Managing insulin resistance: the forgotten pathophysiological component of type 2 diabetes.

Glucagon-like peptide-1 (GLP-1) receptor agonists have gained widespread use in the treatment of individuals with type 2 diabetes because of their potent weight loss promoting effect, ability to augment β-cell function, and cardiovascular protective effects. However, despite causing impressive weight loss, GLP-1 receptor agonists do not normalise insulin sensitivity in people with type 2 diabetes and obesity, and the long-term effects of this class of antidiabetic medication on muscle mass, frailty, and bone density have been poorly studied. Although GLP-1 receptor agonists improve insulin sensitivity secondary to weight loss, the only true direct insulin-sensitising drugs are thiazolidinediones. Because of side-effects associated with type 2 diabetes therapy, these drugs have not gained widespread use. In lieu of the important role of insulin resistance in the cause of type 2 diabetes and in the pathogenesis of atherosclerotic cardiovascular disease in type 2 diabetes, development of potent insulin-sensitising drugs that can be used in combination with GLP-1 receptor agonists remains a large unmet need in the management of individuals with type 2 diabetes.
Competing Interests: Declaration of interests RAD is on advisory boards for AstraZeneca, Novo Nordisk, Boehringer Ingelheim, Intarcia, Aardvark, Renalytix, CORCEPT, and Alnylam; has received research grants from Boehringer Ingelheim, AstraZeneca, 89Bio, Amgen, Medality, and CORCEPT; and is a member of speakers bureaus for AstraZeneca, CORCEPT, and Renalytix. All other authors declare no competing interests.
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