Assessment of thyroid cancer risk associated with glucagon‐like peptide 1 receptor agonist use

To determine the potential association between the use of either glucagon-like peptide-1 receptor agonists (GLP-1RAs) or dipeptidyl peptidase-4 (DPP-4) inhibitors, and the risk of thyroid cancer in individuals with type 2 diabetes. This population-based cohort study used claims data from the Korean National Health Insurance Database, 2014-2020. Two distinct cohorts were established to compare each incretin-based drug with sodium-glucose cotransporter-2 (SGLT2) inhibitors, chosen as active comparators because of their previous non-association with thyroid cancer, and their common usage as add-on therapy to metformin along with GLP-1RAs and DPP-4 inhibitors. The first cohort included 21 722 new users of GLP-1RAs and 326 993 new users of SGLT2 inhibitors, whereas the second cohort included 904 300 DPP-4 inhibitor new users and 112 017 SGLT2 inhibitor new users. The outcome was the time to incident thyroid cancer. Weighted Cox proportional models were used to estimate hazard ratios of thyroid cancer incidence associated with incretin-based drugs of interest. The use of GLP-1RAs was not associated with an increased risk of thyroid cancer (weighted hazard ratio 0.98, 95% confidence interval 0.62-1.53) compared with that of SGLT2 inhibitors. Using DPP-4 inhibitors was also not associated with an increased risk of thyroid cancer (0.95, 0.79-1.14) compared with that of SGLT2 inhibitors. No significant effect modifications were observed across subgroup analyses. Sensitivity analyses, including alternative outcome definition analysis of medullary thyroid cancer, were consistent with the primary analysis results. GLP-1RAs and DPP-4 inhibitors were not associated with an increased risk of thyroid cancer in individuals with type 2 diabetes.

Time to Follow the Evidence: Glycemic Control and Cardiovascular Benefits of New Diabetes Medications

ObjectivesTo evaluate the comparative effectiveness of sodium-glucose cotransporter-2 (SGLT-2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and dipeptidyl peptidase-4 (DPP-4) inhibitors in preventing hyperkalemia in people with type 2 diabetes in...

The increasing use of glucagon-like peptide-1 receptor agonists (GLP-1RA) demands a better understanding of their association with thyroid cancer. 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. 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. 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. 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). 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.

New Glucose-Lowering Agents for Diabetic Kidney Disease.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists reduce cardiovascular and renal risks in type 2 diabetes mellitus (T2DM), but their relative efficacy remains uncertain due to the absence of direct comparative trials. This systematic review and network meta-analysis aimed to evaluate the efficacy and safety of interventions concerning major adverse cardiovascular events (MACE), heart failure, and renal outcomes. A systematic review and network meta-analysis of large-scale, placebo-controlled cardiovascular outcome trials was conducted. PubMed, Embase, and CENTRAL were searched for trials published up to December 2025. The primary outcome was MACE (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke). The secondary outcomes included hospitalization for heart failure (HHF), composite renal outcomes, and all-cause mortality. The evaluated safety outcomes included severe hypoglycemia, diabetic ketoacidosis, amputation, fracture, and genital infections. Data were pooled using a frequentist random-effects model. In total, 14 trials involving 117,633 participants were included. Both drug classes reduced the risk of MACE compared with placebo (SGLT2i: hazard ratio (HR) = 0.89, 95% confidence interval (CI) = 0.84-0.94; GLP-1RA: HR = 0.86, 95% CI = 0.80-0.93), with no statistically significant difference observed between the two (HR = 1.03, 95% CI = 0.94-1.13). SGLT2 inhibitors had a greater efficacy than GLP-1 receptor agonists in reducing HHF (HR = 0.75, 95% CI = 0.66-0.85) and composite renal outcomes (HR = 0.76, 95% CI = 0.66-0.87). Similarly, both classes lowered all-cause mortality. SGLT2 inhibitors exhibited an elevated risk of genital infections (relative risk (RR) = 3.49, 95% CI = 2.63-4.55) and diabetic ketoacidosis (RR = 2.36, 95% CI = 1.33-4.17) compared to GLP-1 receptor agonists. SGLT2 inhibitors and GLP-1 receptor agonists are equally effective in preventing MACE. However, SGLT2 inhibitors offer enhanced protection against heart failure and renal disease progression, whereas GLP-1 receptor agonists exhibit a more favorable safety profile for genital infections and ketoacidosis. These findings support a phenotype-specific treatment approach for patients with T2DM.

ObjectiveTo investigate whether use of glucagon-like peptide 1 (GLP1) receptor agonists is associated with increased risk of thyroid cancer.DesignScandinavian cohort study.SettingDenmark, Norway, and Sweden, 2007-21.ParticipantsPatients who started GLP1 receptor agonist...

Introduction and Objective: The real-world evidence on the association between glucagon-like peptide 1 receptor agonists (GLP-1RAs) and cancer risk remains limited and mixed. Methods: In 2013-2020 national Medicare Claims data, we included cancer naïve patients with type 2 diabetes (T2D). We identified those who initiated GLP-1 RA, sodium-glucose cotransporter 2 inhibitor (SGLT2i), or a dipeptidyl peptidase 4 inhibitor (DPP4i) and conducted 1:1 propensity score matching for confounding adjustment. Cox proportional hazard models were used to estimate hazard ratios (HRs) of nine obesity-associated cancers (thyroid, pancreatic, bladder, colorectal, lung, kidney, breast, endometrial, and prostate cancer). Results: In the matched GLP-1RA vs. SGLT2i cohort (n=21,362 pairs), GLP-1RA users had similar overall cancer risk with SGLT2i users (HR, 1.03 [95% CI, 0.95-1.12]), but were associated with an increased kidney cancer risk (HR, 1.43 [1.06 to 1.92]). In the matched GLP-1RA vs. DPP4i cohort (n=20,962 pairs), the GLP-1RA vs. DPP4i comparison showed no significant difference in overall cancer risk (HR, 0.96 [0.89-1.04]), but revealed a significantly elevated endometrial cancer risk (HR, 1.55 [1.01-2.37]). Conclusion: GLP-1RAs might be associated with an increased risk of certain cancer types. Future studies are needed to validate the potential tumorigenic risk associated with GLP1-RAs. Disclosure Y. Lu: None. H. Dai: None. H. Tang: None. W.T. Donahoo: None. T.J. George: Consultant; BillionToOne, Nihon Medi-Physics, Kahr Medical, Avammune Therapeutics, Exact Sciences, Summit Therapeutics, Arbele. Y. Guo: None. J. Guo: None. J. Bian: None.

Concerns have been raised regarding a link between use of glucagon-like peptide-1 (GLP-1) receptor agonists and increased risk of suicidality and self-harm. To assess the association between use of GLP-1 receptor agonists and the risk of suicide death in routine clinical practice. This active-comparator new-user cohort study used nationwide register data from Sweden and Denmark from 2013 to 2021. Adults 18 to 84 years old who initiated treatment with GLP-1 receptor agonists or the comparator sodium-glucose cotransporter-2 (SGLT2) inhibitors were included. Data were analyzed from March to June 2024. Initiation of treatment with a GLP-1 receptor agonist or SGLT2 inhibitor. The primary outcome was suicide death recorded in the cause of death registers. Secondary outcomes were the composite of suicide death and nonfatal self-harm and the composite of incident depression and anxiety-related disorders. Using propensity score weighting, hazard ratios (HRs) with 95% CIs were calculated separately in the 2 countries and pooled in a meta-analysis. In total, 124 517 adults initiated a GLP-1 receptor agonist and 174 036 initiated an SGLT2 inhibitor; among GLP-1 receptor agonist users, the mean (SD) age was 60 (13) years, and 45% were women. During a mean (SD) follow-up of 2.5 (1.7) years, 77 suicide deaths occurred among users of GLP-1 receptor agonists and 71 suicide deaths occurred among users of SGLT2 inhibitors: weighted incidences were 0.23 vs 0.18 events per 1000 person-years (HR, 1.25; 95% CI, 0.83-1.88), with an absolute difference of 0.05 (95% CI, -0.03 to 0.16) events per 1000 person-years. The HR was 0.83 (95% CI, 0.70-0.97) for suicide death and nonfatal self-harm, and the HR was 1.01 (95% CI, 0.97-1.06) for incident depression and anxiety-related disorders. This cohort study, including mostly patients with type 2 diabetes, does not show an association between use of GLP-1 receptor agonists and an increased risk of suicide death, self-harm, or incident depression and anxiety-related disorders. Suicide death among GLP-1 receptor agonist users was rare, and the upper limit of the confidence interval was compatible with an absolute risk increase of no more than 0.16 events per 1000 person-years.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and dipeptidyl peptidase 4 (DPP4) inhibitors improve hyperglycemia, and SGLT2 inhibitors and GLP-1 receptor agonists reduce the risk of major adverse cardiovascular events (MACEs) among individuals with type 2 diabetes. It is not clear whether efficacy varies by age or sex. To assess whether age or sex are associated with differences in the efficacy of SGLT2 inhibitors, GLP-1 receptor agonists, and DPP4 inhibitors. The MEDLINE and Embase databases and US and Chinese clinical trial registries were searched for articles published from inception to November 2022; in August 2024, the search was updated to capture the trial results. Two reviewers screened for randomized clinical trials of SGLT2 inhibitors, GLP-1 receptor agonists, or DPP4 inhibitors vs a placebo or active comparator in adults with type 2 diabetes. Individual participant data and aggregate data were used to estimate age × treatment interactions and sex × treatment interactions in multilevel network meta-regression models. Hemoglobin A1c (HbA1c) and MACEs. Of the 601 eligible trials identified (592 trials with 309 503 participants reported HbA1c; mean age, 58.9 [SD, 10.8] years; 42.3% were female and 23 trials with 168 489 participants reported MACEs; mean age, 64.0 [SD, 8.6] years; 35.3% were female), individual participant data were obtained for 103 trials (103 reported HbA1c and 6 reported MACEs). The use of SGLT2 inhibitors (vs placebo) was associated with less HbA1c lowering with increasing age for monotherapy (absolute reduction [AR], 0.24% [95% credible interval {CrI}, 0.10% to 0.38%] per 30-year increment in age), for dual therapy (AR, 0.17% [95% CrI, 0.10% to 0.24%]), and for triple therapy (AR, 0.25% [95% CrI, 0.20% to 0.30%]). The use of GLP-1 receptor agonists was associated with greater HbA1c lowering with increasing age for monotherapy (AR, -0.18% [95% CrI, -0.31% to -0.05%] per 30-year increment in age) and for dual therapy (AR, -0.24% [95% CrI, -0.40% to -0.07%]), but not for triple therapy (AR, 0.04% [95% CrI, -0.02% to 0.11%]). The use of DPP4 inhibitors was associated with slightly better HbA1c lowering in older people for dual therapy (AR, -0.09% [95% CrI, -0.15% to -0.03%] per 30-year increment in age), but not for monotherapy (AR, -0.08% [95% CrI, -0.18% to 0.01%]) or triple therapy (AR, -0.01% [95% CrI, -0.06% to 0.05%]). The relative reduction in MACEs with use of SGLT2 inhibitors was greater in older vs younger participants per 30-year increment in age (hazard ratio, 0.76 [95% CrI, 0.62 to 0.93]), and the relative reduction in MACEs with use of GLP-1 receptor agonists was less in older vs younger participants (hazard ratio, 1.47 [95% CrI, 1.07 to 2.02]). There was no consistent evidence for sex × treatment interactions with use of SGLT2 inhibitors and GLP-1 receptor agonists. The SGLT2 inhibitors and GLP-1 receptor agonists were associated with lower risk of MACEs. Analysis of age × treatment interactions suggested that SGLT2 inhibitors were more cardioprotective in older than in younger people despite smaller reductions in HbA1c; GLP-1 receptor agonists were more cardioprotective in younger people.

Key Points Compared with glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter 2 (SGLT2) inhibitors were associated with a lower risk of kidney failure among individuals with type 2 diabetes. Use of combination SGLT2 inhibitor and glucagon-like peptide-1 receptor agonist was infrequent but associated with lower kidney failure risk in high-risk individuals. Providers should prioritize SGLT2 inhibitors in patients with type 2 diabetes to prevent progression to kidney failure. Background The relative effectiveness of sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for kidney protection, both individually and in combination, is incompletely understood. We sought to compare associations of GLP-1 receptor agonists, SGLT2 inhibitors, and both medications in combination with incident kidney failure among individuals with type 2 diabetes. Methods We conducted a target trial emulation study with new user, active comparator design using deidentified electronic health records data from Optum Labs Data Warehouse. We included adults with type 2 diabetes who were prescribed a GLP-1 receptor agonist, SGLT2 inhibitor, or both between January 1, 2015, and June 29, 2024. We estimated the association of medication class with incident kidney failure using inverse probability of treatment weighted Cox proportional hazards regression models in both intention-to-treat and as-treated methodologies. Results There were 504,151 individuals with 2965 kidney failure events during a median 2.35 (interquartile range 1.09–4.32) years of follow-up. Average prescription duration was 0.69 years for GLP-1 receptor agonists, 0.62 years for SGLT2 inhibitors, and 0.44 years for combination therapy. In the intention-to-treat analysis, compared with GLP-1 receptor agonists, the risk of kidney failure was significantly lower with SGLT2 inhibitors (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.73 to 0.91) but no different with combination therapy (HR, 0.72; 95% CI, 0.45 to 1.15). The results were similar in the as-treated model. Among individuals with CKD or heart failure, the risk of kidney failure was significantly lower with combination therapy compared with GLP-1 receptor agonists (HR, 0.54; 95% CI, 0.30 to 0.97). Conclusions SGLT2 inhibitors were associated with a lower risk of kidney failure compared to GLP-1 receptor agonists. Among high-risk patients with type 2 diabetes and CKD or heart failure, combination therapy may further reduce the risk of kidney failure.

Introduction: Concerns have been raised that glucagon-like peptide 1 receptor agonists (GLP1-RAs) may increase the risk of thyroid cancer, but evidence remains conflicting. We therefore investigated if GLP1-RA use, compared with use of dipeptidyl peptidase-4 inhibitors (DPP-4is), was associated with thyroid cancer risk in patients with type 2 diabetes. Methods: This multisite cohort study with subsequent meta-analysis included six population-based databases from Canada (Ontario), Denmark, Norway, South Korea, Sweden, and Taiwan. Study populations comprised patients with type 2 diabetes between 2007 and 2023. Cox regression models estimated hazard ratios (HR) and 95% confidence intervals (CIs) for thyroid cancer among GLP1-RA users compared with DPP-4is. Models were weighted using standardized mortality ratio weights generated from time-specific propensity scores. Site-specific HRs were pooled using a fixed-effects model. Results: We identified 98,147 users of GLP1-RA and 2,488,303 users of DPP-4i, with the median follow-up among users of GLP1-RA ranging from 1.8 to 3.0 years. Overall, use of GLP1-RA relative to use of DPP-4i was not associated with an increased risk of thyroid cancer (pooled weighted HR 0.81, CI 0.59-1.12). Similarly, we observed no increased risk in thyroid cancer with increasing cumulative dose of GLP1-RA among GLP1-RA ever-users. Subgroup analysis of types of thyroid cancer was not possible. Results remained consistent across a range of supplementary analyses. Discussion: In this large multisite study, utilizing data from six population-based databases, we found no evidence that GLP1-RA use is associated with an increased risk of thyroid cancer with follow-up ranging from 1.8 to 3.0 years, providing some reassurance to patients and clinicians about the short-term safety of these drugs. Nevertheless, evidence was insufficient to rule out excess risk with long-term use, due to the short follow-up.

ObjectiveTo determine whether the combined use of glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors is associated with a decreased risk of major adverse cardiovascular events and serious...

Comparative effectiveness of SGLT2 inhibitors and GLP-1 receptor agonists in preventing Alzheimer's disease, vascular dementia, and other dementia types among patients with type 2 diabetes.

&lt;p dir="ltr"&gt;We present a methodological framework for conducting and interpreting subgroup meta-analyses. Methodological steps comprised evaluation of clinical heterogeneity regarding the definition of subpopulations, credibility assessment of subgroup meta-analysis, and translation of relative into absolute treatment effects. We used subgroup data from type 2 diabetes cardiovascular outcomes trials (CVOTs) with glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors, for patients with established cardiovascular disease and those at high cardiovascular risk without manifest cardiovascular disease. First, we evaluated the variability in definitions of the subpopulations across CVOTs using major adverse cardiovascular events (MACE) incidence in the placebo arm as a proxy for baseline cardiovascular risk. As baseline risk did not differ considerably across CVOTs, we conducted subgroup meta-analyses of hazard ratios (HRs) for MACE and assessed the credibility of a potential effect modification. Results suggested using the same overall relative effect for each of the two subpopulations (HR 0.85, 95% CI 0.80 to 0.90 for GLP-1 receptor agonists, and HR 0.91, 95% CI 0.85 to 0.97 for SGLT2 inhibitors). Finally, we calculated five-year absolute treatment effects (number of fewer patients with event per 1000 patients). Treatment with GLP-1 receptor agonists resulted in 30 fewer patients with event in the subpopulation with established cardiovascular disease, and 14 fewer patients with event in patients without manifest cardiovascular disease. For SGLT2 inhibitors, the respective absolute effects were 18 and 8 fewer patients with event per 1000 patients. This framework can be applied to subgroup meta-analyses regardless of outcomes or modification variables.&lt;/p&gt;