A Review of Type 2 Diabetes Drug Classes

The downsides of sulfonylureas are well-known, and include weight increase and hypoglycemia. Therefore, sulfonylureas are widely regarded as less attractive for first-line therapy in obese patients. Secondgeneration sulfonylureas, including glyburide, glipizide, and glimepiride, are more potent than the first-generation drugs (chlorpropamide, tolbutamide, acetohexamide, and tolazamide) and generally have fewer side effects and are of comparable efficacy, but cause weight gain.¹⁰ Most sulfonylureas are metabolized hepatically and cleared renally, and are therefore not recommended in patients with advanced liver or kidney disease. Given the epidemiological association between hyperinsulinemia and cardiovascular disease, there have been concerns that sulfonylureas might increase cardiovascular morbidity.¹¹ Cardiac tissues contain KATP channels similar to those in b cells. However, there was no increase in mortality seen in the UKPDS trial.⁹ In addition, the newest member of the sulfonylureas class, glimepiride, binds less strongly in the myocardium and may therefore actually reduce ischemic pre-conditioning.¹²

Rapid-acting Secretagogs
Rapid- or short-acting secretagogs, also known as meglitinides, have a mode of action that is similar to that of the sulfonylureas. By closing the potassium channels of the pancreatic b cells, they open the calcium channels and enhance insulin secretion. They were developed to have a rapid onset and short metabolic half-life, resulting in preferential targeting of post-prandial hyperglycemia and decreased risk for hypoglycemia later on.¹³ This class consists of repaglinide and, more recently, nateglinide, which is a D-phenylalanine derivative and developed to be even shorter-acting. Meglitinides reduce HbA_1c to a similar extent as sulfonylureas (about 1–2%) but require multiple daily doses. In a study involving 576 patients with type 2 diabetes, pharmacotherapy-naïve patients exhibited less weight gain with repaglinide than with sulfonylurea glyburide (2.5 versus 3.6kg, respectively), although treatment-experienced patients did not exhibit this trend.¹⁴ However, meglitinides have not been assessed for their longterm effectiveness in decreasing microvascular or macrovascular risk.

Insulin Sensitizers

Biguanides
Biguanides reduce hepatic glucose output and increase uptake of glucose by the peripheral tissues, including skeletal muscle. Metformin, the only widely available biguanide, acts primarily by reducing glucose production and thus fasting hyperglycemia in the presence of a sufficient amount of insulin. Metformin only became available in the US in 1995, although it had been marketed in Europe for nearly 20 years.¹⁵ Metformin’s mechanism of action is not completely understood, but it is typically classified as an insulin sensitizer.¹⁶ As with the sulfonylureas, biguanides reduce HbA_1c by approximately 1–2%.¹⁷ In contrast to sulfonylurea therapy, metformin monotherapy is associated with weight loss (or little to no weight gain) and a lower incidence of hypoglycemia. In the UKPDS, obese patients randomized to metformin gained only 1–2kg compared with gains of 5–7kg in patients receiving sulfonylurea or insulin treatment.¹⁸ The drug also has non-glycemic benefits, including reducing low-density lipoprotein cholesterol and triglycerides, and reducing the antifibrinolytic factor plasminogen activator inhibitor. In addition, its lack of b-cell stimulation may have consequent positive effects on other cardiovascular risk factors.¹⁹ The most serious complication of biguanide use is lactic acidosis, which can be fatal. Two of the three drugs in this class (phenformin and buformin) were withdrawn in the 1980s owing to this side effect. Fortunately, the incidence of lactic acidosis with metformin use is low (one case per 33,000 patient-years).²⁰ Nevertheless, this concern does restrict metformin use to patients with sufficient renal function to avoid drug accumulation. It is contraindicated in patients with cardiac or respiratory insufficiency or other conditions associated with hypoxia or reduced perfusion, hepatic dysfunction, alcoholism, or a history of metabolic acidosis.

Thiazolidinediones
Introduced in 1997, thiazolidinediones (TZDs, also known as glitazones) bind to peroxisome proliferator-activated receptor gamma (PPARg), a type of nuclear regulatory protein involved in the transcription of genes that regulate glucose and fat metabolism. This class consists of rosiglitazone, pioglitazone, and troglitazone, although the latter was withdrawn in 2000 owing to a risk for hepatitis and liver damage. As with biguanides, the mechanism of action of the thiazolidinediones is not fully understood, but the two classes of drugs are known to work independently of each other.²¹ Neither class stimulates pancreatic islet cells to secrete more insulin. The most prominent effect of TZDs is to increase insulin-stimulated glucose uptake by skeletal muscle cells.²² This results in a reduction in insulin concentrations, often to an even greater extent than with metformin.²³ Preliminary data also suggest that this drug class may actually prolong b-cell survival.²⁴ Unlike other antidiabetic agents, TZDs have a very slow onset of action. Although effects begin to manifest within two weeks of commencing treatment, the maximal benefit is not seen for around three months. When combined with insulin or with sulfonylureas, the onset and peak effect occur more rapidly, perhaps within four weeks.²⁵