Safety and Effectiveness of Sitagliptin in Type 2 Diabetes
Safety and Effectiveness of Sitagliptin in Type 2 Diabetes
Between 2004 and 2009, 72,738 new users of oral antidiabetic drugs met the inclusion and exclusion criteria (Figure 1). The average age was 52 (SD 9) years, 54% were men, 10% had a history of ischemic heart disease, and 9% had diabetes related complications ( Table 1 ). We identified 8032 (11%) patients who used sitagliptin at any point during the study. Although statistical differences existed between sitagliptin and non-sitagliptin users owing to the large numbers, few clinically important differences existed with the exception that sitagliptin users tended to have higher use of insulin treatment and higher rates of diabetes related complications ( Table 1 ). Among sitagliptin users, most (7293; 91%) used sitagliptin as an add-on treatment with other oral agents, consistent with current clinical practice guidelines.
(Enlarge Image)
Figure 2.
Adjusted hazard ratios and 95% confidence intervals for the outcome of all cause hospital admission or all cause death according to sitagliptin exposure (compared with no sitagliptin use in time varying Cox proportional hazards analysis adjusted for covariates in footnote to Table 2). eGFR=estimated glomerular filtration rate; IHD=ischemic heart disease.
Among patients with a history of ischemic heart disease, sitagliptin users had a similar risk to non-users for the primary composite endpoint (adjusted hazard ratio 1.10, 0.94 to 1.28), the combined endpoint of cardiovascular related hospital admissions or mortality (0.99, 0.77 to 1.27), all cause mortality (1.02, 0.53 to 1.99), all cause hospital admissions (1.10, 0.94 to 1.28), and cardiovascular related hospital admissions (0.98, 0.76 to 1.27). Similarly, in those with estimated glomerular filtration rate below 60 mL/min, sitagliptin users had a similar risk to non-users for the primary composite endpoint (adjusted hazard ratio 1.11, 0.88 to 1.41), the combined endpoint of cardiovascular related hospital admissions or mortality (0.86, 0.34 to 1.37), all cause mortality (0.99, 0.34 to 2.89), all cause hospital admissions (1.10, 0.87 to 1.40), and cardiovascular related hospital admissions (0.92, 0.57 to 1.50) (Figure 2).
Compared with users of metformin plus a sulfonylurea, users of sitagliptin plus a sulfonylurea had a similar risk for our primary composite endpoint (adjusted hazard ratio 1.03, 0.76 to 1.39), whereas use of sitagliptin plus metformin was associated with lower risk (0.82, 0.72 to 0.93). Subsequent post hoc analyses in which we restricted our entire cohort to only new users of metformin (n=55 678), which is recommended first line treatment for most patients with type 2 diabetes, confirmed these results: adjusted hazard ratio 0.85, 0.74 to 0.98 for addition of sitagliptin to metformin compared with addition of a sulfonylurea to metformin. However, an analysis of only new users of sulfonylureas as first line treatment did not show any difference between those patients who switched to sitagliptin plus metformin and users of sulfonylurea who added metformin (adjusted hazard ratio 1.04, 0.71 to 1.53).
Restriction of cohort entry to begin in 2007 did not materially change our results for sitagliptin use compared with non-use for the primary combined endpoint (adjusted hazard ratio 1.00, 0.91 to 1.10). Analyses excluding insulin users produced nearly identical results to our main findings on use of sitagliptin for the composite endpoint (adjusted hazard ratio 1.01, 0.94 to 1.09). Our results were also robust to changes in the definition of exposure whereby we considered patients as unexposed if they stopped the drug of interest for at least two consecutive periods (that is, no restarts allowed) (adjusted hazard ratio 0.97, 0.90 to 1.05), as they were to consideration of a legacy effect of any previous exposure (0.97, 0.91 to 1.04) and censoring of patients after they discontinued all drugs, including insulin, for at least two consecutive periods (0.99, 0.91 to 1.06). The inclusion of the 610 patients using saxagliptin provided nearly identical results to those observed with sitagliptin alone (adjusted hazard ratio 0.98, 0.91 to 1.05). We also found no association between the use of sitagliptin and the risk of acute pancreatitis (adjusted hazard ratio 1.10, 0.68 to 1.77) or the risk of acute upper respiratory tract infections (P=0.97) or pancreatic cancers (P=0.96) compared with sitagliptin non-users. Finally, the inclusion of a high dimensional propensity score did not change any of our estimates materially (adjusted hazard ratio 1.02, 0.95 to 1.10 for sitagliptin users compared with sitagliptin non-users for the primary combined endpoint).
Results
Between 2004 and 2009, 72,738 new users of oral antidiabetic drugs met the inclusion and exclusion criteria (Figure 1). The average age was 52 (SD 9) years, 54% were men, 10% had a history of ischemic heart disease, and 9% had diabetes related complications ( Table 1 ). We identified 8032 (11%) patients who used sitagliptin at any point during the study. Although statistical differences existed between sitagliptin and non-sitagliptin users owing to the large numbers, few clinically important differences existed with the exception that sitagliptin users tended to have higher use of insulin treatment and higher rates of diabetes related complications ( Table 1 ). Among sitagliptin users, most (7293; 91%) used sitagliptin as an add-on treatment with other oral agents, consistent with current clinical practice guidelines.
(Enlarge Image)
Figure 2.
Adjusted hazard ratios and 95% confidence intervals for the outcome of all cause hospital admission or all cause death according to sitagliptin exposure (compared with no sitagliptin use in time varying Cox proportional hazards analysis adjusted for covariates in footnote to Table 2). eGFR=estimated glomerular filtration rate; IHD=ischemic heart disease.
Among patients with a history of ischemic heart disease, sitagliptin users had a similar risk to non-users for the primary composite endpoint (adjusted hazard ratio 1.10, 0.94 to 1.28), the combined endpoint of cardiovascular related hospital admissions or mortality (0.99, 0.77 to 1.27), all cause mortality (1.02, 0.53 to 1.99), all cause hospital admissions (1.10, 0.94 to 1.28), and cardiovascular related hospital admissions (0.98, 0.76 to 1.27). Similarly, in those with estimated glomerular filtration rate below 60 mL/min, sitagliptin users had a similar risk to non-users for the primary composite endpoint (adjusted hazard ratio 1.11, 0.88 to 1.41), the combined endpoint of cardiovascular related hospital admissions or mortality (0.86, 0.34 to 1.37), all cause mortality (0.99, 0.34 to 2.89), all cause hospital admissions (1.10, 0.87 to 1.40), and cardiovascular related hospital admissions (0.92, 0.57 to 1.50) (Figure 2).
Compared with users of metformin plus a sulfonylurea, users of sitagliptin plus a sulfonylurea had a similar risk for our primary composite endpoint (adjusted hazard ratio 1.03, 0.76 to 1.39), whereas use of sitagliptin plus metformin was associated with lower risk (0.82, 0.72 to 0.93). Subsequent post hoc analyses in which we restricted our entire cohort to only new users of metformin (n=55 678), which is recommended first line treatment for most patients with type 2 diabetes, confirmed these results: adjusted hazard ratio 0.85, 0.74 to 0.98 for addition of sitagliptin to metformin compared with addition of a sulfonylurea to metformin. However, an analysis of only new users of sulfonylureas as first line treatment did not show any difference between those patients who switched to sitagliptin plus metformin and users of sulfonylurea who added metformin (adjusted hazard ratio 1.04, 0.71 to 1.53).
Restriction of cohort entry to begin in 2007 did not materially change our results for sitagliptin use compared with non-use for the primary combined endpoint (adjusted hazard ratio 1.00, 0.91 to 1.10). Analyses excluding insulin users produced nearly identical results to our main findings on use of sitagliptin for the composite endpoint (adjusted hazard ratio 1.01, 0.94 to 1.09). Our results were also robust to changes in the definition of exposure whereby we considered patients as unexposed if they stopped the drug of interest for at least two consecutive periods (that is, no restarts allowed) (adjusted hazard ratio 0.97, 0.90 to 1.05), as they were to consideration of a legacy effect of any previous exposure (0.97, 0.91 to 1.04) and censoring of patients after they discontinued all drugs, including insulin, for at least two consecutive periods (0.99, 0.91 to 1.06). The inclusion of the 610 patients using saxagliptin provided nearly identical results to those observed with sitagliptin alone (adjusted hazard ratio 0.98, 0.91 to 1.05). We also found no association between the use of sitagliptin and the risk of acute pancreatitis (adjusted hazard ratio 1.10, 0.68 to 1.77) or the risk of acute upper respiratory tract infections (P=0.97) or pancreatic cancers (P=0.96) compared with sitagliptin non-users. Finally, the inclusion of a high dimensional propensity score did not change any of our estimates materially (adjusted hazard ratio 1.02, 0.95 to 1.10 for sitagliptin users compared with sitagliptin non-users for the primary combined endpoint).
