The pathophysiology of type 2 diabetes mellitus (T2DM) involves insulin resistance, beta cell failure and incretin defect and is known to be a progressive disease caused by progressive beta cell failure.1 While ideal therapy would stop beta cell failure or regenerate new beta cells, we currently do not have clinically proven effective therapies for this purpose. Therefore, in a particular patient, more and more drugs are often required over time to maintain glycemic control.
In previous years, algorithms had been developed to intensify drug treatment in a step-wise manner. However, over the last two to three years, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) have moved away from a standardized approach to drug treatment for T2DM. In the position statement, issued jointly by the ADA and EASD in 2012 and reviewed in this issue, a patient-centered approach was advocated. The current guidelines recommend that when selecting drug therapy, individual patient characteristics like age, body weight, comorbidities, and patient preferences should be taken into account.
Because most patients with T2DM are obese, weight loss is one of the goals when making a drug choice for treatment of T2DM. Weight loss helps control diabetes with fewer drugs and improves the cardiovascular metabolic profile. Common drugs used to treat T2DM, for example sulfonylureas and insulin, cause weight gain. Among the newer therapies, most agents are weight-neutral or cause only a small amount of weight loss. GLP-1 agonists are associated with the most weight reduction among antihyperglycemic agents currently available for T2DM. In a meta-analysis by Vilsbøll et al (reviewed in this issue), patients receiving GLP-1 agonists achieved a greater weight loss (about 3 kg) than those in the control groups. This meta-analysis provides evidence that treatment with GLP-1 agonists is consistently associated with weight loss. Therefore, GLP-1 agonists are an attractive choice for most of the obese T2DM patients. Moreover, these agents do not cause hypoglycemia, which may be an additional advantage in some patients with comorbidities.
In addition to their weight loss effect, some evidence suggests that GLP-1 agonists may have a more positive effect on beta cell function as compared to other drugs.2 In a large, randomized, controlled trial reviewed in this issue, Gallwitz et al showed that exenatide was not only more effective in lowering HbA1c levels, but the effect was more sustained than with glimepiride. Although this study does not prove the beta cell protective effect of GLP-1 agonists, because early sulfonylurea failure is known from other studies,3 it does suggest a role of for GLP-1 agonists early in the course of T2DM. Although sulfonylureas like glyburide, glipizide and glimepiride are still the most commonly used second-line drugs after metformin failure, the results of this study suggest that in patients inadequately controlled by metformin alone, using GLP-1 agonists as the second-line agents may be better than using a sulfonylurea drug. However, because they are injected, GLP-1 agonists may not be easily acceptable to patients, as many are unwilling to try injection therapy until they have run out of oral agent choices. Therefore, while there may be advantages to early initiation, GLP-1 agonists may be more appropriately recommended when insulin therapy is being considered.
Because of progressive beta cell failure, oral agents become ineffective over time, and most patients with T2DM eventually require injection therapy. The choice of drug at that point is a GLP-1 agonist or basal insulin. Numerous studies have compared GLP-1 agonists with basal insulin and found equal HbA1c reduction with both agents; however, GLP-1 agonists provide the additional advantages of weight loss and lower risk of hypoglycemia.4 The 2014 clinical trial by Diamant et al, reviewed in this issue, investigated the durability of the effect of GLP-1 agonists versus basal insulin. In this trial, exenatide once weekly was compared with insulin glargine as the first injectable therapy for patients who were on maximum doses of metformin with or without a sulfonylurea drug. The study showed that exenatide was at least as effective as basal insulin, and the effect was sustained over three years. Thus, GLP-1 agonists could be a viable long-term, injectable treatment option in patients with T2DM who have not yet started taking insulin.
Another important milestone in the natural history of T2DM is the requirement for multiple insulin injections daily. When basal insulin alone becomes inadequate, the addition of nutritional insulin becomes necessary to control blood glucose levels. Many diabetes experts over the years have been using GLP-1 agonists along with basal insulin to delay starting nutritional insulin.5 Use of nutritional insulin is not only unpleasant because of the need for multiple daily injections but is also associated with additional weight gain and a higher risk of hypoglycemia. In the clinical trial by Rosenstock et al, albiglutide once weekly was compared with three-times-daily insulin lispro as an add-on to once-daily insulin glargine. At week 26, the decrease in HbA1c was greater with albiglutide than with insulin lispro, showing that weekly albiglutide was at least as effective as nutritional insulin in improving glycemic control. Thus, GLP-1 agonists may offer a simpler therapeutic option than thrice-daily nutritional insulin when multiple daily insulin injections become necessary. In this context, a GLP-1 agonist may be added to a treatment regimen that already includes basal insulin, or basal insulin may be added to a regimen that already includes a GLP-1 agonist.
In spite of their distinct advantages described above, GLP-1 agonists have received adverse publicity in recent times because of concerns about an association between GLP-1 agonists and pancreatitis and pancreatic cancer. This concern was raised by basic research studies and supported by case reports and observational data.6 In view of the anxiety among providers and patients, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) both conducted comprehensive evaluations of the safety of GLP-1 agonist agents. Both agencies looked extensively at the basic and clinical research data, and FDA conducted its own toxicology studies. They found no evidence of a causal relationship between incretin-based drugs and pancreatitis or pancreatic cancer. Though the FDA and the EMA have not reached a final conclusion and are continuing their surveillance, their extensive review provides reassurance about the safety of these drugs. The vigilance and strict scrutiny received by these drugs should provide confidence that any adverse effects, however minor, will be detected early and made public.
Overall, the evidence at the current time favors more frequent and early use of GLP-1 agonists, particularly in obese patients with T2DM.
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