Lifestyle advice and insulin therapy were the only treatments available for type 2 diabetes in the first half of the 20th century, and sulfonylurea derivatives and metformin were added in the second half. While these four therapies still form the mainstay of treatment today, the last decades have been hallmarked by the rapid development of new glucose-lowering therapies based on increasing insight into the pathophysiological mechanisms involved in type 2 diabetes. However, our comprehension of the type 2 diabetes syndrome is still incomplete, and increasingly stringent oversight by agencies such as the FDA and EMA has demanded that the long-term benefits of these novel drugs are demonstrated in clinical studies. Unfortunately, in this respect some of these classes of drugs still have to prove themselves (such as the incretins and the SGLT2 inhibitors), whereas others have more or less failed to do so (such as acarbose and the thiazolidinediones).
The biguanides: metformin
One of the oldest oral agents available, metformin lowers hepatic glucose production and improves insulin sensitivity. With few side-effects apart from gastro-intestinal upset and excellent long-term outcomes (which include a 30% lowering of all-cause mortality and a possible reduction in the occurrence of cancer) this is drug of first choice for all those with type 2 diabetes.
The sulfonylurea derivatives (SU's) and meglinitides
While the sulfonylurea derivatives have some side-effects, notably some hypoglycaemia and weight gain, their long-term safety data are actually quite reassuring. These drugs are highly efficacious at lowering glucose in the initial stages of type 2 diabetes through their insulin-secretory effects on the beta-cell. Moreover, they have demonstrated their ability to affect long-term outcomes in the UKPDS study. The meglinitides are a variant of this concept, but have not demonstrated any clear benefit over the conventional SU's.
By inhibiting alfa-glucosidase, the intestinal degradation of complex carbohydrates is delayed and as a result post-prandial glucose absorption is prolonged and postprandial glucose excursions are lowered. While the alfa-glucosidase inhibitors are efficacious in lowering glucose and HbA1c, a recent Cochrane analysis found no demonstrable beneficial effect on long-term outcomes. Moreover, severe gastrointestinal side-effects (notably flatulence) have limited their use in most populations.
Thought to be agonists of the Peroxisome Proliferator Activated Receptor-gamma (PPAR-gamma), a promotor-region of many genes, the myriad of effects of the TZD's is still incompletely understood. Their principal action of increasing peripheral insulin sensitivity is probably related to their effects on adipocyte (stem cell) differentiation; but the same effect probably underpins the increase in fractures associated with their use. While all TZD's are efficacious at lowering glucose and glycaemia, the first TZD clinically used (troglitazone) was withdrawn because of severe hepatotoxicity, and the second (rosiglitazone) was withdrawn from the European market after serious concerns arose about its cardiovascular safety. The evidence for long-term beneficial effects for the only TZD still marketed, pioglitazone, is scarce, and recent concerns about an association with bladder cancer, added to the known side-effects of fluid retention, heart-failure and increased fracture-risk have greatly diminished the attractivity of this drug-class in the last few years.
Incretin-based therapy: GLP-1 analogues and DPP-4 inhibitors
The incretins are intestinal hormones, notably Glucagon-Like Peptide-1 (GLP-1) and Glucose-dependent Insulinotropic Polypeptide (GIP) that affect glucose-metabolism in several ways, principally through a glucose-dependent increase in insulin secretion (hence the name 'incretin'). The discovery of the incretin pathways has led to the development of two classes of drugs. The GLP-1 analogues aim to mimick/surpass the effects of the naturally occurring GLP-1. The Di-Peptidyl-Peptidase-4 (DPP-4) inhibitors inhibit the degradation of endogenous GLP-1, thus increasing the incretin effect. Both classes of drugs are registered for clinical use. The GLP-1 analogues are quite efficacious at lowering glycaemia with the added benefit of some weight loss, whereas the DPP-4 inhibitors are more or less weight-neutral and have a more modest effect on glycaemia. The principal side effects of the GLP-1 analogues are nausea and vomiting, and side-effects for the DPP-4 inhibitors seem limited. However, long-term data regarding safety and hard outcomes (such as mortality or complications) are still lacking.
By blocking the Sodium GLucose Transporter 2, which is located in the renal tubular system, the SGLT2-inhibitors block the reabsorption of glucose and increase glucosuria. This is responsible for their modest glucose-lowering effect. However, long-term data regarding their efficacy and safety are lacking. Marketing of the first in this class, dapagliflozin, was stalled by the FDA because there are some concerns regarding side-effects: an increase in urinary tract infections but more worryingly a possible increase in bladder cancer.
Figure 1. The growing global diabetes market. Adapted from Hauber A. Diabetologia 2006;49:247-52.
Drugs in development
The global diabetes market is huge, and hence an attractive target for drug development and the pharmaceutical industry (fig. 1). Thus, an increasing number of pathophysiological routes is explored to come to useful drugs. Most, however, have yet to enter the clinical stage and their future is uncertain.