No randomized clinical trials have directly compared the cardiorenal effectiveness of empagliflozin and GLP-1RA agents with demonstrated cardioprotective effects in patients with a broad spectrum of ...cardiovascular risk. We reported the final-year results of the EMPRISE study, a monitoring program designed to evaluate the cardiorenal effectiveness of empagliflozin across broad patient subgroups.
We identified patients ≥ 18 years old with type 2 diabetes who initiated empagliflozin or GLP-1RA from 2014 to 2019 using US Medicare and commercial claims databases. After 1:1 propensity score matching using 143 baseline characteristics, we evaluated risks of outcomes including myocardial infarction (MI) or stroke, hospitalization for heart failure (HHF), major adverse cardiovascular events (MACE - MI, stroke, or cardiovascular mortality), a composite of HHF or cardiovascular mortality, and progression to end-stage kidney disease (ESKD) (in patients with chronic kidney disease stages 3-4). We estimated hazard ratios (HR) and rate differences (RD) per 1,000 person-years, overall and within subgroups of age, sex, baseline atherosclerotic cardiovascular disease (ASCVD), and heart failure (HF).
We identified 141,541 matched pairs. Compared with GLP-1RA, empagliflozin was associated with similar risks of MI or stroke HR: 0.99 (0.92, 1.07); RD: -0.23 (-1.25, 0.79), and lower risks of HHF HR: 0.50 (0.44, 0.56); RD: -2.28 (-2.98, -1.59), MACE HR: 0.90 (0.82, 0.99); RD: -2.54 (-4.76, -0.32), cardiovascular mortality or HHF HR: 0.77 (0.69, 0.86); RD: -4.11 (-5.95, -2.29), and ESKD 0.75 (0.60, 0.94); RD: -6.77 (-11.97, -1.61). Absolute risk reductions were larger in older patients and in those with baseline ASCVD/HF. They did not differ by sex.
The cardiovascular benefits of empagliflozin vs. cardioprotective GLP-1RA agents were larger in older patients and in patients with history of ASCVD or HF, while they did not differ by sex. In patients with advanced CKD, empagliflozin was associated with risk reductions of progression to ESKD.
ObjectivePoor medication adherence remains highly prevalent and adversely affects health outcomes. Patients frequently describe properties of the pills themselves, like size and shape, as barriers, ...but this has not been evaluated objectively. We sought to determine the extent to which oral medication properties thought to be influential translate into lower objectively-measured adherence.DesignRetrospective cohort study.SettingUS nationwide commercial claims database, 2016–2019.ParticipantsAmong patients initiating first-line hypertension, diabetes or hyperlipidaemia treatment based on clinical guidelines, we measured pill size, shape, colour and flavouring, number of pills/day and fixed-dose combination status as properties.Outcome measuresOutcomes included discontinuation after the first fill (ie, never filling again over a minimum of 1-year follow-up) and long-term non-adherence (1-year proportion of days covered <0.80). We estimated associations between each property and outcomes, by therapeutic class (eg, statins), with multivariable logistic regression.ResultsAcross 604 323 patients, 14.6% discontinued after filling once (ie, were non-persistent), and 54.0% were non-adherent over 1-year follow-up. Large pill size was associated with non-adherence, except for thiazides (eg, metformin adjusted OR (aOR): 1.12, 95% CI: 1.06 to 1.18). Greater pill burden was associated with a higher risk of non-adherence across all classes (eg, metformin aOR: 1.58, 95% CI: 1.53 to 1.64 for two pills/day). Taking less than one pill/day was also associated with higher risk of non-adherence and non-persistence (eg, non-persistence statin aOR: 1.29, 95% CI: 1.20 to 1.38). Pill shape, colour, flavouring and combination status were associated with mixed effects across classes.ConclusionsPill burden and pill size are key properties affecting adherence for almost all classes; others, like size and combination, could modestly affect medication adherence. Clinical interventions could screen patients for potential intolerance to medication and potentially implement more convenient dosing schedules.
Nonrandomized studies using insurance claims databases can be analyzed to produce real-world evidence on the effectiveness of medical products. Given the lack of baseline randomization and ...measurement issues, concerns exist about whether such studies produce unbiased treatment effect estimates.
To emulate the design of 30 completed and 2 ongoing randomized clinical trials (RCTs) of medications with database studies using observational analogues of the RCT design parameters (population, intervention, comparator, outcome, time PICOT) and to quantify agreement in RCT-database study pairs.
New-user cohort studies with propensity score matching using 3 US claims databases (Optum Clinformatics, MarketScan, and Medicare). Inclusion-exclusion criteria for each database study were prespecified to emulate the corresponding RCT. RCTs were explicitly selected based on feasibility, including power, key confounders, and end points more likely to be emulated with real-world data. All 32 protocols were registered on ClinicalTrials.gov before conducting analyses. Emulations were conducted from 2017 through 2022.
Therapies for multiple clinical conditions were included.
Database study emulations focused on the primary outcome of the corresponding RCT. Findings of database studies were compared with RCTs using predefined metrics, including Pearson correlation coefficients and binary metrics based on statistical significance agreement, estimate agreement, and standardized difference.
In these highly selected RCTs, the overall observed agreement between the RCT and the database emulation results was a Pearson correlation of 0.82 (95% CI, 0.64-0.91), with 75% meeting statistical significance, 66% estimate agreement, and 75% standardized difference agreement. In a post hoc analysis limited to 16 RCTs with closer emulation of trial design and measurements, concordance was higher (Pearson r, 0.93; 95% CI, 0.79-0.97; 94% meeting statistical significance, 88% estimate agreement, 88% standardized difference agreement). Weaker concordance occurred among 16 RCTs for which close emulation of certain design elements that define the research question (PICOT) with data from insurance claims was not possible (Pearson r, 0.53; 95% CI, 0.00-0.83; 56% meeting statistical significance, 50% estimate agreement, 69% standardized difference agreement).
Real-world evidence studies can reach similar conclusions as RCTs when design and measurements can be closely emulated, but this may be difficult to achieve. Concordance in results varied depending on the agreement metric. Emulation differences, chance, and residual confounding can contribute to divergence in results and are difficult to disentangle.
Type 2 diabetes (T2D) is associated with an increased risk of kidney stones. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) might lower the risk of nephrolithiasis by altering urine composition. ...However, no studies have investigated the association between SGLT2i use and nephrolithiasis risk in patients receiving routine care in the US.
To investigate the association between SGLT2i use and nephrolithiasis risk in clinical practice.
This new-user, active comparator cohort study used data from commercially insured adults (aged ≥18 years) with T2D who initiated treatment with SGLT2is, glucagon-like peptide 1 receptor agonists (GLP-1RAs), or dipeptidyl peptidase 4 inhibitors (DPP4is) between April 1, 2013, and December 31, 2020. The data were analyzed from July 2021 through June 2023.
New initiation of an SGLT2i, GLP-1RA, or DPP4i.
The primary outcome was nephrolithiasis diagnosed by International Classification of Diseases codes in the inpatient or outpatient setting. New SGLT2i users were 1:1 propensity score matched to new users of a GLP-1RA or DPP4i in pairwise comparisons. Incidence rates, rate differences (RDs), and estimated hazard ratios (HRs) with 95% CIs were calculated.
After 1:1 propensity score matching, a total of 716 406 adults with T2D (358 203 pairs) initiating an SGLT2i or a GLP-1RA (mean SD age, 61.4 9.7 years for both groups; 51.4% vs 51.2% female; 48.6% vs 48.5% male) and 662 056 adults (331 028 pairs) initiating an SGLT2i or a DPP4i (mean SD age, 61.8 9.3 vs 61.7 10.1 years; 47.4% vs 47.3% female; 52.6% vs 52.7% male) were included. Over a median follow-up of 192 (IQR, 88-409) days, the risk of nephrolithiasis was lower in patients initiating an SGLT2i than among those initiating a GLP-1RA (14.9 vs 21.3 events per 1000 person-years; HR, 0.69 95% CI, 0.67-0.72; RD, -6.4 95% CI, -7.1 to -5.7) or a DPP4i (14.6 vs 19.9 events per 1000 person-years; HR, 0.74 95% CI, 0.71-0.77; RD, -5.3 95% CI, -6.0 to -4.6). The association between SGLT2i use and nephrolithiasis risk was similar by sex, race and ethnicity, history of chronic kidney disease, and obesity. The magnitude of the risk reduction with SGLT2i use was larger among adults aged younger than 70 years vs aged 70 years or older (HR, 0.85 95% CI, 0.79-0.91; RD, -3.46 95% CI, -4.87 to -2.05 per 1000 person-years; P for interaction <.001).
These findings suggest that in adults with T2D, SGLT2i use may lower the risk of nephrolithiasis compared with GLP-1RAs or DPP4is and could help to inform decision-making when prescribing glucose-lowering agents for patients who may be at risk for developing nephrolithiasis.
Guidelines for managing venous thromboembolism (VTE) recommend at least 90 days of therapy with oral anticoagulants. Limited evidence exists about the optimal drug for continuing therapy beyond 90 ...days.
To compare having prescriptions dispensed for apixaban, rivaroxaban, or warfarin after an initial 90 days of anticoagulation therapy for the outcomes of hospitalization for recurrent VTE, major bleeding, and death.
This exploratory retrospective cohort study used data from fee-for-service Medicare (2009-2017) and from 2 commercial health insurance (2004-2018) databases and included 64 642 adults who initiated oral anticoagulation following hospitalization discharge for VTE and continued treatment beyond 90 days.
Apixaban, rivaroxaban, or warfarin prescribed after an initial 90-day treatment for VTE.
Primary outcomes included hospitalization for recurrent VTE and hospitalization for major bleeding. Analyses were adjusted using propensity score weighting. Patients were followed up from the end of the initial 90-day treatment episode until treatment cessation, outcome, death, disenrollment, or end of available data. Weighted Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs.
The study included 9167 patients prescribed apixaban (mean SD age, 71 14 years; 5491 59.9% women), 12 468 patients prescribed rivaroxaban (mean SD age, 69 14 years; 7067 56.7% women), and 43 007 patients prescribed warfarin (mean SD age, 70 15 years; 25 404 59.1% women). The median (IQR) follow-up was 109 (59-228) days for recurrent VTE and 108 (58-226) days for major bleeding outcome. After propensity score weighting, the incidence rate of hospitalization for recurrent VTE was significantly lower for apixaban compared with warfarin (9.8 vs 13.5 per 1000 person-years; HR, 0.69 95% CI, 0.49-0.99), but the incidence rates were not significantly different between apixaban and rivaroxaban (9.8 vs 11.6 per 1000 person-years; HR, 0.80 95% CI, 0.53-1.19) or rivaroxaban and warfarin (HR, 0.87 95% CI, 0.65-1.16). Rates of hospitalization for major bleeding were 44.4 per 1000 person-years for apixaban, 50.0 per 1000 person-years for rivaroxaban, and 47.1 per 1000 person-years for warfarin, yielding HRs of 0.92 (95% CI, 0.78-1.09) for apixaban vs warfarin, 0.86 (95% CI, 0.71-1.04) for apixaban vs rivaroxaban, and 1.07 (95% CI, 0.93-1.24) for rivaroxaban vs warfarin.
In this exploratory analysis of patients prescribed extended-duration oral anticoagulation therapy after hospitalization for VTE, prescription dispenses for apixaban beyond 90 days, compared with warfarin beyond 90 days, were significantly associated with a modestly lower rate of hospitalization for recurrent VTE, but no significant difference in rate of hospitalization for major bleeding. There were no significant differences for comparisons of apixaban vs rivaroxaban or rivaroxaban vs warfarin.
Treatment decisions for Coronavirus Disease 2019 (COVID-19) depend on disease severity, but the prescribing pattern by severity and drivers of therapeutic choices remain unclear.
The objectives of ...the study were to evaluate pharmacological treatment patterns by COVID-19 severity and identify the determinants of prescribing for COVID-19.
Using electronic health record data from a large Massachusetts-based healthcare system, we identified all patients aged ≥ 18 years hospitalized with laboratory-confirmed COVID-19 from 1 March to 24 May, 2020. We defined five levels of COVID-19 severity at hospital admission: (1) hospitalized but not requiring supplemental oxygen; (2-4) hospitalized and requiring oxygen ≤ 2, 3-4, and ≥ 5 L per minute, respectively; and (5) intubated or admitted to an intensive care unit. We assessed the medications used to treat COVID-19 or as supportive care during hospitalization.
Among 2821 patients hospitalized for COVID-19, we found inpatient mortality increased by severity from 5% for level 1 to 23% for level 5. As compared to patients with severity level 1, those with severity level 5 were 3.53 times (95% confidence interval 2.73-4.57) more likely to receive a medication used to treat COVID-19. Other predictors of treatment were fever, low oxygen saturation, presence of co-morbidities, and elevated inflammatory biomarkers. The use of most COVID-19 relevant medications has dropped substantially while the use of remdesivir and therapeutic anticoagulants has increased over the study period.
Careful consideration of disease severity and other determinants of COVID-19 drug use is necessary for appropriate conduct and interpretation of non-randomized studies evaluating outcomes of COVID-19 treatments.
While intravenous anti-VEGF agents are known to contribute to arterial thromboembolic events, the cardiovascular (CV) safety of intravitreal anti-VEGF inhibitors remain unclear. Using Medicare and 2 ...U.S. commercial claims datasets (1/2009-12/2017), we identified 1:1 propensity score matched patients aged ≥18 years with DR initiating treatment with (1) intravitreal anti-VEGF injections or (2) laser procedure or intravitreal steroid injections (30,681 matched pairs). We assessed a composite CV outcome myocardial infarction (MI) or stroke, its individual components, and mortality, using an intention-to-treat (ITT) scheme censoring at 180 days and 365 days of follow-up. We estimated pooled HRs and 95% CIs adjusting for 85 baseline covariates. Compared to laser or steroid treatment, intravitreal anti-VEGF injections were associated with a similar risk of the composite CV outcome HR:0.91 (95% CI:078, 1.06), MI 0.91 (0.74, 1.11), stroke 0.92 (0.74, 1.15), or risk of mortality 1.14 (0.87, 1.51) at 6 months of follow up. Results were consistent in an ITT analysis censoring at 365 days (Table). Intravitreal anti-VEGF injections, compared to laser or steroid treatment, had similar risk of CV events and mortality in patients with DR.
SGLT2 inhibitors (SGLT2is) have been shown to reduce the risk of cardiovascular and mortality events in large cardiovascular outcome trials in patients with type 2 diabetes. However, their safety ...profile is controversial, with some trials reporting imbalances in bladder cancer events, all of which occurred relatively soon after randomization. To address this safety concern, we used 3 US healthcare claims databases and 1 UK primary care database (01/2013-12/2020) . In each database, we identified adults newly treated with either SGLT2is (total n=453,726) or GLP-1 receptor agonists (GLP1RAs, n=375,990) (comparison #1) , and SGLT2is (n=347,055) or DPP-4 inhibitors (DPP4is, n=854,141) (comparison #2) . Propensity score-based fine stratification was used to reweigh the cohorts, adjusting for a wide range of patient characteristics at baseline. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for bladder cancer in each database using Cox proportional hazards models. After a median follow-up of 1.8 years, use of SGLT2is may slightly reduce the risk of bladder cancer, compared to GLP1RAs HR (95% CI) =0.90 (0.81-1.00) . Compared to use of DPP4is, SGLT2is are not associated with bladder cancer incidence HR (95% CI) : 1.00 (0.91-1.11) after a median follow-up of 2.0 years (Table) . Overall, the results of this large international cohort study provide reassurance on the short-term effects of SGLT2is on bladder cancer incidence.
Disclosure
D.Abrahami: None. H.Tesfaye: None. H.Yin: None. O.Yu: None. R.W.Platt: Consultant; Amgen Inc., Biogen, Merck & Co., Inc., Nant Pharma, Pfizer Inc. S.Schneeweiss: None. E.Patorno: Research Support; Boehringer Ingelheim International GmbH, National Institutes of Health, Patient-Centered Outcomes Research Institute. L.Azoulay: Consultant; Pfizer Inc.
Funding
Canadian Institutes of Health Research (PJT-169040)
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