Reducing cardiovascular complications in patients with diabetes: exciting new drug therapy on the horizon.
By Ajay K. Singh, MBBS, FRCP, MBA
December 7, 2016
Diabetes mellitus is in epidemic proportions in many parts of the world. Its most consequential and debilitating complications are cardiovascular disease, retinopathy, and nephropathy. Newer agents are now emerging and have the potential to transform the management of diabetes.
In the past six months alone, two exciting studies on reducing cardiovascular outcomes in patients with diabetes were published in the New England Journal of Medicine.1, 2
These studies are focused on pharmaceutical agents that target the incretin system. Incretins are hormones released by enteroendocrine cells into the blood within minutes after eating. The two hormones are glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). GIP is synthesized and released by enterocytes in the duodenum, whereas GLP-1 is released by enterocytes throughout the small bowel and ascending colon. Both of these hormones have pleitrophic effects on islets cells; chief among these is to stimulate insulin secretion by beta cells in the pancreas. Both hormones also have extra-pancreatic effects, including on bone, the cardiovascular system, GI tract and the liver, the central and peripheral nervous system, muscle, and adipose tissue.
In the first study1, the LEADER trial, published online July 2016 in the New England Journal of Medicine, Steven Marso and colleagues examined liraglutide’s long-term role in providing cardiovascular protection. Liraglutide is an analogue of human glucagon- like peptide 1 (GLP-1) that lowers blood glucose, and to a lesser degree leads to weight loss and lowering in blood pressure. In LEADER, the study population was patients with type 2 diabetes and high cardiovascular risk. The trial showed a lower rate of cardiovascular events and lower mortality in patients treated with liraglutide compared to placebo. The drug appeared to be well tolerated except for a higher rate of GI side effects in the liraglutide-treated patients.
In the second and more recent study2, the SUSTAIN-6 study, also published online September 2016 in the New England Journal of Medicine, Marso et al examined the cardiovascular effects of semaglutide, a long-acting GLP-1 analogue. Semaglutide has not been approved as yet. Like the LEADER trial, this study also showed a cardiovascular benefit for semaglutide. In addition, the rates of new or worsening nephropathy were lower in the semaglutide arm; however, the rates of retinopathy complications (vitreous hemorrhage, blindness, or conditions requiring treatment with an intravitreal agent or photocoagulation) were significantly higher in the semaglutide-treated patients.
While the editorial by NEJM Deputy Editor Dr. Julie Ingelfinger is appropriately cautious about concluding that these studies represent, in her words “a home-run,” they are certainly very promising.
While it may be premature to sip the champagne, getting the bottle ready to open seems reasonable. Finally, we may have strategies to reduce the curse of cardiovascular complications among patients with diabetes mellitus.
- Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, Steinberg WM, Stockner M, Zinman B, Bergenstal RM, Buse JB; LEADER Steering Committee.; LEADER Trial Investigators.Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016 Jul 28;375(4):311-22. doi: 10.1056/NEJMoa1603827. http://www.nejm.org/doi/pdf/10.1056/NEJMoa1603827
- Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, Lingvay I, Rosenstock J, Seufert J, Warren ML, Woo V, Hansen O, Holst AG, Pettersson J, Vilsbøll T; SUSTAIN-6 Investigators. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016 Sep 15. http://www.nejm.org/doi/full/10.1056/NEJMoa1607141
- Kim W, Egan JM. The Role of Incretins in Glucose Homeostasis and Diabetes Treatment. Pharmacological reviews. 2008;60(4):470-512. doi:10.1124/pr.108.000604. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2696340/
Dr. Ajay K. Singh is the Senior Associate Dean for Global and Continuing Education and Director, Master in Medical Sciences in Clinical Investigation (MMSCI) Program at Harvard Medical School. He is also Director, Continuing Medical Education, Department of Medicine and Renal Division at Brigham and Women’s Hospital in Boston.