Current, novel combination therapies provide additive benefits for treatment of diabetes
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Prescribing combination therapy to individuals with diabetes early in treatment could allow for better glycemic control and reduced odds of treatment failure, according to a speaker at the virtual Cardiometabolic Health Congress.
“Combination therapy should be considered early, especially if the HbA1c is more than 1.5% above target,” Kathleen Dungan, MD, MPH, associate professor of medicine in the division of endocrinology, diabetes, and metabolism at the Ohio State University School of Medicine, told Healio. “We have evidence that early achievement of glucose control leads to a more durable treatment response over time. The benefits include maximizing benefits of glucose control, weight management and minimizing hypoglycemia while minimizing potential side effects of individual agents, for example, minimizing insulin requirements which cause hypoglycemia and weight gain.”
For individuals with diabetes, Dungan noted that evidence is increasingly showing the benefits of switching to a dual agent early in treatment. Recommendations from the American Diabetes Association state combination therapy should be considered in individuals with an HbA1c 1.5% or more above target. The American Association of Clinical Endocrinology recommends combination therapy when an individual’s HbA1c climbs above 7.5%.
“With this concept of early combination or sequential therapy, there are a number of pros and cons I think that we can all be aware of and think about and ponder,” Dungan said in the presentation. “That is going to involve some shared decision-making with our patients and determining what is the right approach.”
Current combination therapies have a wide range of beneficial additive effects for individuals with diabetes. Dungan discussed multiple trials where the combination of a GLP-1 receptor agonist with an SGLT2 inhibitor had the synergistic effect of lowering HbA1c and weight while also providing beneficial CV and renal effects. Another randomized controlled trial published in 2017 showed combining a GLP-1 receptor agonist with basal insulin resulted in greater HbA1c reductions with less weight gain when compared with prandial insulin.
Oral peptides may allow for coformulation with other oral agents in the future, but there are several hurdles that need to be overcome, according to Dungan. She said small molecule agonists interacting with the GLP-1 receptor may be the key to allowing those types of formulations in the future.
“We would need a lot of data on these coformulations,” Dungan said in the presentation. “We would have to consider this variable absorption and unpredictable pharmacogenetics, particularly with insulin, which has a very tight therapeutic window.”
When discussing the possible combination of weekly basal insulin with a GLP-1 receptor agonist, Dungan said several questions need to be answered, including the amount of the initial dose and what the dosing adjustment should be, the most efficacious injection volume and how to handle day-to-day and week-to-week variability.
Several novel co-agonists are also on the horizon. SGLT 1/2 inhibitors utilize the gut to further reduce glucose levels. Dungan noted the inhibitors have been approved in Europe, but not yet by the FDA. The use of GLP-1 receptor agonists with gastric inhibitory polypeptides could have several additive effects, including improved insulin response, greater weight loss, and lower liver fat. GLP-1 and glucagon receptor dual agonists can have the additive effects of increasing energy expenditure and the GLP-1 receptor agonist can counter the increased hyperglycemia risk caused by the glucagon. This combination could also improve an individual’s lipid profile and reduce liver fat.
Dungan added there is the chance that a tri-agonist involving GLP-1, gastric inhibitory polypeptides and glucagon could offer an alternative for bariatric surgery in the future.
“The possibility of creating a tri-agonist that may be able to replace bariatric surgery is intriguing,” Dungan told Healio. “Bariatric surgery is by far the most effective means for achieving diabetes remission, but also presents challenges in terms of immediate and long-term complications and patient acceptance.”
References:
- Davies MJ, et al. Diabetes Care. 2018;doi:10.2337/dci18-0033.
- Garber AJ, et al. Endocr Pract. 2019;doi:10.4158/CS-2018-0535.
- Maiorino MI, et al. Diabetes Care. 2017;doi:10.2337/dc16-1957.
Perspective
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Kevin M. Pantalone, DO, ECNU, FACE
The early and aggressive intensification of therapy in patients with type 2 diabetes is necessary to attain glycemic targets and reduce the risk of developing complications. The “legacy effect” of early glycemic control on the risk for developing complications has been demonstrated in clinical trials. Unfortunately, nearly 50% of patients with type 2 diabetes do not attain a target HbA1c below 7%, which is the general goal for most patients. In many instances, patients with type 2 diabetes, particularly those with higher HbA1c levels, would benefit from the early initiation of combination therapy or an expedited addition of sequential therapies to increase their probability of HbA1c goal attainment.
Combination therapy with GLP-1 receptor agonist and SGLT-2 inhibitor is very advantageous because of their effects beyond improving glycemia (weight loss, CV risk reduction, etc). In patients who do require basal insulin therapy, the addition of a GLP-1 receptor agonist is advantageous given its synergistic and complementary mechanisms of action to basal insulin, and because the combination may limit the use of insulin to lower doses, thereby reducing the risks for hypoglycemia and weight gain that are frequently observed with basal insulin therapy.
Lastly, there are many great therapeutic combinations currently under development. In the very near future, combination therapy with a once-weekly basal insulin and once-weekly GLP-1 receptor agonist, a once weekly GLP-1 receptor agonist in combination with a once weekly amylin mimetic, and once-weekly GLP-1/GIP dual-agonists or GLP-1/GIP/glucagon tri-agonists may join our therapeutic arsenal. Early studies have suggested that these latter combinations may provide not only significant improvements in glycemic control, but also weight loss outcomes similar to what we have observed in patients who undergo bariatric surgery. The treatment landscape is certainly looking very bright for patients with type 2 diabetes and obesity.
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Dungan K. Diabetes. Presented at: Cardiometabolic Health Congress; Oct. 21-24, 2020 (virtual meeting).
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