Background Recent postmarketing trials produced conflicting results about the risk for hospitalized heart failure (hHF) associated with dipeptidyl peptidase-4 (DPP-4) inhibitors, creating uncertainty about the safety of these antihyperglycemic agents. Objective To examine the associations of hHF with saxagliptin and sitagliptin. Design Population-based, retrospective, new-user cohort study. Setting 18 health insurance and health system data partners in the U.S. Food and Drug Administration’s Mini-Sentinel program. Patients Patients aged 18 years or older with type 2 diabetes who initiated therapy with saxagliptin, sitagliptin, pioglitazone, second-generation sulfonylureas, or long-acting insulin products from 2006 to 2013. Measurements Hospitalized HF, identified by International Classification of Diseases, Ninth Revision, Clinical Modification codes 402.×1, 404.×1, 404.×3, and 428.×× recorded as the principal discharge diagnosis. Results 78 553 saxagliptin users and 298 124 sitagliptin users contributed an average of 7 to 9 months of follow-up data to 1 or more pairwise comparisons. The risk for hHF was not higher with DPP-4 inhibitors than with the other study drugs. The hazard ratios from the disease risk score (DRS)–stratified analyses were 0.83 (95% CI, 0.70 to 0.99) for saxagliptin versus sitagliptin, 0.63 (CI, 0.47 to 0.85) for saxagliptin versus pioglitazone, 0.69 (CI, 0.54 to 0.87) for saxagliptin versus sulfonylureas, and 0.61 (CI, 0.50 to 0.73) for saxagliptin versus insulin. The DRS-stratified hazard ratios were 0.74 (CI, 0.64 to 0.85) for sitagliptin versus pioglitazone, 0.86 (CI, 0.77 to 0.95) for sitagliptin versus sulfonylureas, and 0.71 (CI, 0.64 to 0.78) for sitagliptin versus insulin. Results from the 1:1 propensity score–matched analyses were similar. Results were also similar in subgroups of patients with and without prior cardiovascular disease and in a subgroup defined by the 2 highest DRS deciles. Limitation Residual confounding and short follow-up. Conclusion In this large cohort study, a higher risk for hHF was not observed in users of saxagliptin or sitagliptin compared with other selected antihyperglycemic agents. Primary Funding Source U.S. Food and Drug Administration.

Purpose To validate an algorithm based upon International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM) codes for acute myocardial infarction (AMI) documented within the Mini-Sentinel Distributed Database (MSDD). Methods Using an ICD-9-CM-based algorithm (hospitalized patients with 410.x0 or 410.x1 in primary position), we identified a random sample of potential cases of AMI in 2009 from 4 Data Partners participating in the Mini-Sentinel Program. Cardiologist reviewers used information abstracted from hospital records to assess the likelihood of an AMI diagnosis based on criteria from the joint European Society of Cardiology and American College of Cardiology Global Task Force. Positive predictive values (PPVs) of the ICD-9-based algorithm were calculated. Results Of the 153 potential cases of AMI identified, hospital records for 143 (93%) were retrieved and abstracted. Overall, the PPV was 86.0% (95% confidence interval; 79.2%, 91.2%). PPVs ranged from 76.3% to 94.3% across the 4 Data Partners. Conclusions The overall PPV of potential AMI cases, as identified using an ICD-9-CM-based algorithm, may be acceptable for safety surveillance; however, PPVs do vary across Data Partners. This validation effort provides a contemporary estimate of the reliability of this algorithm for use in future surveillance efforts conducted using the FDA’s MSDD.

Purpose The validity of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes to identify diagnoses of severe acute liver injury (SALI) is not well known. We examined the positive predictive values (PPVs) of hospital ICD-9-CM diagnoses in identifying SALI among health plan members in the Mini-Sentinel Distributed Database (MSDD) for patients without liver/biliary disease and for those with chronic liver disease (CLD). Methods We selected random samples of members (149 without liver/biliary disease; 75 with CLD) with a principal hospital diagnosis suggestive of SALI (ICD-9-CM 570, 572.2, 572.4, 572.8, 573.3, 573.8, or V42.7) in the MSDD (2009–2010). Medical records were reviewed by hepatologists to confirm SALI events. PPVs of codes and code combinations for confirmed SALI were determined by CLD status. Results Among 105 members with available records and no liver/biliary disease, SALI was confirmed in 26 (PPV, 24.7%; 95% CI, 16.9% – 34.1%). Combined hospital diagnoses of acute hepatic necrosis (570) and liver disease sequelae (572.8) had high PPV (100%; 95% CI, 59.0% – 100%) and identified 7/26 (26.9%) events. Among 46 CLD members with available records, SALI was confirmed in 19 (PPV, 41.3%; 95% CI, 27.0% – 56.8%). Acute hepatic necrosis (570) or hepatorenal syndrome (572.4) plus any other SALI code had a PPV of 83.3% (95% CI, 51.6% – 97.9%) and identified 10/19 (52.6%) events. Conclusions Most individual hospital ICD-9-CM diagnoses had low PPV for confirmed SALI events. Select code combinations had high PPV but did not capture all events.