informative to know the rate of rebound weight gain following the cessation of these medications. Second, in theory, these medications have the potential to reduce development of type 2 diabetes in this high-risk population. It would be of utmost importance to explore the amount of risk reduction, if any, in this patient population.
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