Newer oral and noninsulin therapies to treat type 2 diabetes mellitus

Type 2 diabetes mellitus (DM) is caused by hyperglycemia and metabolic alterations due to abnormalities in insulin secretion or insulin action, or both. To achieve desired glycemic targets, different antihyperglycemic drugs are used alone or in combination with other agents, including insulin. First-line options for diabetes treatment are weight loss, lifestyle modification, and metformin. The American Diabetes Association and the European Association for the Study of Diabetes recommend a patient-specific treatment approach to enhance glycemic control while avoiding weight gain and hypoglycemia. This review will focus on the newer oral agents and injectable noninsulin agents that are used to achieve glycemic control. Table 1 lists the noninsulin drugs approved since 2005.

INCRETIN-BASED THERAPIES

The incretins are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which are secreted by the gastrointestinal (GI) tract in response to food intake. Both GLP-1 and GIP stimulate beta cells of the pancreas, which contribute 60% of the insulin secretion after a meal. Type 2 DM is associated with decreased secretion of GLP-1 and lowered responsiveness to GIP. Benefits of the incretin hormones on glycemic control include enhanced satiety, decreased GI motility, increased glucose-dependent insulin secretion, reduced glucagon secretion, and decreased hepatic glucose release. Two incretin-based drug classes are used to treat patients with type 2 DM—oral dipeptidyl peptidase-4 (DPP-4) inhibitors and GLP-1 receptor agonists.

DPP-4 inhibitors

The oral DPP-4 inhibitors block the degradation of the enzyme DPP-4 active site and thus increase the GLP-1 and GIP concentrations by two to three times. Their primary effectiveness centers on controlling insulin and glucagon secretion without increasing weight.

Four DPP-4 inhibitors are approved by the US Food and Drug Administration (FDA) in once-daily oral formulations: sitagliptin, saxagliptin, linagliptin, and alogliptin. Another DPP-4 inhibitor, vildagliptin, is not licensed in the United States but is approved for use in Europe and Japan. Another DPP-4 inhibitor, teneligliptin, is also marketed in Japan.

 

GLP-1 agonists

The GLP-1 drugs mimic the action of native GLP-1. Several GLP-1 agents are available in the United States, and several more are in development.The drug class is divided into three groups:

• Short-acting (4–6 hours): exenatide, lixisenatide
• Intermediate-acting (24 hours): liraglutide
• Long-acting (7 days): exenatide extended-release (ER), dulaglutide, and albiglutide (semaglutide is in phase 3 study).

 

SODIUM-GLUCOSE COTRANSPORTER-2 INHIBITORS

In 2013, canagliflozin became the first sodium-glucose cotransporter-2 (SGLT-2) inhibitor to be FDA-approved for treating patients with type 2 DM, followed in 2014 by dapagliflozin and empagliflozin. Several other drugs in this class are available outside the US or are currently undergoing clinical development, including ipragliflozin, luseogliflozin, tofogliflozin, and ertugliflozin. Currently, no SGLT-2 inhibitors are FDA-approved for type 1 DM, although they have been used off-label and in trials in this patient population.

The SGLT-2 inhibitors do not rely on insulin activity, allowing for their use at any stage of type 2 DM and in combination with other therapies, including insulin.

BILE ACID SEQUESTRANTS

Bile acid sequestrants have been used for years in hyperlipidemia to reduce LDL concentration; however, colesevelam is the only drug in this class approved (2009) for treating type 2 DM, after studies showed colesevelam improves glycemic control.

DOPAMINE-RECEPTOR AGONIST

Bromocriptine, a dopamine-receptor agonist, was FDA-approved for the treatment of Parkinson disease, hyperprolactinemia, and acromegaly in the 1970s. In 2009, a quick-release formulation of bromocriptine (bromocriptine QR) was approved for treatment of type 2 DM.

The precise mechanism of action is unclear, but an American Association of Clinical Endocrinologists expert panel recommendation suggests that it may lower glucose levels by improving hypothalamic-mediated, postprandial insulin sensitivity via increasing morning dopaminergic activity (decreased in patients with type 2 DM) and by reducing hypothalamic adrenergic tone.