What is the interaction between Metformin (Biguanide) and Semaglutide (Glucagon-like peptide-1 receptor agonist)?

From the Guidelines

Metformin does not have a significant impact on semen parameters in most men, but it may potentially improve some semen parameters by addressing underlying metabolic issues in men with diabetes or insulin resistance. For men with diabetes or insulin resistance who are concerned about fertility, taking metformin (typically 500-2000 mg daily in divided doses) may potentially improve some semen parameters by addressing the underlying metabolic issues 1. Metformin works primarily by reducing insulin resistance and improving glucose metabolism, which can indirectly benefit reproductive health in men with metabolic disorders. Some studies suggest modest improvements in sperm concentration, motility, and morphology in certain populations, particularly those with metabolic syndrome or insulin resistance 1. However, metformin is not prescribed specifically as a fertility treatment for men with normal metabolism. If you're concerned about fertility and are considering metformin, it's essential to have a complete fertility evaluation first, as other interventions may be more appropriate depending on your specific situation. Side effects of metformin can include gastrointestinal disturbances like diarrhea and nausea, which typically improve with continued use or extended-release formulations 1.

Key Considerations

• Metformin is the first-line agent for older adults with type 2 diabetes, and it may be used safely in patients with estimated glomerular filtration rate ≥30 mL/min/1.73 m² 1.
• GLP-1 receptor agonists and SGLT2 inhibitors have been shown to reduce major adverse cardiovascular events and cardiovascular deaths in patients with type 2 diabetes, and they may be considered as add-on therapy to metformin 1.
• The cost-effectiveness of newer pharmacologic treatments, including GLP-1 receptor agonists and SGLT2 inhibitors, is uncertain, and they may be of low value as first-line therapy but of intermediate value when added to metformin or background therapy compared with adding nothing 1.

Recommendations

• Metformin should be considered as first-line therapy for men with diabetes or insulin resistance who are concerned about fertility, but a complete fertility evaluation should be performed first to determine the best course of treatment.
• GLP-1 receptor agonists and SGLT2 inhibitors may be considered as add-on therapy to metformin in patients with type 2 diabetes who have established cardiovascular disease or are at high risk for cardiovascular events.
• The potential benefits and risks of metformin and other pharmacologic treatments should be carefully weighed, and treatment decisions should be individualized based on patient-specific factors, including medical history, lifestyle, and preferences.

From the Research

Metformin and Type 2 Diabetes

• Metformin is widely considered the optimal initial therapy for patients with type 2 diabetes mellitus 2
• It is recommended as first-line treatment in various guidelines, including that of the EASD and ADA, due to its efficacy, low cost, weight neutrality, and good safety profile 2
• Metformin's mechanism of action is thought to involve a reduction in hepatic glucose production, although its precise mechanism is still not fully understood 2

Combination Therapy with Metformin

• The combination of insulin and metformin in the treatment of type 2 diabetes has been shown to result in superior glycemic control compared with insulin therapy alone, while reducing insulin requirements and weight gain 3
• Adding new oral glucose-lowering drugs to insulin, such as DPP-4 inhibitors, can lead to a modest HbA1c reduction without weight gain and no increase in hypoglycemia 4
• GLP-1 receptor agonists have become a good alternative when basal insulin fails, particularly using fixed ratio combinations 4

Metformin in Specific Populations

• Metformin's effectiveness varies among women at different stages of menopause, potentially due to differential impacts on inflammatory markers and modulation of the hypothalamic-pituitary-ovarian (HPO) and hypothalamic-pituitary-thyroid (HPT) axes 5
• Metformin has shown promise in addressing other health issues that postmenopausal women may face, such as inflammation in breast tissue, certain types of cancer, endometrial problems, and polycystic ovarian syndrome (PCOS) 5

Efficacy of Metformin-Based Regimens

• A network meta-analysis found that exenatide + metformin and vildagliptin + metformin regimens presented with better efficacy in the treatment of type 2 diabetes mellitus 6
• These regimens were found to improve insulin sensitivity and reduce fasting plasma glucose, fasting plasma insulin, and total cholesterol levels 6