Mu Lin

Does Sitagliptin Affect the Rate of Osteoporotic Fractures in Type 2 Diabetes? Population-Based Cohort Study.

Context: Type 2 diabetes and osteoporosis are both common, chronic, and increase with age, whereas type 2 diabetes is also a risk factor for major osteoporotic fractures (MOFs). However, different treatments for type 2 diabetes can affect fracture risk differently, with metaanalyses showing some agents increase risk (eg, thiazolidinediones) and some reduce risk (eg, sitagliptin). Objective: To determine the independent association between new use of sitagliptin and MOF in a large population-based cohort study. Design, Setting, and Subjects: A sitagliptin new user study design employing a nationally representative Unites States claims database of 72 738 insured patients with type 2 diabetes. We used 90-day time-varying sitagliptin exposure windows and controlled confounding by using multivariable analyses that adjusted for clinical data, comorbidities, and time-updated propensity scores. Main Outcomes: We compared the incidence of MOF (hip, clinical spine, proximal humerus, distal radius) in new users of sitagliptin vs nonusers over a median 2.2 years follow-up. Results: At baseline, the median age was 52 years, 54% were men, and median A1c was 7.5%. There were 8894 new users of sitagliptin and 63 834 nonusers with a total 181 139 person-years of follow-up. There were 741 MOF (79 hip fractures), with 53 fractures (4.8 per 1000 person-years) among new users of sitagliptin vs 688 fractures (4.0 per 1000 person-years) among nonusers (P = .3 for difference). In multivariable analyses, sitagliptin was not associated with fracture (adjusted hazard ratio 1.1, 95% confidence interval 0.8–1.4; P = .7), although insulin (P < .001), sulfonylureas (P < .008), and thiazolidinedione (P = .019) were each independently associated with increased fracture risk. Conclusions: Even in a young population with type 2 diabetes, osteoporotic fractures were not uncommon. New use of sitagliptin was not associated with fracture, but other commonly used second-line agents for type 2 diabetes were associated with increased risk. These data should be considered when making treatment decisions for those with type 2 diabetes at particularly high risk of fractures.

Comparative Effectiveness of Olmesartan and Other Angiotensin Receptor Blockers in Diabetes Mellitus: Retrospective Cohort Study

Olmesartan has been linked with increased risk of cardiovascular mortality and sprue-like enteropathy. We compared outcomes between olmesartan and other angiotensin receptor blockers in a large clinical registry of patients with diabetes mellitus. A retrospective cohort analysis using nationwide US-integrated insurance and laboratory claims was performed in 45 185 incident diabetic angiotensin receptor blocker users, including 10 370 (23%) olmesartan users. Hazard ratios were computed using time-dependant Cox models adjusted for sociodemographic characteristics, comorbidities, laboratory data, drug use, healthcare utilization, and the propensity to receive olmesartan. Blood pressure data were unavailable. Subjects were followed up for 116 721 patient-years. The primary end point was all-cause hospitalization or all-cause mortality and occurred in 10 915 (24%) patients. Average age was 54.3±9.6 years, 52% were men, 17% had cardiovascular disease, and 10% chronic kidney disease. Compared with other angiotensin receptor blockers, the adjusted hazard for olmesartan was 0.99 (95% confidence interval, 0.94–1.05) for all-cause hospitalization and mortality; 0.90 (0.62–1.30) for all-cause mortality; 0.99 (0.94–1.05) for all-cause hospital admission; 0.88 (0.78–1.00) for cardiovascular disease–related admission, and 1.09 (0.98–1.20) for gastrointestinal disease–related hospitalization in the overall cohort. Olmesartan use was associated with an adjusted hazard for the primary outcome of 1.11 (0.99–1.24) in subjects with history of cardiovascular disease and 1.21 (1.04–1.41) in subjects with chronic kidney disease. In conclusion, there is no robust signal for harm with olmesartan use. Risk may be increased in kidney disease; thus, given the widespread availability of alternate agents, olmesartan should be used with caution in this subgroup pending further study.

Medication Adherence Affects Risk of New Diabetes Complications A Cohort Study

Background: Previous outcomes-based studies of adherence to diabetes medications have focused on glycemic control and are limited by questions of temporality and uncontrolled confounding. Objective: This retrospective cohort study of new oral antidiabetic medication users examined the effect of adherence on risk of incident macrovascular and microvascular complications. Methods: A nationwide integrated insurance claims and laboratory database was used to identify new oral antidiabetic medication users between January 2004 and December 2009. People with preexisting complications were excluded and the remaining cohort was followed until development of a new diabetes complication or December 2010. Medication adherence was calculated at 3-month intervals and entered as a time-dependent variable in a Cox proportional hazards model. Covariables entered in the model included patient demographics, clinical laboratory data, a medical frailty indicator and a mortality risk score from the Johns Hopkins adjusted clinical groups system, and medication use at baseline. Results: Among the 54 505 included patients, the median age was 60 years, 28 125 (52%) were men, 1447 (3%) were considered frail, the mean mortality risk score was 33.7 (±11.1), and 9793 (18%) developed a new diabetes complication. Good adherence (medication possession ratio ≥0.8) was associated with a lower risk of a new microvascular or macrovascular diabetes complication (adjusted hazard ratio = 0.96; 95% CI = 0.92-1.00; P = 0.05). Conclusions: This study design addresses limitations of previous studies and found a small but significantly lower risk of new diabetes complications associated with good adherence to oral antidiabetic medications.

The Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers in Patients With Diabetes.

The evidence examining the effect of angiotensin‐converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) on mortality in high‐risk patients is conflicting. To further examine this controversy, the authors compared outcomes between ACE inhibitors and ARBs in a large clinical diabetes registry. A retrospective cohort of 87,472 incident users followed for 105,702 patient‐years was analyzed. Average age was 53.1±10.1 years, 54.2% were men, and 14.4% had cardiovascular disease. All‐cause hospitalization or all‐cause mortality, the composite primary endpoint, occurred in 10,943 (12.5%) patients. Compared with ACE inhibitors, the adjusted hazard for ARBs was 0.90 (95% confidence interval, 0.87–0.94) for all‐cause hospitalization or mortality; 0.95 (0.65–1.40) for mortality; 0.90 (0.87–0.94) for all‐cause hospitalization; and 0.81 (0.74–0.89) for cardiovascular admission. ARB use was associated with a reduced, not increased, risk of hospitalization/mortality relative to ACE inhibition. This was driven by lower hospitalization, with a null mortality result.

Community Pharmacy–Based Inducement Programs Associated With Better Medication Adherence: A Cohort Study

Background: Inducement programs can promote customer loyalty; however, the clinical effects of these programs are unknown. Objective: To examine relationships among inducement program use, medication adherence, and health outcomes. Methods: Alberta residents with ≥ 1 physician visit for diabetes or hypertension between April 2008 and March 2014 were eligible for this study and included if they were new statin users and alive at least 455 days after the first statin dispensation. Group assignment was based on whether all statin dispensations in the first year were obtained from pharmacies with or without inducement programs. Discontinuation was defined as no statin dispensations between 275 and 455 days after the first statin dispensation. Acute coronary syndrome (ACS) hospitalizations or deaths were identified between 456 days and 3 years after the first statin dispensation. Multivariable regression analyses were conducted to examine relationships among inducement program use, discontinuation, and ACS events. Results: Among the 159 998 new statin users, mean age was 60.2 (±13.7) years and 67 534 (42%) were women. Statin discontinuation occurred in 22 455 (28.9%) of 77 803 inducement group participants and 25 816 (31.4%) of 82 195 noninducement group participants (adjusted odds ratio = 0.88; 95% CI = 0.86-0.90). Risk of an ACS event was similar between groups (adjusted hazard ratio = 1.00; 95% CI 0.92-1.08); however, discontinuing statin therapy was associated with a higher risk of an ACS event (adjusted hazard ratio = 1.27; 95% CI = 1.16-1.39). Conclusions: Inducement programs are associated with better adherence and not directly associated with risk of health outcomes.

Time-Varying Risk for Breast Cancer Following Initiation of Glucose-Lowering Therapy in Women with Type 2 Diabetes: Exploring Detection Bias

OBJECTIVES To explore detection bias in the association between glucose-lowering therapies and breast cancer in a cohort of women with type 2 diabetes. METHODS This was a retrospective, population-based cohort study. We identified new users of metformin, sulfonylureas, thiazolidinediones and insulin during the index period of January 1, 2003, to December 31, 2010. The main outcome was incident breast cancer, and patients were followed up from drug exposure index date until death, diagnosis of another type of cancer, termination of medical insurance or December 31, 2010. To explore detection bias, we split follow-up time into 2 discrete time periods of 0 to 3 months and 3 months to 6 years after drug index date. We performed time-varying Cox regression analyses, including duration of cumulative drug exposure and ever/never drug exposure for each glucose-lowering therapy into our model. The reference was no use of the same drug-exposure category. RESULTS There were 22,169 women with type 2 diabetes, with a mean (SD) age of 53.0 (9.2) years and mean (SD) follow up of 2.2 (1.5) years. Hazard ratios for breast cancer in the first 3 months following initiation of metformin, sulfonylurea or thiazolidinedione were 0.66 (0.43 to 1.02), 0.74 (0.44 to 1.25) and 0.67 (0.38 to 1.18), respectively. In the later period of 3 months to 6 years following drug start, hazard ratios (95% CI) for breast cancer were 1.00 (0.98 to 1.02), 1.01 (0.98 to 1.03) and 0.98 (0.95 to 1.01) for metformin, sulfonylurea and thiazolidinedione cumulative exposure, respectively. CONCLUSIONS Our findings suggest that no detection bias exists for glucose-lowering therapies and breast cancer in this population.

Safety of Concomitant Metformin and Proton Pump Inhibitor Use: A Population Retrospective Cohort Study

PURPOSE The purpose of this study was to investigate the effect of concomitant use on important clinical outcomes. METHODS In this retrospective cohort study, a cohort of new metformin users was identified between 2004 and 2010 and followed up until termination of insurance coverage, December 31, 2010, or the outcomes were reached. The primary outcome was a composite of time to all-cause mortality or hospitalization; our secondary outcome was time to cardiovascular hospitalization. Exposures to metformin, a proton pump inhibitor (PPI), and/or a histamine2 receptor antagonist (H2RA) were compared with a Cox proportional hazards model after adjustment. FINDINGS Relative to metformin-only users, metformin and PPI users were at increased risk of the primary outcome (adjusted hazard ratio [HR] = 1.55; 95% CI, 1.46-1.64); metformin and H2RA users also had an elevated risk (adjusted HR = 1.29; 95% CI, 0.97-1.70). Similar patterns were seen with cardiovascular-specific hospitalization. Compared with no drug use, metformin users had an increased risk of the primary outcome, but risk was substantially elevated when patients were taking PPIs or H2RAs, alone or in combination with metformin. IMPLICATIONS Concomitant use of metformin and a PPI or metformin and an H2RA were associated with an increased risk of death or hospitalization. This finding suggests that the harm observed may not be due to a specific drug interaction but uncontrolled confounding secondary to an increased risk in those patients using a PPI or H2RA.

Comparative Effectiveness of Olmesartan and Other Angiotensin Receptor Blockers in Diabetes Mellitus

Olmesartan has been linked with increased risk of cardiovascular mortality and sprue-like enteropathy. We compared outcomes between olmesartan and other angiotensin receptor blockers in a large clinical registry of patients with diabetes mellitus. A retrospective cohort analysis using nationwide US-integrated insurance and laboratory claims was performed in 45 185 incident diabetic angiotensin receptor blocker users, including 10 370 (23%) olmesartan users. Hazard ratios were computed using time-dependant Cox models adjusted for sociodemographic characteristics, comorbidities, laboratory data, drug use, healthcare utilization, and the propensity to receive olmesartan. Blood pressure data were unavailable. Subjects were followed up for 116 721 patient-years. The primary end point was all-cause hospitalization or all-cause mortality and occurred in 10 915 (24%) patients. Average age was 54.3±9.6 years, 52% were men, 17% had cardiovascular disease, and 10% chronic kidney disease. Compared with other angiotensin receptor blockers, the adjusted hazard for olmesartan was 0.99 (95% confidence interval, 0.94–1.05) for all-cause hospitalization and mortality; 0.90 (0.62–1.30) for all-cause mortality; 0.99 (0.94–1.05) for all-cause hospital admission; 0.88 (0.78–1.00) for cardiovascular disease–related admission, and 1.09 (0.98–1.20) for gastrointestinal disease–related hospitalization in the overall cohort. Olmesartan use was associated with an adjusted hazard for the primary outcome of 1.11 (0.99–1.24) in subjects with history of cardiovascular disease and 1.21 (1.04–1.41) in subjects with chronic kidney disease. In conclusion, there is no robust signal for harm with olmesartan use. Risk may be increased in kidney disease; thus, given the widespread availability of alternate agents, olmesartan should be used with caution in this subgroup pending further study.

Comparative Effectiveness of Olmesartan and Other Angiotensin Receptor Blockers in Diabetes MellitusNovelty and Significance

Olmesartan has been linked with increased risk of cardiovascular mortality and sprue-like enteropathy. We compared outcomes between olmesartan and other angiotensin receptor blockers in a large clinical registry of patients with diabetes mellitus. A retrospective cohort analysis using nationwide US-integrated insurance and laboratory claims was performed in 45 185 incident diabetic angiotensin receptor blocker users, including 10 370 (23%) olmesartan users. Hazard ratios were computed using time-dependant Cox models adjusted for sociodemographic characteristics, comorbidities, laboratory data, drug use, healthcare utilization, and the propensity to receive olmesartan. Blood pressure data were unavailable. Subjects were followed up for 116 721 patient-years. The primary end point was all-cause hospitalization or all-cause mortality and occurred in 10 915 (24%) patients. Average age was 54.3±9.6 years, 52% were men, 17% had cardiovascular disease, and 10% chronic kidney disease. Compared with other angiotensin receptor blockers, the adjusted hazard for olmesartan was 0.99 (95% confidence interval, 0.94–1.05) for all-cause hospitalization and mortality; 0.90 (0.62–1.30) for all-cause mortality; 0.99 (0.94–1.05) for all-cause hospital admission; 0.88 (0.78–1.00) for cardiovascular disease–related admission, and 1.09 (0.98–1.20) for gastrointestinal disease–related hospitalization in the overall cohort. Olmesartan use was associated with an adjusted hazard for the primary outcome of 1.11 (0.99–1.24) in subjects with history of cardiovascular disease and 1.21 (1.04–1.41) in subjects with chronic kidney disease. In conclusion, there is no robust signal for harm with olmesartan use. Risk may be increased in kidney disease; thus, given the widespread availability of alternate agents, olmesartan should be used with caution in this subgroup pending further study.

Comparative Effectiveness of Olmesartan and Other Angiotensin Receptor Blockers in Diabetes MellitusNovelty and Significance: Retrospective Cohort Study

Olmesartan has been linked with increased risk of cardiovascular mortality and sprue-like enteropathy. We compared outcomes between olmesartan and other angiotensin receptor blockers in a large clinical registry of patients with diabetes mellitus. A retrospective cohort analysis using nationwide US-integrated insurance and laboratory claims was performed in 45 185 incident diabetic angiotensin receptor blocker users, including 10 370 (23%) olmesartan users. Hazard ratios were computed using time-dependant Cox models adjusted for sociodemographic characteristics, comorbidities, laboratory data, drug use, healthcare utilization, and the propensity to receive olmesartan. Blood pressure data were unavailable. Subjects were followed up for 116 721 patient-years. The primary end point was all-cause hospitalization or all-cause mortality and occurred in 10 915 (24%) patients. Average age was 54.3±9.6 years, 52% were men, 17% had cardiovascular disease, and 10% chronic kidney disease. Compared with other angiotensin receptor blockers, the adjusted hazard for olmesartan was 0.99 (95% confidence interval, 0.94–1.05) for all-cause hospitalization and mortality; 0.90 (0.62–1.30) for all-cause mortality; 0.99 (0.94–1.05) for all-cause hospital admission; 0.88 (0.78–1.00) for cardiovascular disease–related admission, and 1.09 (0.98–1.20) for gastrointestinal disease–related hospitalization in the overall cohort. Olmesartan use was associated with an adjusted hazard for the primary outcome of 1.11 (0.99–1.24) in subjects with history of cardiovascular disease and 1.21 (1.04–1.41) in subjects with chronic kidney disease. In conclusion, there is no robust signal for harm with olmesartan use. Risk may be increased in kidney disease; thus, given the widespread availability of alternate agents, olmesartan should be used with caution in this subgroup pending further study.