clinical topic updates
Role of Obesity in Late Complications Associated With Type 2 Diabetes
For patients with type 2 diabetes who are overweight or obese, complications such as cardiovascular disease and obstructive sleep apnea highlight the need for weight loss in addition to glycemic control. After a certain point, the relationship between body mass index and cardiovascular death becomes almost linear.
Chief, Diabetes Section
“For a number of reasons, we should be treating obesity in patients with type 2 diabetes more aggressively than we currently do.”
Obesity in type 2 diabetes is both complicated and simple at the same time. Patients who are obese are more likely to die from cardiovascular disease compared with those who are not obese; as body mass index increases, so does the rate of cardiovascular death. How and why does this occur? That is where the complexity begins. On a basic level, we have learned about healthy fat deposition vs unhealthy fat; that abdominal or visceral fat deposition provides a connection between obesity and heart disease, as does deposition in the heart, which is more of a direct connection.
But most of the connections between unhealthy fat and cardiovascular risk are not as direct. For instance, secretion of adipokines from unhealthy fat can be deleterious. Angiotensin, which functions normally to constrict blood vessels, may contribute to abnormal endothelial function when secreted as an adipokine. Additionally, pathologic obesity is an indicator of the poor handling of lipids, and this may be paralleled over time by the storing of fat particles in the blood vessel walls (ie, the first step in the development of atherosclerotic cardiovascular disease).
One of the challenges with obesity is that we think of it as being a fat-oriented disease, and, although it is, we also need to remain mindful of its other features. For example, obstructive sleep apnea is more likely to present in patients who are obese and has been associated with many different forms of cardiovascular disease, including heart failure. We can see devastating end-stage heart disease in individuals with obstructive sleep apnea who are in their 60s and 70s. Further, we can see right-sided heart failure in patients with diabetes and obesity, and the combined effects of elevated myocardial pressures and the aforementioned accumulation of fat plaques in the coronary arteries result in a complex, aggressive form of cardiovascular disease. All of this underscores that, for a number of reasons, we should be treating obesity in patients with type 2 diabetes more aggressively than we currently do.
As relates to therapeutic choices in diabetes and their impact on these complications, both the sodium-glucose cotransporter-2 (SGLT2) inhibitors and the glucagon-like peptide 1 (GLP-1) receptor agonists, in combination with metformin, have shown cardiovascular and renal benefits. It is fairly clear that patients with heart failure should be prescribed an SGLT2 inhibitor as the primary drug, but, beyond heart failure, it depends on each patient’s situation. Costs aside, the combination SGLT2s and GLP-1s are conceptually appealing. Oftentimes, for morbid obesity, we would choose a GLP-1 receptor agonist first. In my experience, SGLT2 inhibitors do not produce a substantial amount of weight loss in those who are not also participating in an aggressive lifestyle program. Even in patients with established chronic kidney disease, if they have morbid obesity, they may be better off and better served by a GLP-1 receptor agonist because they will get weight loss, some renal protection, and certainly cardiovascular protection beyond heart failure.
Bhaskaran K, Dos-Santos-Silva I, Leon DA, Douglas IJ, Smeeth L. Association of BMI with overall and cause-specific mortality: a population-based cohort study of 3.6 million adults in the UK. Lancet Diabetes Endocrinol. 2018;6(12):944-953. doi:10.1016/S2213-8587(18)30288-2
Carbone S, Canada JM, Billingsley HE, Siddiqui MS, Elagizi A, Lavie CJ. Obesity paradox in cardiovascular disease: where do we stand? Vasc Health Risk Manag. 2019;15:89-100. doi:10.2147/VHRM.S168946
de Farias Lelis D, de Freitas DF, Machado AS, Crespo TS, Santos SHS. Angiotensin-(1-7), adipokines and inflammation. Metabolism. 2019;95:36-45. doi:10.1016/j.metabol.2019.03.006
Lee MMY, Petrie MC, McMurray JJV, Sattar N. How do SGLT2 (sodium-glucose cotransporter 2) inhibitors and GLP-1 (glucagon-like peptide-1) receptor agonists reduce cardiovascular outcomes? Completed and ongoing mechanistic trials. Arterioscler Thromb Vasc Biol. 2020;40(3):506-522. doi:10.1161/ATVBAHA.119.311904
Linton MF, Yancey PG, Davies SS, et al. The role of lipids and lipoproteins in atherosclerosis. Accessed June 28, 2021. https://www.ncbi.nlm.nih.gov/books/NBK343489/
Malone JI, Hansen BC. Does obesity cause type 2 diabetes mellitus (T2DM)? Or is it the opposite? Pediatr Diabetes. 2019;20(1):5-9. doi:10.1111/pedi.12787
Piché M-E, Tchernof A, Després J-P. Obesity phenotypes, diabetes, and cardiovascular diseases [published correction appears in Circ Res. 2020;127(3):e107]. Circ Res. 2020;126(11):1477-1500. doi:10.1161/CIRCRESAHA.120.316101
Tietjens JR, Claman D, Kezirian EJ, et al. Obstructive sleep apnea in cardiovascular disease: a review of the literature and proposed multidisciplinary clinical management strategy. J Am Heart Assoc. 2019;8(1):e010440. doi:10.1161/JAHA.118.010440