New Drugs for Management of Diabetes: Insulin Analogues, Inhaled Insulin, Pramlintide, and Novel Peptides

Diabetes mellitus has reached epidemic proportions and contributes to considerable morbidity and mortality in the form of metabolic, microvascular, and macrovascular complications. Although there is no cure, large controlled studies demonstrate the importance of strict glycemic control in reducing progression of microvascular disease and associated morbidity. Insulin replacement is necessary for all patients with type 1 diabetes. In treatment of type 2 diabetes, more timely addition of insulin as patients fail to attain glycemic targets on combinations of oral agents has become widely accepted. Pharmacokinetic properties of human insulins limit their ability to mimic physiologic insulin secretion. Analog insulins (prandial and basal) are designed with improved physiologic pharmacokinetic characteristics to enable more simplified insulin dosage adjustments and a reduced risk for hypoglycemia. Inhaled administration has emerged as a promising route for noninvasive prandial insulin. Clinical trials are under way to further characterize safety and efficacy of inhaled insulin preparations. Despite numerous pharmacologic advancements, the majority of diabetic patients continue to have inadequate glycemic control. New information regarding biochemistry and pathophysiology of the disease is providing exciting opportunities for drug development. Promising new therapeutic classes include the synthetic analog of amylin (pramlintide), glucagon-like peptide (GLP-1) derivatives, and dipeptidyl peptidase IV inhibitors. Intriguingly, GLP-1 hormones may have important biologic actions aside from stimulating insulin release, including inhibition of gastric motility and acid secretion, suppression of glucagon secretion, and islet cell proliferation. Although additional studies are needed, perhaps these emerging agents will have greater efficacy and safety because of a higher degree of selectivity for their molecular targets.