Dipeptidyl Peptidase-4 Inhibitors for the Treatment of Type 2 DM
Dipeptidyl Peptidase-4 Inhibitors for the Treatment of Type 2 DM
Recent clinical guidelines issued by the National Institute for Health and Clinical Excellence recommend DPP-4 inhibitors as second-line therapy (after first-line therapy with metformin) in lieu of sulfonylurea agents in patients at significant risk for hypoglycemia or its consequences, such as older adults with hazardous jobs (e.g., those whose work is performed at heights or with heavy machinery) or those who live alone. The DPP-4 inhibitors are clinically desirable for many reasons, including a low risk of hypoglycemia when used as monotherapy because of their glucose-dependent mechanism of action, a relatively mild adverse-effect profile, a relatively low risk for drug-drug interactions, weight neutrality, simple daily oral administration, lack of a need for dose titration, and a minimal need for therapeutic monitoring. The DPP-4 inhibitors target multiple pathophysiologic pathways present in people with type 2 diabetes, and promising in vitro and animal data highlighting the potential for β-cell protection with DPP-4 inhibitors point toward the possible utility of these agents early in the disease process to maintain β-cell function.
The DPP-4 inhibitors have been criticized for their lack of efficacy in terms of A1C-lowering potential when compared with other drugs. The DPP-4 inhibitors are particularly suited, however, to address PPG because of their glucose-dependent mechanism of action, thus making this drug class a possible treatment intervention for those close to A1C goal where hypoglycemia is particularly undesirable.
As the number of DPP-4 inhibitors on the market increases, differences between the agents become important when deciding which agent is best suited for an individual patient. Because there are no clinical studies, to our knowledge, comparing agents from the DPP-4 inhibitor class in a head-to-head trial format, the only information that can be used to make a sound clinical judgment in this regard is from available clinical trial data and the limited postmarketing reporting data available for sitagliptin and vildagliptin.
In an effort to compare the clinical efficacy data for sitagliptin, vildagliptin, saxagliptin, and alogliptin, Table 6 outlines mean adjusted placebo-corrected changes in A1C, FPG, and PPG for each agent from phase III clinical trial data. Whereas these comparisons are not perfect due to differences in inclusion criteria and baseline glycemic parameters used in the trials included in the table, the mean placebo-corrected values provide a general overview of the effectiveness of each individual agent depending on concurrent therapies. Overall, when evaluating the placebo-corrected A1C changes from baseline, the DPP-4 inhibitors decrease A1C from baseline by approximately 0.5–1.0%, with most falling on the lower end of this range. Although there are subtle differences in A1C, FPG, and PPG changes depending on background therapy and dose, no obvious advantages for one agent over another were noted for these parameters.
Other important factors when comparing agents from a therapeutic class are ease of use and safety. When comparing the DPP-4 inhibitors in terms of their pharmacokinetic properties, the four agents included in this review are quite similar (Table 1). The DPP-4 inhibitors are sometimes preferred by patients over GLP-1 agonists because incretin mimetic agents are administered by subcutaneous injection, but when comparing the DPP-4 agents, they can all be administered orally once/day. The one potential outlier in this regard is vildagliptin, which is dosed at 50 mg twice/day in Europe for patients requiring 100 mg/day. This is due to an observed increase in hepatic enzyme levels when dosed as 100 mg once/day. Likewise, renal dosage adjustments are recommended for the marketed agents and likely for those agents in phase III studies, with no apparent advantages for any one agent in this regard. Safety data in patients with renal impairment are needed, however, before a definitive assessment can be made about the safety of vildagliptin in renally impaired patients. Although the DPP-4 inhibitors as a class have a relatively low risk of drug interactions, saxagliptin appears to be the agent with the highest risk for interacting with other drugs due to it being a substrate of CYP3A4.
This is a potentially important patient-specific consideration when choosing a DPP-4 agent.
In terms of safety, all of the DPP-4 inhibitors were generally well tolerated and demonstrated similar adverse-effect profiles in clinical trials. Although there are theoretical advantages for agents with a higher specificity for DPP-4 inhibition versus DPP-8 and DPP-9 isoenzymes due to previously discussed toxicities associated with DPP-8 and DPP-9 inhibition, the clinical implications and relevance of enzyme specificity remain to be seen. Questions do remain, however, regarding less common adverse events with the DPP-4 inhibitors, such as severe skin-related and immune-mediated adverse events. Because these events were rarely seen in clinical trials, any difference in the rates of these events for the individual agents in this class will be determined by diligent postmarketing surveillance and increased clinical experience with this class of drugs. Long-term prospective studies are also needed to assess the cardiovascular safety of these agents in a heterogeneous at-risk population.
The DPP-4 inhibitors are generally weight neutral when used as monotherapy, but clinical trial data indicate that there may be considerations in terms of weight gain when used with other oral antidiabetic agents. For instance, when saxagliptin was studied as add-on therapy to background sulfonylurea therapy, weight gains of 0.7 and 0.8 kg were seen in the treatment groups receiving saxagliptin 2.5 and 5 mg, respectively. These weight changes were significantly greater (Table 4) when compared with a 0.3-kg weight gain in the placebo plus glyburide uptitration group. Likewise, in a study examining the addition of vildagliptin to background pioglitazone therapy, the group receiving vildagliptin 50 mg twice/daily gained significantly more weight than did the group receiving placebo.
The risk of hypoglycemia may likewise be dependent on the use of background or concurrent oral antidiabetic drugs. One group reported a 14.6% rate of hypoglycemia for patients receiving saxagliptin plus glyburide versus 10.1% for those in the glyburide uptitration group. Although this difference did not reach statistical significance, it indicates that low doses of sulfonylureas may be warranted if used in combination with DPP-4 inhibitors.
Overall, when comparing agents from the DPP-4 inhibitor class, there appears to be no obvious overwhelming advantages to support the use of one agent over another. Increased clinical experience with these agents in a heterogeneous population and further outcomes data may indicate clinical advantages for specific agents in certain subsets of the population; however, only time will tell.
Comparison of the Dipeptidyl Peptidase-4 Inhibitors
Recent clinical guidelines issued by the National Institute for Health and Clinical Excellence recommend DPP-4 inhibitors as second-line therapy (after first-line therapy with metformin) in lieu of sulfonylurea agents in patients at significant risk for hypoglycemia or its consequences, such as older adults with hazardous jobs (e.g., those whose work is performed at heights or with heavy machinery) or those who live alone. The DPP-4 inhibitors are clinically desirable for many reasons, including a low risk of hypoglycemia when used as monotherapy because of their glucose-dependent mechanism of action, a relatively mild adverse-effect profile, a relatively low risk for drug-drug interactions, weight neutrality, simple daily oral administration, lack of a need for dose titration, and a minimal need for therapeutic monitoring. The DPP-4 inhibitors target multiple pathophysiologic pathways present in people with type 2 diabetes, and promising in vitro and animal data highlighting the potential for β-cell protection with DPP-4 inhibitors point toward the possible utility of these agents early in the disease process to maintain β-cell function.
The DPP-4 inhibitors have been criticized for their lack of efficacy in terms of A1C-lowering potential when compared with other drugs. The DPP-4 inhibitors are particularly suited, however, to address PPG because of their glucose-dependent mechanism of action, thus making this drug class a possible treatment intervention for those close to A1C goal where hypoglycemia is particularly undesirable.
As the number of DPP-4 inhibitors on the market increases, differences between the agents become important when deciding which agent is best suited for an individual patient. Because there are no clinical studies, to our knowledge, comparing agents from the DPP-4 inhibitor class in a head-to-head trial format, the only information that can be used to make a sound clinical judgment in this regard is from available clinical trial data and the limited postmarketing reporting data available for sitagliptin and vildagliptin.
In an effort to compare the clinical efficacy data for sitagliptin, vildagliptin, saxagliptin, and alogliptin, Table 6 outlines mean adjusted placebo-corrected changes in A1C, FPG, and PPG for each agent from phase III clinical trial data. Whereas these comparisons are not perfect due to differences in inclusion criteria and baseline glycemic parameters used in the trials included in the table, the mean placebo-corrected values provide a general overview of the effectiveness of each individual agent depending on concurrent therapies. Overall, when evaluating the placebo-corrected A1C changes from baseline, the DPP-4 inhibitors decrease A1C from baseline by approximately 0.5–1.0%, with most falling on the lower end of this range. Although there are subtle differences in A1C, FPG, and PPG changes depending on background therapy and dose, no obvious advantages for one agent over another were noted for these parameters.
Other important factors when comparing agents from a therapeutic class are ease of use and safety. When comparing the DPP-4 inhibitors in terms of their pharmacokinetic properties, the four agents included in this review are quite similar (Table 1). The DPP-4 inhibitors are sometimes preferred by patients over GLP-1 agonists because incretin mimetic agents are administered by subcutaneous injection, but when comparing the DPP-4 agents, they can all be administered orally once/day. The one potential outlier in this regard is vildagliptin, which is dosed at 50 mg twice/day in Europe for patients requiring 100 mg/day. This is due to an observed increase in hepatic enzyme levels when dosed as 100 mg once/day. Likewise, renal dosage adjustments are recommended for the marketed agents and likely for those agents in phase III studies, with no apparent advantages for any one agent in this regard. Safety data in patients with renal impairment are needed, however, before a definitive assessment can be made about the safety of vildagliptin in renally impaired patients. Although the DPP-4 inhibitors as a class have a relatively low risk of drug interactions, saxagliptin appears to be the agent with the highest risk for interacting with other drugs due to it being a substrate of CYP3A4.
This is a potentially important patient-specific consideration when choosing a DPP-4 agent.
In terms of safety, all of the DPP-4 inhibitors were generally well tolerated and demonstrated similar adverse-effect profiles in clinical trials. Although there are theoretical advantages for agents with a higher specificity for DPP-4 inhibition versus DPP-8 and DPP-9 isoenzymes due to previously discussed toxicities associated with DPP-8 and DPP-9 inhibition, the clinical implications and relevance of enzyme specificity remain to be seen. Questions do remain, however, regarding less common adverse events with the DPP-4 inhibitors, such as severe skin-related and immune-mediated adverse events. Because these events were rarely seen in clinical trials, any difference in the rates of these events for the individual agents in this class will be determined by diligent postmarketing surveillance and increased clinical experience with this class of drugs. Long-term prospective studies are also needed to assess the cardiovascular safety of these agents in a heterogeneous at-risk population.
The DPP-4 inhibitors are generally weight neutral when used as monotherapy, but clinical trial data indicate that there may be considerations in terms of weight gain when used with other oral antidiabetic agents. For instance, when saxagliptin was studied as add-on therapy to background sulfonylurea therapy, weight gains of 0.7 and 0.8 kg were seen in the treatment groups receiving saxagliptin 2.5 and 5 mg, respectively. These weight changes were significantly greater (Table 4) when compared with a 0.3-kg weight gain in the placebo plus glyburide uptitration group. Likewise, in a study examining the addition of vildagliptin to background pioglitazone therapy, the group receiving vildagliptin 50 mg twice/daily gained significantly more weight than did the group receiving placebo.
The risk of hypoglycemia may likewise be dependent on the use of background or concurrent oral antidiabetic drugs. One group reported a 14.6% rate of hypoglycemia for patients receiving saxagliptin plus glyburide versus 10.1% for those in the glyburide uptitration group. Although this difference did not reach statistical significance, it indicates that low doses of sulfonylureas may be warranted if used in combination with DPP-4 inhibitors.
Overall, when comparing agents from the DPP-4 inhibitor class, there appears to be no obvious overwhelming advantages to support the use of one agent over another. Increased clinical experience with these agents in a heterogeneous population and further outcomes data may indicate clinical advantages for specific agents in certain subsets of the population; however, only time will tell.
