Sex Differences in Cardiovascular Effectiveness of Newer Glucose‐Lowering Drugs Added to Metformin in Type 2 Diabetes Mellitus
Bibliographic record
Abstract
Background Randomized controlled trials showed that newer glucose‐lowering agents are cardioprotective, but most participants were men. It is unknown whether benefits are similar in women. Methods and Results Among adults with type 2 diabetes mellitus not controlled with metformin with no prior use of insulin, we assessed for sex differences in the cardiovascular effectiveness and safety of sodium‐glucose‐like transport‐2 inhibitors ( SGLT ‐2i), glucagon‐like peptide‐1 receptor agonists ( GLP ‐1 RA ), dipeptidyl peptidase‐4 inhibitors, initiated as second‐line agents relative to sulfonylureas (reference‐group). We studied type 2 diabetes mellitus American adults with newly dispensed sulfonylureas, SGLT ‐2i, GLP ‐1 RA , or dipeptidyl peptidase‐4 inhibitors (Marketscan‐Database: 2011–2017). We used multivariable Cox proportional hazards models with time‐varying exposure to compare time to first nonfatal cardiovascular event (myocardial infarction/unstable angina, stroke, and heart failure), and safety outcomes between drugs users, and tested for sex–drug interactions. Among 167 254 type 2 diabetes mellitus metformin users (46% women, median age 59 years, at low cardiovascular risk), during a median 4.5‐year follow‐up, cardiovascular events incidence was lower in women than men (14.7 versus 16.7 per 1000‐person‐year). Compared with sulfonylureas, hazard ratios ( HR s) for cardiovascular events were lower with GLP ‐1 RA (adjusted HR ‐women: 0.57, 95% CI : 0.48–0.68; aHR ‐men: 0.82, 0.71–0.95), dipeptidyl peptidase‐4 inhibitors ( aHR ‐women: 0.83, 0.77–0.89; aHR ‐men: 0.85, 0.79–0.91) and SGLT ‐2i ( aHR ‐women: 0.58, 0.46–0.74; aHR ‐men: 0.69, 0.57–0.83). A sex‐by‐drug interaction was statistically significant only for GLP ‐1 RA ( P =0.002), suggesting greater cardiovascular effectiveness in women. Compared with sulfonylureas, risks of adverse events were similarly lower in both sexes for GLP ‐1 RA ( aHR ‐women: 0.81, 0.73–0.89; aHR ‐men: 0.80, 0.71–0.89), dipeptidyl peptidase‐4 inhibitors ( aHR ‐women: 0.82, 0.78–0.87; aHR ‐men: 0.83, 0.78–0.87) and SGLT ‐2i ( aHR ‐women: 0.68, 0.59–0.78; aHR ‐men: 0.67, 0.59–0.78) (all sex–drug interactions for adverse events P >0.05). Conclusions Newer glucose‐lowering drugs were associated with lower risk of cardiovascular events than sulfonylureas, with greater effectiveness of GLP ‐1 RA in women than men. Overall, they appeared safe, with a better safety profile for SGLT ‐2i than for GLP ‐1 RA regardless of sex.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.006 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".