New medications for diabetes mellitus

Two modern-day epidemics, HIVAIDS and type 2 diabetes mellitus, have inspired impassioned calls for more effective interventions. In the 1980s, the rapid spread of HIV, with its associated severe, acute illness and high mortality, prompted activist groups and others to call for the accelerated approval of medications that showed promise of efficacy. There was no treatment available, and people were dying quickly. More recently, pressure to develop new drugs for type 2 diabetes has been stimulated by the remarkable worldwide increase in the incidence of this disease (54% in the past 7 years in the United States1) and the recognition that intensive glycemic control is highly effective in reducing the development and progression of its long-term complications. Of course, type 2 diabetes today differs from HIVAIDS in the 1980s in at least two relevant ways: it is already treatable with fairly safe and effective agents and interventions, and it is a chronic illness, not a swiftly fatal one. Thus, patients who adhere to the current treatments for diabetes can live quite a long time, during which they may be subject to the adverse effects of any new medications they receive; this makes the riskbenefit equation dramatically different from that for the early AIDS drugs. The pace of the development of new medications for diabetes may seem frustratingly slow to patients, but it has arguably never been faster. Nine classes of medications are now available for the treatment of type 2 diabetes, as compared with four barely a decade ago (see table)

Approved Antidiabetes Medications in the United States.). Although the Food and Drug Administration (FDA) has been criticized for being too slow in approving new medications, it has also been accused of being haphazard in its approvals. The history of troglitazone the first thiazolidinedione to be approved, only to be withdrawn 2 years later because of severe hepatotoxicity should serve as a cautionary tale. With more than 30 available medications that can be used either as monotherapy or in numerous combinations, it is fair to ask how many drugs are necessary to combat the epidemic of type 2 diabetes, and at what cost. In theory, newer classes of antidiabetes medications might be welcome additions to the existing armamentarium; however, those that have been developed recently are generally no more potent,

and often less effective in lowering glycemia, than the three oldest classes (insulin, the sulfonylureas, and the biguanides), all of which are more than 50 years old (seetable). Moreover, the newer classes are uniformly more expensive and are associated with adverse effects some that are shared by the older drugs, but others that are new. Ironically, the two oral antidiabetes medicines that are most effective in lowering glycemia are also the oldest and were discovered accidentally, without the benefit of our contemporary understanding of their mechanisms of action or of the pathophysiology of type 2 diabetes. They were also discovered without highthroughput screening and other drug-development tools that we now have at our disposal. With the approval of sitagliptin (Januvia, Merck) on October 17, 2006, and the pending approval of vildagliptin (Galvus, Novartis), we now have a ninth class of antidiabetes medications. The concept behind these dipeptidyl peptidase IV (DPP-IV) inhibitors, known as the gliptins, derives from the recognition that glucagon-like peptide (GLP) 1,7-37 a naturally occurring gastrointestinal peptide that stimulates insulin secretion, suppresses glucagon levels, and slows gastric emptying is rapidly inactivated by DPP-IV. Given that the main therapeutic effectiveness of the gliptins is mediated by their ability to increase levels of GLP, which is not a very effective glucose-lowering agent, it is not surprising that these agents are relatively ineffective in lowering glycated hemoglobin levels. Moreover, although they have been developed to be relatively specific for the GLP substrate and not to increase the levels of the many other DPP-IV substrates, none of them is so selective as to preclude alteration of the other substrates, including proteins involved in immunity and other hormones. The potential for unexpected consequences thus remains relatively high. What is surprising is that despite these concerns and limitations, and despite the paucity of published data from long-term clinical trials on its efficacy and safety, sitagliptin was approved

by the FDA. At the time of its approval, there was only one published, peer-reviewed, moderately large clinical trial; it included 392 treated patients who were followed for 18 weeks to judge the efficacy and safety of the drug.2 Results of three other clinical trials were published within 1 month after the approval. The 24-week trials included a monotherapy study involving 467 treated patients, a study of sitagliptin added to pioglitazone therapy in 175 patients, and a study in which sitagliptin was added to metformin therapy in 453 patients.3-5 All the studies were placebo-controlled, and in all of them, sitagliptin achieved a reduction in the glycated hemoglobin value of 0.5 to 0.9 percentage point as compared with placebo. Such results indicate that sitagliptin is one of the less effective glycemia-lowering drugs introduced in recent years. Moreover, the drug has no obvious extraglycemic benefits. The GLP analogues, for example, are associated with some weight loss, whereas sitagliptin does not appear to affect weight. Although sitagliptin seems relatively safe, causing no increase in severe adverse events, the published data reflect testing in only a limited number of patients for a limited period (641 patient-years in total). Since nearly 20 million people in the United States have type 2 diabetes, there is potential for extensive use of new diabetes medications. For example, within 1 year after the approval of troglitazone in 1997, an estimated 600,000 U.S. patients were receiving it. Although severe hepatotoxicity had not been identified in preliminary testing in about 5000 people, cases of severe idiosyncratic liver disease began to appear within 6 months after approval, ultimately reaching a prevalence of approximately 1 in 15,000 patients who were receiving the drug. In the first 6 weeks after the approval of sitagliptin, business reports suggested that it accounted for 14% of new prescriptions for antidiabetes medications. The criteria that the FDA uses in approving antidiabetes medications are based primarily on safety and on effectiveness in lowering glycated hemoglobin levels. Considering the potential for

unanticipated adverse events, especially with medications that have as many biochemical effects as the DPP-IV inhibitors, and the plethora of antidiabetes medications that are currently available, many of which are more effective than sitagliptin, one wonders: why the rush to approve the gliptins? The ability of clinicians to judge the merits of new medications is already limited most receive their information about them from drug companies' representatives and promotional materials. The dearth of peer-reviewed, published studies on sitagliptin makes it difficult for physicians to weigh the benefits and risks of the medication or to describe them to their patients. No one wants to slow the development of effective new drugs, especially for a disease with a prevalence that is reaching epidemic proportions. However, the FDA's approval process for new antidiabetes medications should take into account their additional and unique contributions, especially when their glucose-lowering efficacy is similar to or less than that of currently available medications. A host of medications that are already available are effective as monotherapy or in combination with metformin or one of the thiazolidinediones (the approved uses of sitagliptin). The fact that these medications achieve better glycemic control than sitagliptin suggests the need for caution in approving a new medication that has received limited testing. The failure of clinicians and their patients with diabetes to implement currently available interventions aggressively and effectively is, I suspect, the major barrier to good care. This problem will not be fixed by making more medications available. Ensuring the effective and cost-effective use of the medications that have already been established by high-quality clinical trials to control glycemia or prevent diabetes should be a higher priority than flooding the market with ever more medications.