Role of Incretins in the Management of Type 2DM and Obesity

Obesity and Type 2 Diabetes are progressive, chronic diseases that have grown to pandemic prevalence over the past decades.

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Obesity and Type 2 Diabetes are progressive, chronic diseases that have grown to pandemic prevalence over the past decades. Although not all people with type 2 diabetes have obesity, most have abnormal adiposity, which is the core driver of insulin resistance and contributor to β-cell failure.

Weight loss of 15% or more is known to reverse the underlying metabolic abnormalities of type 2 diabetes and improve glucose control, as well as risk factors for cardiometabolic disease, and quality of life.

Until 2021, the only intervention that could routinely result in maintenance of weight loss of this magnitude was bariatric surgery.

A combination of weight centric and glucocentric approach in the management of type 2 DM with pharmacotherapy and lifestyle interventions is the need of the hour.

Incretins namely GIP (from K cells in duodenum) and GLP-1 (from L cells in ileum and colon ) facilitate the release of insulin from the pancreas in response to a meal, an effect that is blunted in type 2 Diabetes. GLP-1 analogues, improve fasting blood glucose through its direct action on the pancreatic islets and decreases postprandial hyperglycemia through inhibition of gastric emptying. They decrease body weight by decreasing homeostatic and hedonic food intake, lower inflammation and apoptosis and decrease fat mass.

There has been continuous improvement of the pharmacokinetic profile of GLP-1R agonism over time.

Liraglutide 3 mg (Saxenda), approved in 2014 and Semaglutide 2.4 mg (Wegovy) in 2021 for the treatment of obesity in adults.

Tirzepatide is a dual GIP and GLP-1 RA recently developed in 2022 for the treatment of type 2 diabetes that can improve both markers of beta cell function and insulin sensitivity compared with selective GLP-1 RA therapy. The SURPASS trials showed superiority of all three maintenance doses (5,10 and 15mg) on glycemic control, and body weight reduction (of at least 10% and 15%) not only vs placebo but also vs long-acting GLP-1 RAs and basal insulin regimens.

GLP-1 also, lower systolic blood pressure, plasma LDL cholesterol and triglyceride concentrations. They reduce the risk of a major adverse cardiovascular event (MACE) by 14%, death by 13%, non-fatal stroke by 12%, and broad composite kidney outcome by 17%.

As per the current treatment guidelines proposed by the American Diabetes Association, and the European Association for the Study of Diabetes the use of SGLT2 inhibitors or GLP1R agonists with known cardiovascular benefits should be prioritized in patients with type 2 DM.

GLP-1 RAs may also help prevent renal complications of type 2 diabetes like new-onset macroalbuminuria, reduced urinary albumin excretion or slowed the decline in the estimated glomerular filtration rate (eGFR) over time.

The shift in emphasis to prioritize weight loss is important as a proactive approach to addressing a key driver of the disease process of type 2 diabetes that will have benefits well beyond lowering glucose alone.

GLP-1 are capable of lowering plasma glucose comparable to insulin regimens, but with a lower risk of hypoglycemia and the added benefit of weight loss and ability to prevent CV events in high-risk patients.

Individualization and precision treatment is key.

References

Obesity management as a primary treatment goal for type 2 diabetes: time to reframe the conversation. – Ildiko Lingvay, Priya Sumithran, Ricardo V Cohen, Carel W le Roux
Management of type 2 diabetes with the dual GIP/GLP-1 receptor agonist tirzepatide: a systematic review and meta-analysis – Thomas Karagiannis, ^1,2 Ioannis Avgerinos,^1,2 Aris Liakos,^1,2 Stefano Del Prato,³ David R. Matthews,^4,5 Apostolos Tsapas, ^1,2,4 and Eleni Bekiari¹.
GLP-1 receptor agonists in the treatment of type 2 diabetes – state-of-the-art – Michael A Nauck ¹, Daniel R Quast ², Jakob Wefers ², Juris J Meier ²