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What is Saxagliptin’s Place in Therapy?

New DPP-4 Inhibitor Approved
On July 31, 2009 the Food and Drug Administration (FDA) approved saxagliptin (Onglyza), a dipeptidyl peptidase-4 (DPP-4) inhibitor as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.¹ Saxagliptin is only the second DPP-4 inhibitor to reach the U.S. market, joining sitagliptin (Januvia), which was approved in October 2006. Vitagliptin (Galvus), a compound developed by Novartis, never reached the U.S. market because of safety concerns that the drug caused serious skin reactions and kidney adverse events. Alogliptin, a compound developed by Takeda, was to be FDA approved this year; however, FDA is requiring the manufacturer to conduct additional studies assessing alogliptin’s cardiovascular risks.

By inhibiting DPP-4, saxagliptin blocks the rapid inactivation of incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).² These incretin hormones are secreted from the gastrointestinal tract in response to a meal and bind to pancreatic β-cells resulting in insulin secretion. In addition, data have shown that incretin hormones are also β-cell protective by increasing differentiation and proliferation and reducing apoptosis.³ Glucagon-like peptide-1 also produces glucose-dependent suppression of glucagon secretion and slows gastric emptying; it appears to be responsible for most of the incretin effect on the β-cell.² Patients with type 2 diabetes have reduced levels of incretin hormones. A review of available efficacy and safety data with saxagliptin and a discussion highlighting its place in therapy will be presented below.

Phase 3 Efficacy and Safety Data
Six, randomized, double-blind, placebo-controlled, 24-week, Phase 3 studies involving more than 4000 patients with type 2 diabetes have been conducted with saxagliptin; 4 studies have been published in peer reviewed journals as of August 2009.^1,4-7 Two studies evaluated the efficacy and safety of saxagliptin given as monotherapy, 2 studies evaluated the use of saxagliptin plus metformin, 1 study assessed saxagliptin plus glyburide, and 1 study evaluated saxagliptin plus pioglitazone or rosiglitazone.

Monotherapy
Rosenstock and colleagues evaluated the efficacy and safety of saxagliptin given as monotherapy to treatment-naive patients who were inadequately controlled on diet and exercise alone.⁴ A total of 401 patients with a baseline mean glycosylated hemoglobin A1C (HbA1C) of 7.9% were randomized to saxagliptin 2.5 mg/day (n = 100), 5 mg/day (n = 106), 10 mg/day (n = 98), or placebo (n = 95) for 24 weeks. Treatment with saxagliptin resulted in statistically significant decreases in adjusted mean HbA1C changes from baseline compared to placebo. Reductions in HbA1C were -0.43% for the 2.5 mg/day, -0.46% for the 5 mg/day, and -0.54% for the 10 mg/day doses compared to +0.19% for the placebo group (p<0.0001 for all comparisons). In addition, adjusted mean fasting plasma glucose (FPG) was significantly reduced from baseline for saxagliptin 2.5 mg/day (-15 mg/dL, p=0.0002), 5 mg/day (-9 mg/dL, p=0.0074), and 10 mg/day (-17 mg/dL, p<0.0001) compared to a rise in the placebo group (+6 mg/dL). More patients treated with saxagliptin achieved HbA1C levels of < 7% (35% for 2.5 mg/day [p=NS], 38% for 5 mg/day [p=0.0443], 41% for 10 mg/day [p=0.0133]) compared to the placebo group (24%). The frequency of adverse events was similar across all 3 treatment groups. No cases of confirmed hypoglycemia, defined as a fingerstick glucose of ≤ 50 mg/dL, were observed in any patients, and saxagliptin was not associated with weight gain.

The second monotherapy trial has not been published; however, brief results are presented in the prescribing information.¹ A total of 365 treatment-naive patients inadequately controlled on diet and exercise were randomized to 1 of 4 groups: saxagliptin 2.5 mg every morning, 5 mg every morning, 2.5 mg every morning with possible titration to 5 mg every morning, or 5 mg every evening (n = 71 to 74 patients per group). After 24 weeks of treatment, the mean placebo-corrected reduction in HbA1C with saxagliptin 2.5 mg every morning was -0.4%. Saxagliptin 5 mg every morning or 5 mg every evening resulted in mean placebo-corrected reductions in HbA1C of -0.4% and -0.3%, respectively.

Combination Therapy
Jadzinsky and colleagues evaluated the efficacy and safety of saxagliptin given in combination with metformin to treatment-naive patients who were inadequately controlled on diet and exercise alone.⁵ A total of 1306 patients with a baseline mean HbA1C of 9.5% were randomized to saxagliptin 5 mg/day plus metformin (n = 320), saxagliptin 10 mg/day plus metformin (n = 323), saxagliptin 10 mg/day monotherapy (n = 335), or metformin monotherapy (n = 328) for 24 weeks. Metformin was titrated up weekly in 500 mg/day increments to a maximum daily dose of 2000 mg. Combination therapy with both doses of saxagliptin plus metformin resulted in statistically significant reductions in HbA1C and FPG from baseline compared to monotherapy with either agent. Adjusted mean reductions in HbA1C at week 24 were -2.5% for saxagliptin 5 mg/day plus metformin, -2.5% for saxagliptin 10 mg/day plus metformin, -1.7% for saxagliptin 10 mg/day, and -2.0% for metformin monotherapy (p<0.0001 for combination therapy versus monotherapy). Reductions in FPG and percentage of patients reaching a HbA1C level of < 7% were both significantly greater with combination therapy compared to monotherapy. Adjusted mean changes from baseline in FPG at week 24 were -60 mg/dL for saxagliptin 5 mg/day plus metformin, -62 mg/dL for saxagliptin 10 mg/day plus metformin, -31 mg/dL for saxagliptin 10 mg/day, and -47 mg/dL for metformin monotherapy (p<0.05 for combination therapy versus monotherapy). The proportion of patients with an HbA1C of < 7% was 60.3% for saxagliptin 5 mg/day plus metformin, 59.7% for saxagliptin 10 mg/day plus metformin, 32.2% for saxagliptin 10 mg/day, and 41.1% for metformin monotherapy (p<0.0001 for combination therapy versus monotherapy). Adverse events occurred at a similar rate across all 4 groups (range 53.4% to 58.5%), with the majority of events being mild or moderate in intensity. Headache, diarrhea, nasopharyngitis, and elevated blood pressure were the most common adverse events observed across the groups. The investigators did note; however, that mean systolic and diastolic blood pressures decreased in all groups by week 24.

The efficacy and safety of saxagliptin added onto metformin therapy in patients inadequately controlled on metformin alone has also been evaluated.⁶ DeFronzo and colleagues randomized 743 patients with a mean baseline HbA1C of 8.0% to saxagliptin 2.5 mg/day plus metformin (n = 192), saxagliptin 5 mg/day plus metformin (n = 191), saxagliptin 10 mg/day plus metformin (n = 181), or metformin plus placebo (n = 179) for 24 weeks. Patients had been receiving stable doses of metformin (1500 to 2000 mg/day) for at least 8 weeks prior to study entry. The addition of saxagliptin to metformin resulted in statistically significant reductions in HbA1C and FPG. Adjusted mean reductions in HbA1C from baseline to week 24 were -0.59% for saxagliptin 2.5 mg/day plus metformin, -0.69% for saxagliptin 5 mg/day plus metformin, -0.58% for saxagliptin 10 mg/day plus metformin compared to an increase of 0.13% for the placebo plus metformin group (all p<0.0001 compared to placebo group). Reductions in FPG were -14.3 mg/dL for saxagliptin 2.5 mg/day plus metformin, -22.0 mg/dL for saxagliptin 5 mg/day plus metformin, -20.5 mg/dL for saxagliptin 10 mg/day plus metformin compared to +1.2 mg/dL for the placebo plus metformin group (all p<0.0001 compared to placebo group). More than twice as many patients achieved HbA1C of < 7.0% with saxagliptin 2.5 mg/day, 5 mg/day, and 10 mg/day compared to placebo (37%, 44%, 44% vs. 17%, respectively, all p<0.0001). Treatment with saxagliptin was well-tolerated. The incidence of adverse events was similar for the saxagliptin groups and placebo group; hypoglycemic events and weight reductions were similar to placebo.

Similar results were observed when saxagliptin was given to patients inadequately controlled on a sulfonylurea, pioglitazone, or rosiglitazone.^1,7 The addition of saxagliptin 2.5 mg/day or 5 mg/day to glyburide resulted in significant improvements in HbA1C and FPG.⁷ When compared to uptitrated glyburide (daily dose of 15 mg/day, n = 267), the addition of saxagliptin 2.5 mg/day (n = 248) and 5 mg/day (n = 253) to glyburide 7.5 mg/day resulted in statistically significant adjusted mean decreases from baseline to week 24 in HbA1C (-0.54% for 2.5 mg/day, -0.64% for 5 mg/day vs. +0.08% for glyburide, p<0.0001 for both). In addition, more patients on saxagliptin 2.5 mg/day plus glyburide (22.4%) and saxagliptin 5 mg/day plus glyburide (22.8%) achieved an HbA1C of < 7% compared to glyburide alone (9.1%, p<0.0001 for both). Reported hypoglycemic events were similar across the 3 treatment groups: 13.3% for saxagliptin 2.5 mg/day plus glyburide, 14.6% for saxagliptin 5 mg/day plus glyburide, and 10.1% for glyburide monotherapy.

Results from the combination therapy trial assessing the efficacy of saxagliptin added onto pioglitazone 30 mg or 45 mg/day or rosiglitazone 4 or 8 mg/day have not been published, but are presented briefly in the prescribing information.¹ The addition of saxagliptin 2.5 mg/day and 5 mg/day to a thiazolidinedione resulted in statistically significant reductions in HbA1C compared to thiazolidinedione monotherapy. After 24 weeks of treatment, the adjusted mean change in HbA1C from baseline was -0.7% for the saxagliptin 2.5 mg/day group, -0.9% for the saxagliptin 5 mg/day group compared to -0.3% for thiazolidinedione monotherapy.

DPP-4s and Practice Guidelines
In January 2009, the American Diabetes Association (ADA) in conjunction with the European Association for the Study of Diabetes updated a consensus statement on the treatment of type 2 diabetes that was originally published in 2006.⁸ The consensus statement categorizes treatments into 2 tiers. Tier 1 is defined as well-validated treatments, and Tier 2 is defined as less well-validated treatments. According to the guidelines, DPP-4 inhibitors are not listed as a Tier 1 or Tier 2 agent. The ADA states that DPP-4 inhibitors lower HbA1C levels by 0.6% to 0.9%, are weight neutral, and relatively well-tolerated. They also point out that these agents do not cause hypoglycemia; however, they may interfere with the immune system as increases in upper respiratory tract infections have been observed in clinical trials. The DPP-4 inhibitors are listed as “other therapies” in the current treatment algorithm because these agents are expensive and long-term safety has not been established. An overview of the tier recommendations is summarized in Table 1.

The American Association of Clinical Endocrinologists (AACE) also published medical guidelines for the management of diabetes.⁹ The 2007 AACE guidelines list DPP-4 inhibitors, given as monotherapy or as combination therapy with other oral agents, as one of the preferred therapies for patients with type 2 diabetes. Treatment choice in these guidelines depends on initial HbA1C values. For patients who are naive to pharmacologic therapy with an HbA1C value between 6% to 7%, monotherapy with either metformin, thiazolidinediones, sulfonylureas, DPP-4 inhibitors, or α-glucosidase inhibitors are recommended. Combination therapy is recommended at the end of 2 to 3 months of monotherapy if glycemic control is not optimal. When HbA1C values are 7% to 8%, combination therapy that may contain 2 or 3 of the drug classes mentioned above is recommended. Insulin may be an appropriate adjunctive therapy if glycemic control remains suboptimal. For patients with type 2 diabetes currently treated pharmacologically, the combination therapies mentioned above may be administered or exenatide may be given with sulfonylureas, metformin, metformin plus a sulfonylurea, or a thiazolidinedione. In addition, pramlintide may be used in combination with prandial insulin if needed.

Saxagliptin’s Place in Therapy
The recommended daily dose of saxagliptin is 2.5 mg or 5 mg once daily, taken at any time of the day.¹ Since Phase 3 data showed that 10 mg/day of saxagliptin was no more effective than the 5 mg/day dose, the manufacturer recommends 5 mg/day as the maximum daily dose. The 2.5 mg dose is recommended for patients with moderate or severe renal impairment (creatinine clearance ≤ 50 mL/min) and for patients on strong cytochrome P450 3A4/5 inhibitors. The drug has no labeled contraindications and adverse events appear to be mild. Upper respiratory tract infection, urinary tract infection, and headache occurred more frequently in patients given saxagliptin compared to placebo. In addition, hypersensitivity reactions manifesting as hives and facial edema were more common in saxagliptin-treated patients than placebo, although these reactions were rare. When given with a sulfonylurea, hypoglycemia occurred more frequently with combination therapy compared to sulfonylurea monotherapy, and peripheral edema was more frequent in patients taking saxagliptin plus a thiazolidinedione compared to thiazolidinedione monotherapy.

Based on current practice guidelines, saxagliptin will most likely be used as add-on therapy for patients who fail to achieve glycemic control with other oral antidiabetic agents. Use of saxagliptin will result in HbA1C reductions ranging from 0.5% to 1% and will help more people obtain HbA1C levels of < 7%. In addition, saxagliptin appears to be associated with minimal adverse events. The incidence of hypoglycemia was generally similar in patients given saxagliptin compared to placebo, and the drug is weight neutral.

References