Mickelson, Mindy M

OBJECTIVE To examine kidney disease outcomes associated with dipeptidyl peptidase 4 inhibitors (DPP-4i). RESEARCH DESIGN AND METHODS In this target trial emulation, claims data from enrollees in commercial, Medicare Advantage, and traditional Medicare health plans were used to identify adults ≥21 years old with type 2 diabetes, with moderate cardiovascular risk, and without stage 3 or worse chronic kidney disease (CKD) initiating alogliptin, linagliptin, saxagliptin, or sitagliptin between 2014 and 2021. The primary outcome was a composite of incident CKD stages 3–5, kidney failure, or kidney replacement therapy. Random treatment assignment was emulated using propensity scores, estimated using the super learner ensemble method and incorporated as inverse probability of treatment weights into proportional hazards models. RESULTS The weighted study cohort included 3,026 individuals starting alogliptin, 38,213 starting linagliptin, 14,934 starting saxagliptin, and 115,091 starting sitagliptin. One year after treatment initiation, the primary outcome occurred in 1.4%, 2.7%, 2.2%, and 2.4% of patients initiating alogliptin, linagliptin, saxagliptin, and sitagliptin, respectively, increasing to 3.2%, 6.2%, 5.0%, and 5.4%, respectively, at 3 years. Alogliptin was associated with lower risk of stage 3 or worse CKD than linagliptin (hazard ratio [HR] 0.50; 95% CI 0.37–0.69), saxagliptin (HR 0.63; 95% CI 0.45–0.86), and sitagliptin (HR 0.58; 95% CI 0.42–0.79), while saxagliptin was associated with lower risk than linagliptin (HR 0.80; 95% CI 0.73–0.87). Conversely, linagliptin was associated with higher risk than sitagliptin (HR 1.15, 95% CI 1.10–1.21). CONCLUSIONS Alogliptin was associated with lower risk of moderate-to-severe kidney disease than other DPP-4i, while linagliptin was associated with higher risk. Limitations include lack of laboratory data and potential unmeasured confounding.

Introduction To assess the within-class variation in kidney outcomes following initiation of sulfonylurea therapy. Research design and methods We used claims data of enrollees in commercial, Medicare Advantage, and traditional Medicare health plans between 2014 and 2021 to emulate a target trial including adults ≥21 years with type 2 diabetes at moderate cardiovascular risk to compare initiation of glimepiride, glipizide, or glyburide on the incidence of chronic kidney disease (CKD) stage 3 or worse, including initiation of kidney replacement therapy (primary outcome); secondary outcomes examined incident CKD stages 3-4, kidney failure (including kidney replacement therapy), all-cause mortality, and hypoglycemia requiring emergency department or hospital care. Random treatment assignment was emulated using propensity scores, estimated using the super learner ensemble method, and incorporated as inverse probability of treatment weights into proportional hazards models. Results The weighted study cohort included 295 092 individuals starting glimepiride (n=134 926), glipizide (n=145 984), and glyburide (n=14 182). One year after treatment initiation, stage 3 or worse CKD developed in 2.1% of patients in the glimepiride group, 2.2% in the glipizide group, and 1.8% in the glyburide group. Glyburide was associated with a lower risk of kidney complications compared with both glimepiride (HR 0.84, 95% CI 0.76 to 0.92) and glipizide (HR 0.81, 95% CI 0.73 to 0.89), despite a higher risk of severe hypoglycemia (HR 1.47, 95% CI 1.27 to 1.71 vs glipizide and HR 1.22, 95% CI 1.05 to 1.42 vs glimepiride). In contrast, the risk of kidney complications was modestly increased with glipizide compared with glimepiride use (HR 1.04, 95% CI 1.00 to 1.07). Conclusions Glyburide was associated with a modestly lower risk of kidney complications, despite a higher risk of hypoglycemia, while glipizide was associated with a higher risk of kidney complications. These hypothesis-generating findings suggest important within-class differences that warrant consideration in clinical decision-making and future research. Despite rigorous prespecified causal inference analytic methods, the risk of unmeasured confounding and bias by indication with the use of observational data remains. Trial registration number NCT05214573 .

Background SGLT2 (sodium‐glucose cotransporter 2) inhibitors reduce major adverse cardiovascular events (MACE) in type 2 diabetes. However, no direct comparison of individual SGLT2 inhibitor drugs has been conducted, particularly among adults with moderate cardiovascular risk who comprise most people with type 2 diabetes. Methods We used data for commercial, Medicare Advantage, and Medicare fee‐for‐service beneficiaries to emulate a target trial of adults (≥21 years) with type 2 diabetes and moderate cardiovascular risk who started canagliflozin, dapagliflozin, or empagliflozin between 2015 and 2020. We estimated propensity scores using the super learner ensemble method and incorporated them as inverse probability of treatment weights into Cox models, estimating risk of MACE, expanded MACE, and hyperglycemic and hypoglycemic crises through December 31, 2022. Results The weighted cohort, balanced on all baseline covariates, included 137 232 patients (mean age 65.7 years [SD, 8.1], 75.3% non‐Hispanic White, 57.0% male, 81.9% on metformin, 11.4% on glucagon‐like peptide‐1 receptor agonists) starting canagliflozin (N=42 877), dapagliflozin (N=17 871), or empagliflozin (N=7648). The risk of MACE was lower among patients starting empagliflozin versus canagliflozin (hazard ratio [HR], 0.92 [95% CI, 0.87–0.97]), driven by reduced risk of all‐cause mortality (HR, 0.86 [95% CI, 0.80–0.94]). There was no difference in MACE between empagliflozin versus dapagliflozin or dapagliflozin versus canagliflozin therapy. There was no difference in remaining outcomes between the three drugs. Conclusions The 3 most used SGLT2 inhibitor medications demonstrate similar effectiveness on cardiovascular outcomes among patients with type 2 diabetes at moderate cardiovascular risk, with differences between these drugs small in magnitude. Clinicians and health systems should prioritize enhancing access to these cardioprotective therapies.

Introduction To examine within-class sulfonylurea safety, we compared risks of major adverse cardiovascular events (MACE) and severe hypoglycemia among adults with type 2 diabetes (T2D) and moderate cardiovascular risk following sulfonylurea initiation. Research design and methods We conducted a target trial emulation including adults ≥21 years old with T2D and moderate cardiovascular risk who initiated glimepiride, glipizide or glyburide between 2014 and 2021, using claims data from Optum Labs Data Warehouse and the Medicare fee-for-service 100% sample. Study outcomes were MACE (primary), expanded MACE and its components and emergency department or hospital encounters for hypoglycemia, ascertained during follow-up through 2022. Inverse probability of treatment weighting (IPTW) was applied using propensity scores estimated using the super learner ensemble, and outcomes were examined using IPTW Cox proportional hazards models. Results The weighted study cohort comprised 314 699 patients (mean age 66.9 years, 52.0% men, 76.6% non-Hispanic white). At 1 year, MACE was experienced by 2.5%, 2.7% and 2.8% of patients starting glimepiride, glipizide and glyburide, respectively. Compared with glimepiride, glyburide and glipizide were associated with higher risk of MACE (HR 1.10, 95% CI 1.05 to 1.16 for glyburide; HR 1.05, 95% CI 1.03 to 1.07 for glipizide). At 1 year, severe hypoglycemia was experienced by 0.3%, 0.3% and 0.4% of patients starting glimepiride, glipizide and glyburide, respectively. Glyburide was associated with a greater risk of severe hypoglycemia compared with glipizide (HR 1.43, 95% CI 1.23 to 1.65), while glipizide was associated with a lower risk compared with glimepiride (HR 0.82, 95% CI 0.77 to 0.87). Conclusions Among adults with T2D and moderate cardiovascular risk, glimepiride was associated with lowest risk of MACE and glipizide with lowest risk of severe hypoglycemia. These results can help inform treatment selection if sulfonylureas are used for glucose-lowering.

Background Glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) and sodium–glucose cotransporter‐2 inhibitors (SGLT2is) have favorable cardiovascular outcomes compared with dipeptidyl peptidase‐4 inhibitors (DPP4is) and sulfonylureas in adults with type 2 diabetes and high cardiovascular risk. How these benefits vary across lower levels of cardiovascular risk is unknown. Methods We used nationwide claims data to emulate a comparative effectiveness trial and examine the heterogeneity of treatment effects of GLP‐1RAs, SGLT2is, DPP4is, and sulfonylureas on major adverse cardiovascular events (MACEs) among adults with type 2 diabetes and moderate cardiovascular risk (annualized MACE risk 1%–5%, estimated using the annualized claims‐based MACE estimator). Results Among 386 276 included adults with type 2 diabetes, 25.2% had baseline ACME–predicted MACE risk >1% to ≤2% (lower‐risk patients) and 13.3% had ACME–predicted risk >4% to ≤5% (higher‐risk patients). By year 3 of treatment, higher‐risk patients derived greater absolute benefit than lower‐risk patients when treated with GLP‐1RAs versus sulfonylureas (absolute reduction in the estimated rate of MACE of 3.1% in higher‐risk patients and 1.6% in lower‐risk patients), SGLT2is versus sulfonylureas (absolute reduction, 3.9% in higher‐risk patients and 1.3% in lower‐risk patients), and GLP‐1RAs versus DPP4is (absolute reduction, 1.6% in higher‐risk patients and 0.5% in lower‐risk patients). The relative benefits for MACE were also greater in higher‐risk than lower‐risk patients with SGLT2is versus DPP4is (hazard ratio [HR], 0.78 [95% CI, 0.70–0.87] in higher‐risk patients; HR, 0.99 [95% CI, 0.88–1.12] in lower‐risk patients). Conversely, the relative benefits of DPP4is and GLP‐1RAs versus sulfonylureas were greater in lower‐risk patients: HR 0.76 (95% CI, 0.71–0.81) in lower‐risk and HR 0.91 (95% CI, 0.97–0.96) in higher‐risk patients for DPP4is versus sulfonylureas; HR 0.67 (95% CI, 0.58–0.78) in lower‐risk and HR 0.80 (95% CI, 0.70–0.93) in higher‐risk patients for GLP‐1RAs versus sulfonylurea. Benefits of SGLT2is and GLP‐1RAs were comparable across all risk levels. Conclusions Cardiovascular benefits of SGLT2is and GLP‐1RAs exist across all levels of moderate cardiovascular risk, reinforcing the importance of choosing glucose‐lowering therapies that can prevent MACE in all people with type 2 diabetes.

Importance The increasing use of glucagon-like peptide-1 receptor agonists (GLP-1RA) demands a better understanding of their association with thyroid cancer. Objective To estimate the risk of incident thyroid cancer among adults with type 2 diabetes being treated with GLP-1RA vs other common glucose-lowering medications. Design, Setting, and Participants This was a prespecified secondary analysis of a target trial emulation of a comparative effectiveness study using claims data for enrollees in commercial, Medicare Advantage, and Medicare fee-for-service plans across the US. Eligible participants were adults with type 2 diabetes at moderate risk for cardiovascular disease and without history of thyroid cancer who had newly filled prescriptions for GLP-1RA, sodium-glucose cotransporter 2 inhibitor (SGLT2i), dipeptidyl peptidase-4 inhibitor (DPP4i), or sulfonylurea from January 1, 2014, to December 31, 2021. Data were analyzed February 1 to October 31, 2024. Main Outcomes and Measures Overall and piecewise (<1, 1-2, and ≥2 years since treatment initiation) hazard ratios (HRs) for thyroid cancer with use of GLP-1RA vs the other 3 drug classes were estimated using inverse propensity score weighted Cox proportional hazards models. Modified intention-to-treat (mITT) (primary) and as-treated (sensitivity) analyses were performed. Results Of 351 913 patients (mean [SD] age, 65.3 [8.5] years; 173 391 [49.3%] females and 178 522 [50.7%] males), 41 112 started treatment with GLP-1RA; 76 093, with DPP4i; 43 499, with SGLT2i; and 191 209, with sulfonylurea therapy. The numbers of patients diagnosed with thyroid cancer were 69 (0.17%) in the GLP-1RA group, 172 (0.23%) in the DPP4i group, 72 (0.17%) in the SGLT2i group, and 381 (0.20%) in the sulfonylurea group. In the mITT analysis, GLP-1RA initiation was not significantly associated with increased overall risk for thyroid cancer compared to the other 3 diabetes drugs (HR, 1.24; 95% CI, 0.88-1.76). However, the risk for thyroid cancer was significantly higher within the first year after GLP-1RA initiation (HR, 1.85; 95% CI, 1.11-3.08) and was amplified in the overall as-treated analysis that censored patients when therapy was discontinued or another medication was added (HR, 2.07; 95% CI, 1.10-3.95). Conclusions and Relevance This secondary analysis of a target trial emulation of a comparative effectiveness study found that despite the low absolute risk of thyroid cancer among patients receiving GLP-1RA therapy, there was an increased risk of new thyroid cancer diagnoses within the first year of GLP-1RA initiation compared to 3 other diabetes drugs. This finding may have been due to enhanced early detection; therefore, further research is necessary to understand the underlying causes of this association.

Abstract Introduction: Patient and stakeholder involvement enhances the conduct and applicability of comparative effectiveness research (CER). However, examples of engagement practices for CER leveraging real-world data (i.e., data from routine clinical practice) are scarce. Notably, these studies differ from traditional clinical trials in their technical complexity and minimal prospective data collection, posing unique challenges for stakeholder involvement. This paper describes patient and stakeholder engagement in a CER study of type 2 diabetes (T2D) medications using real-world data from a large administrative claims database. Methods: A Patient and Stakeholder Advisory Group (PSAG) was formed to guide study design, conduct, and dissemination. The PSAG (n = 12) included individuals with T2D, clinicians, health systems leaders, professional society representatives, and a payer representative. Members were surveyed post-study initiation to assess their participation goals and experiences to date. Results: PSAG members influenced key design and methodological decisions, including cohort selection and adding an aim focused on patient preference elicitation. Survey results indicated high satisfaction with engagement processes and a desire for ongoing involvement. Most PSAG members cited their main goals as impacting the lives of people with T2D and ensuring the research’s relevance to clinicians. Conclusions: Best practices for engaging stakeholders in CER using real-world data are underdeveloped. Our experience suggests that an inclusive, stakeholder-engaged approach enriches the research process and ensures diverse perspectives are integrated into study design and conduct. Ongoing efforts will focus on assessing long-term engagement outcomes and PSAG member satisfaction.

Key Points Sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists were superior to dipeptidyl peptidase-4 inhibitor and sulfonylurea for preventing kidney complications in patients with type 2 diabetes at moderate cardiovascular disease risk. Sodium-glucose cotransporter 2 inhibitor therapy compared favorably with glucagon-like peptide-1 receptor agonists for kidney disease outcomes. Background CKD is a serious diabetes-related complication. While guidelines recommend use of sodium-glucose cotransporter 2 inhibitor (SGLT2i) and glucagon-like peptide-1 receptor agonist (GLP-1RA) therapies to mitigate cardiorenal risk in high-risk patients, the benefit of early initiation of these agents relative to other commonly prescribed glucose-lowering agents in patients at lower baseline cardiovascular disease (CVD) risk remains less clear. Methods This retrospective observational study emulated an idealized target trial using claims data from OptumLabs data warehouse to test the comparative association of treatment with a dipeptidyl peptidase-4 inhibitor (DPP-4i), SGLT2i, GLP-1RA, or sulfonylurea (SU) on a primary kidney composite outcome of incident CKD stages 3–5, kidney failure, or need for KRT in patients with type 2 diabetes and moderate CVD risk. A secondary composite outcome included all components of the primary composite outcome plus death. Results A total of 364,714 adults aged 21 years or older initiating treatment with a DPP-4i ( N =78,843), GLP-1RA ( N =42,049), SGLT2i ( N =45,466), or SU ( N =198,356) were identified. Relative to DPP-4i, SGLT2i (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.67 to 0.74; P < 0.001) and GLP-1RA (HR, 0.87; 95% CI, 0.83 to 0.92; P < 0.001) treatment was superior for the primary composite outcome. Similarly, SGLT2i (HR, 0.69; 95% CI, 0.66 to 0.73) and GLP-1RA (HR, 0.86; 95% CI, 0.82 to 0.91) treatment was associated with risk reductions for the primary outcome relative to SU treatment. When comparing SGLT2i with GLP-1RA therapy, SGLT2is were superior for the primary composite outcome (HR, 0.81; 95% CI, 0.75 to 0.86; P < 0.001). Similar findings were observed for the secondary composite outcome across all comparisons. Conclusions SGLT2is and GLP-1RAs were superior to DPP-4is and SUs for preventing kidney complications in a type 2 diabetes population with moderate baseline CVD risk. Clinical Trial registry name and registration number: NCT05214573.

In this emulated comparative effectiveness target trial of glucagon-like peptide 1 (GLP-1) receptor agonist, sodium–glucose cotransporter 2 (SGLT2) inhibitor, dipeptidyl peptidase 4 (DPP-4) inhibitor, and sulfonylurea therapy among adults with type 2 diabetes at moderate cardiovascular disease risk, sulfonylurea use was associated with a significantly higher risk of hypoglycemia requiring emergency department or hospital care than treatment with DPP-4 inhibitors, GLP-1 receptor agonists, or SGLT2 inhibitors. This consideration can guide the choice of glucose-lowering therapy in this highly prevalent patient population, in whom avoidance of hypoglycemia is important, yet among whom the risk of severe hypoglycemia has not been examined previously.

This mixed-methods study sought to identify pharmacotherapy preferences among 40 noninsulin-treated adults with type 2 diabetes receiving care at two U.S. health care systems. Participants ranked by relative importance various health outcomes and medication attributes and then contextualized their rankings. Most participants ranked blindness (63%), death (60%), heart attack (48%), and heart failure (48%) as the most important health outcomes and glucose-lowering efficacy (68%) as the most important medication attribute, followed by oral administration (45%) and lack of gastrointestinal side effects (38%).