Objective: To review the multifactorial and progressive nature of type 2 diabetes mellitus (T2DM), the consequences of its progression, and the potential of traditional and newer therapies to delay the progression of this disease.
Methods: The relevant literature is reviewed, and the mechanisms of action of novel agents for treatment of T2DM are discussed.
Results: The global prevalence of diabetes has been increasing in recent decades, reaching near-epidemic proportions, and is projected to more than double by 2030. More than 90% of cases of diabetes in most countries consist of T2DM, but many individuals remain undiagnosed or are diagnosed only after their disease has progressed considerably. Inadequate glycemic control in a majority of patients with T2DM is due to the progressive nature of the disease, delay in initiating pharmacotherapy, and failure to intensify treatment more quickly in patients who do not achieve glycemic targets. Traditional oral therapies are usually effective at lowering hyperglycemia initially but do not prevent disease progression; thus, many patients ultimately require insulin. Furthermore, because most antidiabetic therapies are associated with weight gain or risk of hypoglycemia (or both), patients may not adhere to treatment recommendations.
Conclusion: A new therapeutic approach focuses on the use of the incretin hormone glucagon-like peptide-1. Analogues of this hormone delay the progression of beta-cell dysfunction and promote beta-cell regeneration in animal models. In clinical trials, they have been shown to improve glycemic control by increasing glucose-stimulated insulin secretion and suppressing glucagon secretion. At high concentrations, they also slow gastric emptying and increase satiety, which often promotes weight loss. Another approach is to inhibit the enzyme dipeptidyl-peptidase 4, which rapidly inactivates glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, thereby increasing endogenous incretin levels.