Safety and Effectiveness of Sitagliptin in Type 2 Diabetes
Safety and Effectiveness of Sitagliptin in Type 2 Diabetes
Objective. To determine if the use of sitagliptin in newly treated patients with type 2 diabetes is associated with any changes in clinical outcomes.
Design. Retrospective population based cohort study.
Setting. Large national commercially insured US claims and integrated laboratory database.
Participants. Inception cohort of new users of oral antidiabetic drugs between 2004 and 2009 followed until death, termination of medical insurance, or December 31 2010.
Main Outcome Measure. Composite endpoint of all cause hospital admission and all cause mortality, assessed with time varying Cox proportional hazards regression after adjustment for demographics, clinical and laboratory data, pharmacy claims data, healthcare use, and time varying propensity scores.
Results. The cohort included 72,738 new users of oral antidiabetic drugs (8032 (11%) used sitagliptin; 7293 (91%) were taking it in combination with other agents) followed for a total of 182,409 patient years. The mean age was 52 (SD 9) years, 54% (39,573) were men, 11% (8111) had ischemic heart disease, and 9% (6378) had diabetes related complications at the time their first antidiabetic drug was prescribed. 14,215 (20%) patients met the combined endpoint. Sitagliptin users showed similar rates of all cause hospital admission or mortality to patients not using sitagliptin (adjusted hazard ratio 0.98, 95% confidence interval 0.91 to 1.06), including patients with a history of ischemic heart disease (adjusted hazard ratio 1.10, 0.94 to 1.28) and those with estimated glomerular filtration rate below 60 mL/min (1.11, 0.88 to 1.41).
Conclusions. Sitagliptin use was not associated with an excess risk of all cause hospital admission or death compared with other glucose lowering agents among newly treated patients with type 2 diabetes. Most patients prescribed sitagliptin in this cohort were concordant with clinical practice guidelines, in that it was used as add-on treatment.
Glycemic control is considered one of the cornerstones in the management of type 2 diabetes. In addition to lifestyle changes, most patients will need glucose lowering treatment; most international guidelines recommend metformin as first line treatment. Over the past few years, several new treatments have been introduced, most notably the new class of oral "incretin" drugs known as the dipeptidyl peptidase-4 (DPP-4) inhibitors. The DDP-4 inhibitors lower blood glucose by inactivating DPP-4, an enzyme responsible for metabolizing the gastrointestinal hormone glucagon-like peptide-1, which is responsible for augmenting the release of insulin in response to a rise in blood glucose.
Sitagliptin was the first DPP-4 inhibitor based treatment to be marketed in the United States in 2007, followed by saxagliptin in 2009. DPP-4 inhibitors are considered weight neutral and have been shown to modestly improve modulators of cardiovascular risk, including triglycerides, low density lipoprotein cholesterol, high density lipoprotein cholesterol, and blood pressure; however, the data are relatively inconsistent across studies. Several pooled safety analyses have suggested potential benefits associated with DPP-4 inhibitors. A recent meta-analysis of 18 phase III randomized controlled trials reported that DDP-4 inhibitors were associated with a 52% (95% confidence interval 0.31% to 0.75%) relative risk reduction in major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction or acute coronary syndrome, stroke, arrhythmias, and heart failure) compared with other active or placebo treatment. However, no evaluation of broader outcomes of interest to clinicians such as all cause death or all cause hospital admissions were reported. To date, evidence on the potential benefits or risks of DPP-4 inhibitors is lacking, and, given recent experiences with other novel glucose lowering treatments such as thiazolidinediones, concerns exist.
Although several studies assessing specific safety endpoints (pancreatitis, upper respiratory tract infections, renal failure) have been done, to our knowledge no large comparative effectiveness studies have evaluated sitagliptin, the most widely prescribed and longest marketed DPP-4 inhibitor in the United States, in "real world" patients with broader outcomes including all cause hospital admissions or mortality. We thus designed this study to compare outcomes associated with sitagliptin treatment compared with other glucose lowering agents. We hypothesized that the use of sitagliptin would not be associated with increased risk of hospital admission, mortality, or cardiovascular events.
Abstract and Introduction
Abstract
Objective. To determine if the use of sitagliptin in newly treated patients with type 2 diabetes is associated with any changes in clinical outcomes.
Design. Retrospective population based cohort study.
Setting. Large national commercially insured US claims and integrated laboratory database.
Participants. Inception cohort of new users of oral antidiabetic drugs between 2004 and 2009 followed until death, termination of medical insurance, or December 31 2010.
Main Outcome Measure. Composite endpoint of all cause hospital admission and all cause mortality, assessed with time varying Cox proportional hazards regression after adjustment for demographics, clinical and laboratory data, pharmacy claims data, healthcare use, and time varying propensity scores.
Results. The cohort included 72,738 new users of oral antidiabetic drugs (8032 (11%) used sitagliptin; 7293 (91%) were taking it in combination with other agents) followed for a total of 182,409 patient years. The mean age was 52 (SD 9) years, 54% (39,573) were men, 11% (8111) had ischemic heart disease, and 9% (6378) had diabetes related complications at the time their first antidiabetic drug was prescribed. 14,215 (20%) patients met the combined endpoint. Sitagliptin users showed similar rates of all cause hospital admission or mortality to patients not using sitagliptin (adjusted hazard ratio 0.98, 95% confidence interval 0.91 to 1.06), including patients with a history of ischemic heart disease (adjusted hazard ratio 1.10, 0.94 to 1.28) and those with estimated glomerular filtration rate below 60 mL/min (1.11, 0.88 to 1.41).
Conclusions. Sitagliptin use was not associated with an excess risk of all cause hospital admission or death compared with other glucose lowering agents among newly treated patients with type 2 diabetes. Most patients prescribed sitagliptin in this cohort were concordant with clinical practice guidelines, in that it was used as add-on treatment.
Introduction
Glycemic control is considered one of the cornerstones in the management of type 2 diabetes. In addition to lifestyle changes, most patients will need glucose lowering treatment; most international guidelines recommend metformin as first line treatment. Over the past few years, several new treatments have been introduced, most notably the new class of oral "incretin" drugs known as the dipeptidyl peptidase-4 (DPP-4) inhibitors. The DDP-4 inhibitors lower blood glucose by inactivating DPP-4, an enzyme responsible for metabolizing the gastrointestinal hormone glucagon-like peptide-1, which is responsible for augmenting the release of insulin in response to a rise in blood glucose.
Sitagliptin was the first DPP-4 inhibitor based treatment to be marketed in the United States in 2007, followed by saxagliptin in 2009. DPP-4 inhibitors are considered weight neutral and have been shown to modestly improve modulators of cardiovascular risk, including triglycerides, low density lipoprotein cholesterol, high density lipoprotein cholesterol, and blood pressure; however, the data are relatively inconsistent across studies. Several pooled safety analyses have suggested potential benefits associated with DPP-4 inhibitors. A recent meta-analysis of 18 phase III randomized controlled trials reported that DDP-4 inhibitors were associated with a 52% (95% confidence interval 0.31% to 0.75%) relative risk reduction in major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction or acute coronary syndrome, stroke, arrhythmias, and heart failure) compared with other active or placebo treatment. However, no evaluation of broader outcomes of interest to clinicians such as all cause death or all cause hospital admissions were reported. To date, evidence on the potential benefits or risks of DPP-4 inhibitors is lacking, and, given recent experiences with other novel glucose lowering treatments such as thiazolidinediones, concerns exist.
Although several studies assessing specific safety endpoints (pancreatitis, upper respiratory tract infections, renal failure) have been done, to our knowledge no large comparative effectiveness studies have evaluated sitagliptin, the most widely prescribed and longest marketed DPP-4 inhibitor in the United States, in "real world" patients with broader outcomes including all cause hospital admissions or mortality. We thus designed this study to compare outcomes associated with sitagliptin treatment compared with other glucose lowering agents. We hypothesized that the use of sitagliptin would not be associated with increased risk of hospital admission, mortality, or cardiovascular events.