Alicia Gilsenan

Introduction At the time of dapagliflozin’s approval in Europe (2012) to treat patients with type 2 diabetes mellitus, concerns regarding acute liver injury and severe complications of urinary tract infection (sUTI) led to two post-authorization safety (PAS) studies of these outcomes to monitor the safety of dapagliflozin in real-world use. Objective To investigate the incidence of hospitalization for acute liver injury (hALI) or sUTI (pyelonephritis or urosepsis) among patients initiating dapagliflozin compared with other glucose-lowering drugs (GLDs). Methods These two noninterventional cohort studies identified initiators of dapagliflozin and comparator GLDs in November 2012–February 2019 using data from three longitudinal, population-based data sources: Clinical Practice Research Datalink (UK), the HealthCore Integrated Research Database (USA), and the Medicare database (USA). Outcomes (hALI and sUTI) were identified with electronic algorithms. Incidence rates were estimated by exposure group. Incidence rate ratios (IRRs) were calculated comparing dapagliflozin to comparator GLDs, using propensity score trimming and stratification to address confounding. The sUTI analyses were conducted separately by sex. Results In all data sources, hALI and sUTI incidence rates were generally lower in dapagliflozin initiators than comparator GLD initiators. The adjusted IRR (95% confidence interval) pooled across data sources for hALI was 0.85 (0.59–1.24) and for sUTI was 0.76 (0.60–0.96) in females and 0.74 (0.56–1.00) in males. Findings from sensitivity analyses were largely consistent with the primary analyses. Conclusions These real-world studies do not suggest increased risks of hALI or sUTI, and they suggest a potential decreased risk of sUTI with dapagliflozin exposure compared with other GLDs.

Introduction Dapagliflozin is a sodium-glucose cotransporter 2 inhibitor approved to treat type 2 diabetes mellitus (T2DM), among other conditions. When dapagliflozin was approved in Europe for treating T2DM (2012), potential safety concerns regarding its effect on kidney function resulted in this post-authorization safety study to assess hospitalization for acute kidney injury (hAKI) among dapagliflozin initiators in a real-world setting. Objective The aim of this study was to evaluate the incidence of hAKI in adults with T2DM initiating dapagliflozin compared with other glucose-lowering drugs (GLDs). Methods This noninterventional cohort study identified new users of dapagliflozin and comparator GLDs from November 2012 to February 2019 from three longitudinal, population-based data sources: Clinical Practice Research Datalink (CPRD; United Kingdom), the HealthCore Integrated Research Database (HIRD; United States [US]), and Medicare (US). Electronic algorithms identified occurrences of hAKI, from which a sample underwent validation. Incidence rates for hAKI were calculated, and incidence rate ratios (IRRs) compared hAKI in dapagliflozin with comparator GLDs. Propensity score trimming and stratification were conducted for confounding adjustment. Results In all data sources, dapagliflozin initiators had a lower hAKI incidence rate than comparator GLD initiators (adjusted IRRs: CPRD, 0.44 [95% confidence interval (CI), 0.22–0.86]; HIRD, 0.76 [95% CI, 0.62–0.93]; Medicare, 0.69 [95% CI, 0.59–0.79]). The adjusted IRR pooled across the data sources was 0.70 (95% CI, 0.62–0.78). Results from sensitivity and stratified analyses were consistent with the primary analysis. Conclusions This study, with > 34,000 person-years of real-world dapagliflozin exposure, suggests a decreased risk of hAKI in patients with T2DM exposed to dapagliflozin, aligning with results from dapagliflozin clinical trials. Study registration European Union Post-Authorisation Studies Register, EUPAS 11684; ClinicalTrials.gov, NCT02695082.

Introduction This study aimed to estimate risks of cardiovascular and cerebrovascular events in patients treated with lisdexamfetamine dimesylate (LDX) compared with patients previously treated with other attention-deficit/hyperactivity disorder (ADHD) medications (amphetamine, dexamphetamine, methylphenidate or atomoxetine). Methods This population-based cohort study used data from Danish and Swedish medical and administrative national registers. The LDX cohort included adult patients initiating LDX with at least 12 months’ data preceding first LDX dispensing (index date). A random sample of patients treated with at least one non-LDX ADHD medication in the 6–24 months (but not less than 6 months) before index date (previous-users cohort) were matched to LDX users on age, sex, region and calendar year. The primary outcome, a composite of major adverse cardiovascular and cerebrovascular events (MACE), included first hospitalisation for acute myocardial infarction or stroke and out-of-hospital coronary heart disease or cerebrovascular disease death. Incidence rates (IRs) and IR ratios (IRRs) with 95% confidence intervals (CIs) of MACE were estimated using Poisson regression. Results From Denmark/Sweden, 5516/40,163 LDX users and 27,494/200,389 previous users were included. In Denmark, IRs of MACE/1000 person-years (95% CI) were similar for LDX (1.63 [0.85–3.14]) and previous users (1.61 [1.28–2.01]). In Sweden, IRs (95% CI) were 1.40 (1.09–1.79) in LDX users and 1.17 (1.00–1.38) in previous users. Adjusted MACE IRRs (95% CI) for LDX versus previous use were 1.01 (0.48–2.13) in Denmark, 1.13 (0.75–1.71) in Sweden, and 1.10 (0.77–1.58) in the pooled analysis. Conclusion Our findings suggest little to no increased risk of cardiovascular and cerebrovascular events in patients treated with LDX compared with patients previously treated with other ADHD medications.

The phase 3 trials of the bone anabolic drug teriparatide were prematurely terminated because of a preclinical finding of osteosarcoma in rats treated with high doses of teriparatide for near lifetime. Even so, results from these and subsequent clinical trials showed efficacy and tolerability. Based on the phase 3 results and additional preclinical investigations, Forteo (teriparatide) was approved for use in the United States with an indication for the treatment of osteoporosis in patients at high risk for fracture, a boxed warning regarding potential risk of osteosarcoma, a 2‐year lifetime limitation of use, other risk mitigations, and a requirement to assess for risk of osteosarcoma in humans treated with teriparatide. Subsequent investigations included five real‐world studies directed at assessing a connection between teriparatide and osteosarcoma risk in humans. The early studies did not identify an increased risk of osteosarcoma but were inadequate to sufficiently characterize risk, given the low incidence of this rare form of bone cancer. Learning from these efforts, two studies were undertaken using claims data to identify large cohorts of patients treated with teriparatide and assess whether these patients were found to have osteosarcoma by linking pharmacy claims data with data from cancer registries. These studies showed no increase in osteosarcoma in patients using teriparatide compared with unexposed groups, as well as to the expected population‐based background incidence of the disease. Based on this real‐world evidence and the totality of data collected from postmarketing use and other clinical investigations, the label was updated in 2020. The changes included addition of information from large observational studies using real‐world evidence, removal of the boxed warning, and a revision of the 2‐year lifetime limitation. Thus, observational studies with large sample sizes using real‐world data can provide supportive evidence to facilitate regulatory decisions including the elimination of a boxed warning. © 2022 Eli Lilly and Company. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Introduction A multinational post-authorization safety study assessed cardiovascular safety in initiators of prucalopride for chronic constipation compared with a matched cohort of polyethylene glycol 3350 initiators. The primary safety outcome was major adverse cardiovascular events (MACE), a composite of hospitalization for acute myocardial infarction, stroke, or in-hospital cardiovascular death. We report the validation process for MACE endpoints in United Kingdom (UK) data sources: Clinical Practice Research Datalink (CPRD GOLD), The Health Improvement Network (THIN), and the Information Services Division (ISD) Scotland. Methods Modified electronic algorithms from prior research identified potential MACE cases. Validation followed a common protocol, adapted for each database, with all information anonymized: (1) direct confirmation via linkage to hospital records (CPRD GOLD); (2) requests for additional clinical information through questionnaires (CPRD GOLD), free-text (THIN), or abstraction of hospital records (ISD); (3) manual review of electronic records of potential events retrieved by the algorithm (CPRD GOLD/THIN); and (4) event adjudication by three clinicians, blinded to exposure, for all remaining events. Results Electronic algorithms identified 260 potential MACE cases: 38 confirmed via linkage to hospital records (CPRD GOLD), 56 ruled out as non-cardiovascular death cases (THIN), and three unavailable for review (ISD), leaving 163 potential cases. After manual review with additional information (steps 2 and 3), 45 were considered noncases (CPRD GOLD/THIN). Upon final adjudication (step 4), remaining potential events were adjudicated as definite (n = 62), probable (n = 10), possible (n = 13), or noncases (n = 33). Conclusions Given the limitations of relying solely on computer algorithms to identify cardiovascular outcomes, validation with clinical review is essential to guide interpretation.

Summary The Forteo Patient Registry estimated the incidence of osteosarcoma in US patients treated with teriparatide and enrolled in the study between 2009 and 2019. No incident cases of osteosarcoma were identified among patients registered, and the crude incidence rate was 0 (95% confidence interval [CI], 0–10.2) cases per million person-years. Purpose The prospective, voluntary Forteo Patient Registry was established to estimate the incidence of osteosarcoma in patients who have received treatment with teriparatide (Forteo). Methods Information on US adults prescribed teriparatide and enrolled in the Forteo Patient Registry 2009–2019 was linked with data from participating state cancer registries annually (2010–2019) to identify incident osteosarcoma cases using a standardized linkage algorithm. Teriparatide exposure was ascertained from self-reported data that included teriparatide initiation and demographics necessary to complete linkage. Osteosarcoma cases diagnosed on or after January 1, 2009, were identified by participating state cancer registries. The crude incidence rate (IR) and standardized incidence ratio (SIR) of observed cases to the expected number of cases adjusted to the background rate (3 per million person-years) and corresponding 95% CIs for the occurrence of osteosarcoma were calculated whereby the cumulative amount of person-time observed was adjusted for mortality. Results Data for 75,247 enrolled patients (representing 361,763 cumulative person-years) were linked to each of 42 participating state cancer registries (covering 93% of the US population), which included information on 6180 cases of osteosarcoma. No matches with incident cases of osteosarcoma following registry enrollment were found. The crude IR was 0 (95% CI, 0–10.2) cases per million person-years and the SIR was 0 (95% CI, 0–3.0). Conclusions The ability to draw conclusions about the incidence of osteosarcoma among patients participating in the registry was limited due to the smaller than expected amount of patient follow-up time and the fact that no cases were identified.

Purpose: Strategies to identify and validate acute myocardial infarction (AMI) and stroke in primary‐care electronic records may impact effect measures, but to an unknown extent. Additionally, the validity of cardiovascular risk factors that could act as confounders in studies on those endpoints has not been thoroughly assessed in the United Kingdom Clinical Practice Research Datalink's (CPRD's) GOLD database. We explored the validity of algorithms to identify cardiovascular outcomes and risk factors and evaluated different outcome‐identification strategies using these algorithms for estimation of adjusted incidence rate ratios (IRRs).Methods: First, we identified AMI, stroke, smoking, obesity, and menopausal status in a cohort treated for overactive bladder by applying computerized algorithms to primary care medical records (2004–2012). We validated these cardiovascular outcomes and risk factors with physician questionnaires (gold standard for this analysis). Second, we estimated IRRs for AMI and stroke using algorithm–identified and questionnaire–confirmed cases, comparing these with IRRs from cases identified through linkage with hospitalization/mortality data (best estimate).Results: For AMI, the algorithm's positive predictive value (PPV) was >90%. Initial algorithms for stroke performed less well because of inclusion of codes for prevalent stroke; algorithm refinement increased PPV to 80% but decreased sensitivity by 20%. Algorithms for smoking and obesity were considered valid. IRRs based on questionnaire‐confirmed cases only were closer to IRRs estimated from hospitalization/mortality data than IRRs from algorithm‐identified cases.Conclusions: AMI, stroke, smoking, obesity, and postmenopausal status can be accurately identified in CPRD. Physician questionnaire–validated AMI and stroke cases yield IRRs closest to the best estimate.

The Osteosarcoma Surveillance Study was initiated in the United States in 2003 to monitor for a potential association between the osteoporosis treatment teriparatide and osteosarcoma. Osteosarcoma occurs at a background incidence rate of approximately 2.5 cases per million per year in US adults aged 40 years or older. For this study, incident cases of osteosarcoma diagnosed between January 1, 2003, and December 31, 2016, were identified through participating cancer registries in the United States. Information on prior exposure to medications and possible risk factors was obtained by self‐report (or proxy report) in telephone interviews. Exposure information was verified through medical record abstraction for a sample of patients. A standardized incidence ratio was estimated to compare the observed and expected numbers of osteosarcoma patients with a prior history of teriparatide treatment. Interviews were completed for 24% (1173) of patients diagnosed with osteosarcoma between 2003 and 2016; three reports of teriparatide use before diagnosis were identified. Based on the background incidence rate, the expected number of osteosarcoma cases among patients treated with teriparatide was 4.17. Given the three observed cases, the standardized incidence ratio was 0.72 (90% confidence interval [CI], 0.20 to 1.86). Demographic characteristics were similar for interviewed and noninterviewed patients. Agreement was >90% between self‐reported and chart‐recorded exposure to osteoporosis medications. Mean age of interviewed patients was 61 years; 53% of patients were male, 84% were white, and 5% were Hispanic. The prevalence of suspected risk factors for development of osteosarcoma among the osteosarcoma cohort was 19% for history of radiation and 4% for history of Paget's disease of bone. These findings showed that the incidence of osteosarcoma associated with teriparatide use during the 15‐year surveillance period was no different than would be expected based on the background incidence rate of osteosarcoma. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Purpose: During preclinical testing, teriparatide caused a dose‐dependent increase in the incidence of osteosarcoma in rats. This study compared the incidence rate of osteosarcoma among patients aged ≥65 years treated with teriparatide vs a matched‐comparator cohort.Methods: This population‐based comparative‐cohort study matched exposure details for each teriparatide user, identified via Medicare Part D prescription claims, and up to four comparators based on age, sex, zip code, date of claim for filled prescription, and number of unique therapeutic classes dispensed. Outcomes were identified via linkage with participating cancer registries. All US state cancer registries were invited to participate.Results: Overall, 153 316 patients in the teriparatide cohort and 613 247 in the comparator cohort were linked to 811 osteosarcoma cases from 26 participating state cancer registries (68% of US patients aged ≥65 years diagnosed 2007‐2014). Analysis on a subset of cohorts revealed they were balanced for known osteosarcoma risk factors and Charlson comorbidity index. Mean duration of teriparatide treatment was 10 months. No osteosarcoma cases were observed in the teriparatide cohort; the incidence rate in the comparator cohort was consistent with the background incidence rate among adults aged ≥65 years. The incidence rate ratio was 0.0 (95% confidence interval, 0.0‐3.2).Conclusions: For US patients aged ≥65 years, incidence of osteosarcoma among those treated with teriparatide ranges from 0 to 3.2 times the incidence of osteosarcoma in those treated with other medications. Given low incidence of osteosarcoma, this range of effect is inconsistent with a large absolute increase in osteosarcoma risk.