Incretin-acting drugs in Type 2 Diabetes Mellitus

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Incretin-acting drugs in Type 2 Diabetes Mellitus

Type 2 Diabetes Mellitus (T2DM) is an epidemic and alarming metabolic disorder. The Centers for Disease Control and Prevention (CDC) estimated that in 2005 the prevalence of diabetes in the United States was 20.8 million. Diabetes is diagnosed in 14.6 million persons and undiagnosed in 6.2 million. T2DM is 90% to 95% of prevalent diabetes. About 41 million people in the United States are believed to have pre-diabetes.
The main etiologic pathways of T2DM are insulin resistance and lack of compensatory insulin secretion. Insulin resistance is usually longstanding and begins at a young age because of heredity combined with environmental factors (sedentary lifestyle and calorie overconsumption leading to overweight). Longstanding insulin resistance is associated with dyslipidemia, central obesity, hypertension, and hyperglycemia. Thus, it is very frequent the coexistence of cardiovascular disease and T2DM.
Treatment of T2DM involves diet, exercise, education, and almost always, drugs too. Eventually, most patients with T2DM require drug treatment, often with multiple drugs (combination therapy). Progressive insulin secretory loss seems to be the main reason for the general treatment rule �add new drug(s), don't switch them�. The pharmacologic options for the treatment of T2DM have become more complex and confusing since the introduction of several new drugs and arising new data about the safety and efficacy of older drugs.

Incretin-acting drugs correspond to the newest big class of anti-diabetic drugs approved for treatment of T2DM. Glucagon-like peptide 1 (GLP-1) receptor agonists (a.k.a. �Incretin Mimetics� subclass), are prototyped by exenatide; and dipeptidyl-peptidase-4 (DPP-4) inhibitors include sitagliptin and vildagliptin as reference. This drugs act on the �Incretin System�, potentiating physiologic incretin�s actions [Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006;368:1696-1705]. Some other similar drugs - have been (or currently yet are) under clinical trials and may be available in a near future; for example � liraglutide - a GLP-1 analog which is being developed by Novo Nordisk, and is now under phase III clinical trials (http://www.novonordisk.com/investors/rd_pipeline/rd_pipeline.asp?showid=4).
Exenatide (like GLP-1) lowers glycemia by stimulating insulin secretion and inhibiting glucagon secretion. It also appears to inhibit gastric emptying and enhance satiety, leading to weight loss in many patients. It can have important gastro-intestinal (GI) side effects such as nausea, vomiting, and diarrhea. Despite this, many patients like it, maybe because side effects usually will decrease within weeks and there can happen significant weight loss in very overweight patients. Characteristically, exenatide is given in doses of 5 μg twice daily at meals, advancing after a month to 10 μg twice daily. Patients may tell that nausea is more tolerable if they have a little food in their stomach at the time of dosing. Since incretin-acting drugs all have a glucose-dependent insulin secretion and glucagon suppression, there is a lower risk of hypoglycemia while using this drugs alone or when they are combined with metformin and/or thiazolidinediones (the �glitazones� in medical slang - rosiglitazone and pioglitazone). HbA1c lowering with exenatide has been 0.9 to 1.1 percentage points.

Dipeptidyl-peptidase-4 (DPP-4) is the peptidase which normally degrades incretins to inactive products. Inhibitors of DPP-4 (sitagliptin and vildagliptin) enhance GLP-1 and GIP levels to high physiologic levels and thereby reduce HbA1c concentrations, ordinarily about 0.6 to 0.8 percentage points. Because both DPP-4 inhibitors are oral, they may be preferred to the injectable exenatide. The side effects for these drugs (sitagliptin and vildagliptin) are relatively minor and cause little nausea, vomiting, or diarrhea. They also do not cause significant weight loss (like metformin, they seem to be weight neutral).

JAMA (Journal of American Medical Association) published a meta-analysis of clinical trials involving incretin-acting therapies, which concluded that the efficacy of these agents was generally similar to that of other (cheaper, older and better known) anti-diabetes therapies. On the other hand, money (�the nightmare of everybody�) is an important factor to consider - incretin-acting drugs are very expensive� In some specific cases, these newer drugs are very useful, but many times it is pertinent to ask � �why pay more for the same efficacy?�...

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