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44th Annual Meeting of the European Association for the Study of Diabetes

Rome, Italy / September 6-11, 2008

The highly-targeted dipeptidyl peptidase-4 (DPP-4) inhibitors have been a promising clinical advance both because of their activity and because of the insight they are generating into the pathophysiology of type 2 diabetes mellitus (DM2).

The DPP-4 enzyme rapidly inactivates glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which play critical roles in nutrient metabolism and induction of satiety. Specifically, GLP-1 regulates nutrient assimilation via inhibition of gastric emptying and food intake. It also controls blood glucose following nutrient absorption via stimulation of glucose-dependent insulin secretion, insulin biosynthesis, islet proliferation, and inhibition of glucagon secretion. Unlike GLP-1, which exerts multiple non-incretin activities in the regulation of blood glucose, the primary action of GIP is the stimulation of glucose-dependent insulin secretion but it may also play a role in adipocyte biology. Overall, the major role of incretins is in glucose homeostasis. As a result, by preserving the incretins GLP-1 and GIP, DPP-4 inhibitors generate a long list of favourable downstream effects on the characteristic pathophysiological pathways of diabetes, including impaired ß-cell function. Sitagliptin was the first approved DPP-4 inhibitor, but saxagliptin, which is in development, is one of the leading new DPP-4 inhibitors that are being studied for their potential in combination therapy with other commonly used oral anti-glycemic agents.

“With the new phase III studies combining saxagliptin with standard therapies for type 2 diabetes, we have seen significant improvements in all the key markers for glucose control with very good tolerability,” reported Dr. Anthony Barnett, Professor of Medicine, University of Birmingham, UK. Due to the improved efficacy and safety, he anticipates early use of treatment strategies in which a DPP-4 inhibitor is added to a conventional agent in order to increase the proportion of patients at target HbA1c levels. While studies are ongoing, several DPP-4 inhibitors are moving forward quickly. Trials are ongoing with alogliptin, and vildagliptin has been approved in Europe. In studies with saxagliptin, combination trials have been completed with a sulfonylurea, metformin, and a thiazolidinedione. These studies have been remarkably consistent in demonstrating improved glycemic control with little increase in adverse events, including hypoglycemia. DPP-4 inhibitors are not associated with weight gain.

Results with Metformin

In the phase III metformin study, 1306 patients who were treatment-naive (or who had received less than one month of therapy) were randomized to one of four groups: saxagliptin 10 mg/placebo; metformin 500 mg/placebo; saxagliptin 5 mg/metformin 500 mg; or saxagliptin 10 mg/metformin 500 mg. In all groups receiving metformin, upward titration was permitted to a maximum of 2000 mg daily. The double-blind study was conducted over 24 weeks when the primary end point was change in HbA1c from baseline. Secondary end points included percentage of patients with HbA_1c <u><</u>7%, percentage of patients with HbA_1c <u><</u>6.5%, change in fasting plasma glucose (FPG) and change in postprandial glucose (PPG). An HbA_1c level between 8% and 12% was an entry criterion.

Both monotherapies were active but both of the combinations were significantly better for all measures of glycemic control, including the proportion of patients at either of the defined targets. Critical to the acceptable benefit:risk ratio of pursuing a first-line combination, the tolerability and the rate of hypoglycemia, which was uncommon in all groups, were comparable. The trial provides the basis for predicting that combination therapy is a viable first-line approach. “Not surprisingly, the greatest reductions were achieved in those with the highest baseline HbA^1c, so this appears to be a particularly reasonable approach when the likelihood of getting to goal on a monotherapy is low,” reported a multinational team of investigators that included researchers from the Institute for Clinical Research and Development, Mainz, Germany, and the Department of Nutrition, Durand Hospital, Buenos Aires, Argentina.

In this study, HbA1c levels were reduced from baseline by an average of 2.5% by either combination therapy vs. 1.7% for saxagliptin and 2.0% for metformin when either was administered as monotherapy (P<0.0001 for the combination vs. either monotherapy). Perhaps more importantly for the promise of first-line combination therapy, approximately 60% of patients on either combination achieved an HbA1c of <u><</u>7.0% vs. only 32% of those on saxagliptin and 41% of those on metformin alone (P<0.0001 for the combination vs. either monotherapy). For the more rigorous HbA1c goal of <u><</u>6.5%, >45.3% attained this goal on combination saxagliptin 5 mg plus metformin vs. 20.3% of those receiving saxagliptin alone and 29% for those receiving metformin alone (P<0.0001 for the combination vs. either monotherapy) (Figure 1).

Figure 1. HbA_1c Levels

The reductions in FPG at the end of 24 weeks vs. baseline were also substantially and highly significantly greater (P<0.0001) on either combination (approximately 60 mg/dL [3.33 mmol/L]) than on saxagliptin (31 mg/dL) or metformin (47 mg/dL). The difference in PPG favouring the combination was of a similar magnitude. At 120 min during an oral glucose tolerance test (OGTT), the reductions were 137 mg/dL for both of the combinations, 106 mg/dL for saxagliptin alone and 97 mg/dL for metformin alone (P<0.0001 for either combination vs. metformin alone). In the group with a baseline HbA_1c >10%, which represented nearly 25% of the study population, the average reduction in HbA_1c was 3.3% on the combination vs. 2.5% on saxagliptin and 2.7% on metformin. When the patient population was stratified by several characteristics, such as age, gender or duration of diabetes, the combination was consistently more efficacious.

The only adverse events that occurred in >5% of patients was nasopharyngitis, diarrhea, headache and hypertension, but the degree to which these were treatment-related is unclear. The incidence was similar in all four of the treatment arms with no trends observed. Hypoglycemia was an uncommon event in all treatments: the rates were 3.4% on the low-dose combination, 5% on the high-dose combination, 1.5% on saxagliptin monotherapy and 4% on metformin alone. These differences were not significant. There were modest body weight reductions in all groups, ranging from 1.1 kg on saxagliptin monotherapy to 1.8 kg on the low-dose combination, but also without intergroup statistical differences.

DPP-4 Inhibition and Sulfonylurea Combination Strategies

These results provide a proof of principle for early use of DPP-4 inhibitors with other first-line therapies and were reinforced by two other phase III studies with similar designs and outcomes. In each of these studies, which are part of a clinical trial programme that has randomized more than 4000 patients to a saxagliptin arm, the high degree of tolerability has been a consistent feature. In the phase III sulfonylurea study, 768 patients were initiated on open-label glyburide at a dose of 7.5 mg and then randomized to receive saxagliptin 2.5 mg, saxagliptin 5 mg or an addition of glyburide 2.5 mg. After randomization, uptitration of glyburide was allowed in the glyburide-only arm to a maximum of 15 mg. The primary end point was change in HbA_1c from baseline. Secondary end points included decreases in FPG and PPG. At baseline, the average HbA_1c was 8.4% and the mean FPG was 173 mg/dL (9.90 mmol/L). As is typical for treatment studies of diabetes, the average age was 55 years.

By the end of the study, 92% of those in the glyburide-only arm had been titrated up to the full dose of 15 mg/day. Despite this dose, both of the combination arms with saxagliptin were associated with significantly greater reductions in HbA_1c. These were 0.54% for the 2.5-mg dose, 0.64% for the 5-mg dose and 0.08% for the glyburide-only group (P<0.0001 for either combination vs. glyburide alone). FPG was reduced by 7.1 mg/dL (0.39 mmol/L) and 9.7 mg/dL (0.54 mmol/L) in the low- and high-dose saxagliptin arms, respectively, but increased by 0.7 mg/dL (0.04 mmol/L) in the placebo arm (P=0.02 for the lower dose of saxagliptin and P=0.002 for the higher dose of saxagliptin vs. glyburide alone). The differences in PPG were also highly statistically significant, favouring either combination over glyburide alone. At 120 min during an OGTT, these were reduced by 30.9 mg/dL for the lower dose of saxagliptin and by 34.2 mg/dL for the higher dose but increased by 7.6 mg/dL on glyburide alone (differences between both doses of saxagliptin and glyburide P<0.0001).

For the clinician, the most important result is the proportion of patients at target. In this study, this result was expressed as the proportion of patients discontinuing therapy due to failure to maintain an HbA_1c <7%. While the discontinuation rates for this reason were 18.1% on the low dose of saxagliptin and 16.6% on the higher dose, the rate was 29.6% on glyburide alone. Again, the addition of saxagliptin was not associated with statistically significant increases in the rate of adverse events, which were low in all groups. Those that occurred in >5% of patients included urinary tract infections, headache, nasopharyngitis, upper respiratory tract infection and diarrhea. Hypoglycemia was reported by 13.3% of those on the low-dose combination, 14.6% of those on the high-dose combination and 10% of those on uptitrated glyburide. These differences were not statistically significant. “These results demonstrate that the addition of saxagliptin to moderate-dose sulfonylurea improved glycemic control without introducing any additional safety or tolerability concerns, including hypoglycemia, compared to uptitration of glyburide monotherapy,” reported this team of investigators, which included those from the Universidade Federal de São Paulo, Brazil, and Cebu Doctors’ University Hospital, Cebu City, Philippines.

DPP-4 Inhibition and Thiazolidinedione Combination Strategies

In the third of this series of studies, 565 patients with DM2 who had already been initiated and maintained on a stable dose of a thiazolidinedione (pioglitazone 30 or 45 mg or rosiglitazone 4 or 8 mg) but were not adequately controlled (>7.0% HbA_1c) were randomized to receive saxagliptin 2.5 mg, saxagliptin 5 mg or placebo. As in the other studies, the mean age of patients was approximately 54 years. The mean baseline HbA_1c was 8.3% and the mean FPG was 161.8 mg/dL (9.0 mmol/L). The addition of saxagliptin 2.5 mg lowered the HbA_1c by 0.66% from baseline (P=0.0007) while the 5-mg dose of saxagliptin reduced it by 0.94% (P<0.0001 vs. baseline). There was a 0.3% increase in HbA_1c in the placebo group over the 24 weeks of the study. FPG levels were reduced from baseline by 14.3 mg/dL (0.79 mmol/L) in the saxagliptin 2.5-mg group, 17.3 mg/dL (0.96 mmol/L) in the saxagliptin 5-mg group and by 2.8 mg/dL (0.15 mmol/L) in the placebo cohort (P<0.0001 vs. baseline for either combination but not significant for placebo).

The adjusted mean change from baseline PPG at 120 min during an OGTT was reduced by a mean of 54.7 mg/dL in the 2.5 mg saxagliptin group, 64.6 mg/dL in the 5 mg saxagliptin group but only by 14.6 mg/dL in the placebo group (P<0.0001 for either dose of saxagliptin vs. placebo). Again, from the clinical perspective, the proportion of patients at a goal HbA_1c of <7% was increased by approximately 60% with the addition of either dose of saxagliptin when compared to the stable dose of thiazolidinedione plus placebo (42% in both saxagliptin groups vs. 26% in the placebo group). Also, as in the trials with metformin and a sulfonylurea, there were no significant differences in the rate of adverse events, the discontinuations due to adverse events or in the rate of hypoglycemia (4.1%, 2.7% and 3.8% for the saxagliptin 2.5 mg, saxagliptin 5 mg and placebo arms, respectively).

In smaller studies, alogliptin also generated evidence of encouraging efficacy and tolerability when combined with common first-line agents. In a study of 363 patients on the sulfonylurea glyburide who were evaluated after being randomized to alogliptin 12.5 mg, alogliptin 25 mg or placebo, the proportions of patients who achieved <u>></u>1% reduction in HbA1c were 28.6% in the 12.5-mg group, 30% in the 25-mg group and 8.7% in the placebo group (P<0.001 for either dose of alogliptin vs. placebo). As in the studies with saxagliptin, rates of adverse events and hypoglycemia did not differ between those who received the DPP-4 inhibitor and those who received placebo. In another study of 372 patients, the same doses of alogliptin or placebo were combined with pioglitazone. Again, mean reductions in HbA_1c were significantly greater (P<0.001) for either dose of alogliptin (0.66% and 0.80%, respectively) vs. 0.19% for placebo. There were no significant differences in adverse events, hypoglycemia or weight gain.

ß-cell Function

The efficacy and safety of DPP-4 inhibitors in combination regimens are encouraging because DPP-4 inhibition has been associated with fundamental improvements in ß-cell biology, including restoration of ß-cell mass, according to Dr. Juris J. Meier, Department of Medicine, St. Josef Hospital, Ruhr University, Bochum, Germany. “In human studies, DPP-4 inhibitors clearly improve glycemic control, but the experimental studies suggest that the mechanism may not just improve glucose metabolism but act on disease pathophysiology,” Dr. Meier explained. “In animals, DPP-4 inhibitors improve glucose intolerance, insulin secretion and insulin sensitivity, but they also prevent ß-cell destruction and increase ß-cell regeneration.” Although Dr. Meier cautioned that the regeneration in ß-cell mass is slow and has not yet been demonstrated in humans, he indicated that DPP-4 inhibitor therapies might be unlike previous options for anti-diabetic treatment because of their ability to treat the disease rather than the symptoms.

“GLP-1 and GIP are implicated in activation of pathways that promote ß-cell proliferation and inhibit ß-cell apoptosis. GLP-1 has also been implicated in endocrine cell differentiation, enhanced glucose sensitivity, inhibition of excess alpha-cell glucagon secretion and induction of pro-insulin gene expression,” Dr. Meier told delegates. He indicated that the activity of these agents on “ß-cell function may have long-term therapeutic benefits in the treatment of DM2,” which not only includes prolonged control but also inhibition of disease progression.

Summary

The introduction of DPP-4 inhibitors has provided an important additional therapeutic option for improving glycemic control in DM2. In a series of phase III studies, the addition of the developmental DPP-4 inhibitor saxagliptin to metformin, a sulfonylurea, or a thiazolidinedione significantly improved all tested measures of glycemic control without significantly increasing the rate of adverse events, including the incidence of hypoglycemia. These agents are not associated with any significant metabolic disturbances and are weight-neutral. Most promising for clinical application, the addition of a DPP-4 inhibitor significantly increased the proportion of patients at glycemic targets, whether defined as a HbA1c of <u><</u>7.0% or <u><</u>6.5%. In the context of good tolerability, this advantage is important because of the difficulty of achieving tight glycemic control with current monotherapies. Increasing the proportion of patients at evidence-based targets has major implications for reducing the long-term complications of DM2.

Note: At the time of printing, alogliptin, saxagliptin and vildagliptin are not approved for use in Canada.