Two drug classes, sodium-glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, have recently attracted significant attention of the medical research community in studies focused on weight loss, glycemic control, and cardiovascular and renal system protection.1-5 A recent literature review summarized the research evidence of an additive effect of this drug combination on lowering the hemoglobin A1c (HBA1c) levels, systolic blood pressure, and body weight in patients with type 2 diabetes (T2D).6
Endocrinology Advisor discussed the latest insights on the use of SGLT2 inhibitor and GLP-1 receptor agonist combination therapy for T2D with Robert S. Busch, MD, endocrinologist at Albany Medical Center Division of Community Endocrinology, New York, and lead author of the clinical feature review article on combination SGLT2 inhibitor and GLP-1 receptor agonist therapy for T2D, published in Postgraduate Medicine.7
Endocrinology Advisor: What is the mechanism of action of SGLT2 inhibitors and GLP-1 receptor agonists?
Robert S. Busch, MD: SGLT2 inhibitors block the uptake of glucose by the kidney, so the glucose gets urinated out, accompanied by salt and water. As a consequence, the fasting blood glucose, postprandial blood glucose, and average blood glucose (HBA1c) decrease. At the same time, weight and blood pressure are also lowered because of the drug’s glucuretic effect.
GLP-1 receptor agonists stimulate the pancreas to secrete insulin only if blood glucose is elevated, so they do not cause hypoglycemia. This effect is also known as insulin on demand. GLP-1 receptor agonists are “smart” secretagogues. They decrease appetite and create a sense of fullness and decrease postprandial glucose by lowering the appearance of glucose by mouth, stomach, and liver. Specifically, GLP-1 receptor agonists lower glucagon levels and, thereby, lower glucose produced by the liver.
Endocrinology Advisor: How do these 2 medication types work together in T2D?
Dr Busch: They complement each other because they work by different mechanisms. They also complement each other because they both induce weight loss, lower the risk for heart disease, lower blood pressure, and do not cause hypoglycemia.
Endocrinology Advisor: How much clinical evidence supports the use of combination SGLT2 inhibitor and GLP-1 receptor agonist therapy for T2D?
Dr Busch: There are real-world studies looking at the effects of SGLT2 inhibitor and GLP-1 receptor agonist combination treatment in patients with T2D, but the first and only randomized clinical trial to date is the DURATION-8 trial. It reported the results on combining Bydureon weekly, a GLP-1 receptor agonist, with Farxiga daily, an SGLT2 inhibitor, in patients with T2D. The findings showed this drug combination to have combined efficacy for HBA1c lowering and additive efficacy for weight loss. This drug combination is very powerful, and neither of the 2 drugs induces hypoglycemia, which is very appealing.
Endocrinology Advisor: What is the safety profile of SGLT2 inhibitor and GLP-1 receptor agonist combination treatment?
Dr Busch: There is nothing unexpected about the safety profile of this drug combination: yeast infections and volume depletion are associated with the SGLT2 inhibitor, and nausea and gastrointestinal effects are associated with the GLP-1 receptor agonist. The beneficial effects of this treatment combination include weight loss, blood pressure lowering, and cardiac protection.
Endocrinology Advisor: Does this treatment combination have any advantages in terms of medication adherence?
Dr Busch: Weight loss help patients adhere to this treatment regimen. The SGLT2 inhibitor is a pill given either alone or with metformin, and the GLP-1 receptor agonist is a shot given either daily or weekly, using a small needle or device that does not really hurt. So, this type of treatment regimen is convenient for patients. In addition, both medications are affordable: the SGLT2 inhibitors have vouchers that make them free with commercial insurance, and GLP-1 receptor agonists also have vouchers that make them affordable for patients with commercial insurance.
Endocrinology Advisor: Patients with which clinical characteristic are most likely to benefit from this treatment combination?
Dr Busch: Overweight patients with T2D whose HbA1c is not in goal are good candidates for this treatment combination. Also, if the patients are hypertensive, it is beneficial to give the SGLT2 inhibitor. Furthermore, the risk for cardiac disease can be lowered with each of the 2 classes of medication when used separately.
Endocrinology Advisor: What is your clinical experience with this treatment combination in patients with T2D?
Dr Busch: This is a game-changing regimen for patients with T2D: it helps them lose weight, optimize A1C levels, and lower blood pressure, which means they can be tapered off from some of the other medications such as insulin or other secretagogues. Ease, convenience, and affordability are also associated with this treatment regimen.
Endocrinology Advisor: What type of research is currently underway with these 2 classes of medications?
Dr Busch: This is a very active area of research; I am aware of several clinical trials currently underway. SGLT2 inhibitors are studied for renal protection (canagliflozin in the CREDENCE trial, dapagliflozin in the Dapa-CKD trial) and their ability to lower the incidence of heart failure in patients with T2D (dapagliflozin in the DECLARE-TIMI58 trial). Empagliflozin, another SGLT2 inhibitor, is studied for heart failure protection in patients with chronic heart failure with or with T2D (EMPEROR trial). Furthermore, sotagliflozin, an oral inhibitor of both SGLT1 and SGLT2, is studied for renal and cardiovascular protection in patients with T2D and moderate renal impairment (SCORED trial). Sotagliflozin is also being studied in patients with T2D and stage 4 chronic kidney disease.
GLP-1 receptor agonists are being studied for their weight loss effects, and additional cardiovascular studies are planned for this drug class. Dulaglutide, a GLP-1 receptor agonist, is currently studied for cardiovascular protection in patients with T2D (REWIND trial). In addition, an oral GLP-1 receptor agonist, oral semaglutide, is intensively being studied in the PIONEER trial.
Dr Busch serves on the speakers’ bureau for Eli Lilly and Company, Boehringer-Ingelheim, AstraZeneca, and Janssen Pharmaceutica. He receives research support from Novo Nordisk, Amgen, Ironwood Pharmaceuticals, Eli Lilly and Company, AstraZeneca, Amarin Corporation, and Janssen Pharmaceutica.
- Kanoski SE, Hayes MR, Skibicka KP. GLP-1 and weight loss: unraveling the diverse neural circuitry. AM J Physiol Regul Integr Comp Physiol. 2016;310(10):R885-R895.
- Andrianesis V, Glykofridi S, Doupis J. The renal effects of SGLT2 inhibitors and a mini-review of the literature. Ther Adv Endocrinol Metab. 2016;7(5-6):212-228.
- Røder ME. Major adverse cardiovascular event reduction with GLP-1 and SGLT2 agents: evidence and clinical potential. Ther Adv Chronic Dis. 2018;9(1):33-50.
- Cavaiola TS, Pettus J. Cardiovascular effects of sodium glucose cotransporter 2 inhibitors. Diabetes Metab Syndr Obes. 2018;11:133-148.
- Prasad-Reddy L, Isaacs D. A clinical review of GLP-1 receptor agonists: efficacy and safety in diabetes and beyond. Drugs Context. 2015;4:212283.
- Goncalves E, Bell DSH. Combination treatment of SGLT2 inhibitors and GLP-1 receptor agonists: Symbiotic effects on metabolism and cardiorenal risk [published online April 5, 2018]. Diabetes Ther. doi: 10.1007/s13300-018-0420-6
- Busch RS, Kane MP. Combination SGLT2 inhibitor and GLP-1 receptor agonist therapy: a complementary approach to the treatment of type 2 diabetes. Postgraduate Medicine. 2017;129(7):686-697.