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68th Scientific Sessions of the American Diabetes Association

San Francisco, California / June 6-10, 2008

Advances in the understanding of signalling systems involved in the interplay between the gut and the pancreas has generated two new drug classes for the treatment of type 2 diabetes. Both promote the activity of glucagon-like peptide-1 (GLP-1), a hormone released from the gut that stimulates insulin release from the ß cell. A GLP-1 mimetic, exenatide, provided an initial strategy to act on this target but it requires injection, which is a significant limitation for type 2 diabetes patients at an early stage of their disease when insulin is not required. The first oral alternative, sitagliptin, inhibits the enzyme depeptidyl peptidase-4 (DPP-4), which rapidly degrades GLP-1. The efficacy of both types of agents is well established by the studies leading to their use, but the newer data suggesting that these agents may be protective of the ß-cell has switched the orientation about where they may be included in a treatment algorithm.

“Now we have seven choices of classes of medications to treat patients who are failing on metformin alone. What might be the reason to use them in clinical practice? I find the most convincing reason based on the evidence to date is that in combination, metformin and a DPP-4 inhibitor preserve the advantages of metformin. They do not produce hypoglycemia and there is no weight gain expected from the combination,” stated Dr. Michael A. Nauck, Diabetes Center, Bad Lauterberg, Germany.

The new data build on the efficacy studies. In one of the phase III studies, which compared the combination of sitagliptin and metformin to metformin monotherapy, 66% of those on the combination achieved the end point of an HbA1c level <7.0% vs. 38% of those on metformin alone (P<0.001). In a study comparing sitagliptin to the sulfonylurea glipizide when both were combined with metformin, the mean HbA1c rates over time could be nearly superimposed when graphed. In both groups, the average HbA1c remained <7.0% at the end of 52 weeks, but those on the sulfonylurea were on average 2.5 kg heavier than those on sitagliptin (P<0.001). Moreover, the rates of hypoglycemia were 32% and 4.9% (P<0.001), favouring the arm with sitagliptin.

Effects of DPP-4 Inhibition on the ß Cell

These rates of efficacy are important, but the potential effects of DPP-4 inhibitors on the ß cell may be more significant for extended glucose control and even for patient outcome. The differences in how incretins and sulfonylureas stimulate the ß cell differ profoundly. Rather than the chronic stimulation associated with sulfonylureas, which some researchers have speculated leads to ß-cell exhaustion over time, the ß-cell stimulation produced by incretins is physiological, producing a correlation between ß-cell insulin release and glucose level. There are increasing data, including those presented here this week at the ADA, that suggest greater ß-cell responsiveness after treatment with DPP-4 inhibitors for periods of up to 24 weeks.

In a re-analysis of data from phase III studies of sitagliptin, which associated sitagliptin with improvement in ß-cell function as measured by homeostasis model assessment ß-cell function (HOMA-ß), proinsulin:insulin ratio and insulogenic measures, the greatest improvements were in those with the greatest baseline ß-cell dysfunction after adjusting for baseline HbA1c levels. In another analysis of the phase III data, the sitagliptin/metformin combination was associated with increases in static and dynamic ß-cell responsiveness relative to metformin alone. The improvement increased when the combination of metformin 2000 mg/sitagliptin 100 mg was compared to metformin 1000 mg/sitagliptin 100 mg.

Another study evaluated a self-selected subset of patients who underwent a frequently sampled meal tolerance test over 54 weeks. Substantial improvements in ß-cell function, as measured with HOMA-ß, were observed with sitagliptin alone and with metformin alone, but the greatest improvements were observed with the combination, which also provided the greatest improvement in HbA1c (Figure 1).

Figure 1. Improvements in ß-cell Function and Glucose Control

The Role of GLP-1

The ability of agents that favourably affect incretins to improve ß-cell function is not unexpected. A series of studies have demonstrated that GLP-1 is involved in numerous signalling pathways important to physiologic ß-cell function. Citing a series of specific experimental studies, Dr. Nauck reported that GLP-1 increases ß-cell neogenesis from islet precursor cells, increases ß-cell replication from mature ß cells and reduces ß-cell apoptosis. Additional studies have associated GLP-1 with an increase in the percentage of islet cells involved in insulin secretion. The studies have been conducted with both incretin mimetics and DPP-4 inhibitors. The results are interesting for what they suggest about chronic treatment regimens and sustained glucose control over time. “If you put this altogether—I am talking about what determines ß cell numbers, the size of the islet cells, the function and the improvement in glucose competence—you end up with up with more actively secreting ß-cell mass, which is what we can measure and clinically test. On all these levels, there is a positive influence of GLP-1,” Dr. Nauck told delegates.

Moreover, GLP-1 appears to be directly linked or responsive to other signalling systems that control gastric motility, appetite and hepatic glucose production. According to Dr. Daniel J. Drucker, Director, Banting and Best Diabetes Centre, University of Toronto, Ontario, there is increasing evidence that DPP-4 inhibitors and incretin mimetics exert their effects by potentiating GLP-1 activation of neural circuits involved in these physiologic processes. He cited studies linking DPP-4 inhibition to decreased glucagon secretion and improved satiety as well as improved ß-cell survival. He suggested that DPP-4 inhibitors may not just be additive but synergistic with selected anti-diabetic agents that increase GLP-1 release. “Some drugs used to treat type 2 diabetes—metformin representing a prime example—may be associated with increased levels of plasma GLP-1, which makes them intriguing candidates for combination therapy with DPP-4 inhibitors,” Dr. Drucker remarked.

Broad effects beyond incretin-associated ß-cell stimulation have been suggested in studies of several DDP-4 inhibitors in development, which includes vildagliptin, alogliptin and saxagliptin. In a study designed to provide insight about the mechanisms by which vildagliptin reduces postprandial glucose excursions, 18 patients with type 2 diabetes were randomized to the DPP-4 inhibitor or placebo. As expected, the active therapy was associated with significant reductions in the postprandial blood spikes, but it also significantly delayed gastric emptying and suppressed glucagon release. Although the relative contribution of these effects to glucose control independent of ß-cell stimulation is still being evaluated, the authors claimed that these secondary effects are likely to be an important contributing factor in preventing postprandial hyperglycemia.

There is evidence that the more physiologic patterns of glucose control with DPP-4 inhibitors are meaningful clinically in regard to both efficacy and safety. In an evaluation of hypoglycemia in the phase III study comparing sitagliptin to glipizide in the presence of metformin, there was an 11-fold reduction in the risk of hypoglycemia for sitagliptin relative to glipizide in patients <65 years but a 29-fold reduction in risk among those over the age of 65.

The difference reflects the higher susceptibility of older patients to hypoglycemia, providing a greater relative advantage for sitagliptin as patients age.

Explained Dr. Jack L. Leahy, Chief, Division of Endocrinology, Diabetes and Metabolism, University of Vermont, Burlington, “A fundamental feature of normal islet cell function is the ability to adapt and compensate for altered metabolic demands. Type 2 diabetes stems, in part, from a failure of this adaptive system. Insulin secretion is defective even before blood glucose values rise above the normal glucose tolerance.” He observed, “By the time prediabetes is present, there is both a loss of the first-phase insulin response to glucose and a 40% reduction in ß-cell mass,” which are findings he indicated encourage fresh strategies such as incretin-based therapies.

This result is consistent with the concept that ß-cell function declines with any form of stress, whether by progressive diabetes, chronic stimulation by sulfonylureas or age. The movement toward DPP-4 inhibitors stems not only from efficacy in clinical trials but the potential of ß-cell preservation.

Summary

Compounds that act on the incretin system permit a highly physiologic approach to the treatment of type 2 diabetes. Unlike sulfonylureas, these agents permit meal-stimulated insulin secretion and appear to preserve ß-cell function. Activities on other related signalling systems, such as gastric motility, appetite and metabolism, may also contribute to incretin-induced glucose control. Based on relative preservation of ß-cell function, available agents such as sitagliptin, which improve incretin function, are considered to be suitable for early use, particularly in combination with metformin.