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Aims: Metformin is increasingly used off‐label as the treatment of gestational diabetes (GDM). Our objective was to determine if metformin versus insulin initiation is associated with the adverse pregnancy outcomes. Materials and Methods: We conducted a retrospective cohort study using data from the Clinical Practice Research Datalink, its pregnancy register, and Hospital Episode Statistics from 1998 to 2018. We included pregnancies of women who initiated metformin or insulin between 20 weeks gestation and pregnancy end. The primary outcome was a composite outcome of large for gestational age (LGA) and macrosomia. The secondary outcomes included small for gestational age (SGA), preterm birth, caesarean delivery, and hypertensive disorders during pregnancy (HDP). Inverse probability weighted‐Cox proportional hazards models were to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CI), comparing those who initiated metformin versus insulin at cohort entry, accounting for baseline covariates. Results: Our cohort included pregnancies of 1297 women initiating metformin and of 895 women initiating insulin. Compared to insulin initiation, metformin initiation was associated with a decreased risk of LGA or macrosomia (HR 0.64, 95% CI 0.49, 0.78), Caesarean delivery (HR 0.83, 95% CI 0.69, 0.98), and preterm birth (HR 0.83, 95% CI 0.58, 1.08). The HRs for HDP and SGA were 0.92 (95% CI 0.57, 1.27) and 1.33 (95% CI 0.67, 2.00), respectively. Conclusions: Our study suggests that, compared to initiating insulin, initiating metformin is associated with decreased risks of adverse pregnancy outcomes among women with GDM. These findings provide important real‐world evidence regarding the use of metformin for GDM. [ABSTRACT FROM AUTHOR]

Background: While the benefits of levothyroxine are well‐established for overt hypothyroidism, they are unclear for subclinical hypothyroidism (SCH) among pregnant women. Objective: To estimate the effect of initiation of levothyroxine on pregnancy loss among women with SCH with an emulated target trial using observational data. Methods: We emulated a target trial using the United Kingdom's Clinical Practice Research Datalink to account for the staggered timing of diagnosis and treatment of SCH and the time of entry of women into prenatal care. We emulated multiple nested trials (at each gestational week) and used an intention‐to‐treat approach to define levothyroxine use (≥1 prescription in the 7 days prior to trial entry), with eligible users matched to non‐users (1:4) on time of diagnosis, gestational week of the first eligible trial and high‐dimensional propensity score. Pregnancy losses included spontaneous abortion and stillbirth. A pooled logistic regression model with bootstrap resampling was used to estimate the hazard ratios (HR) and 95% confidence intervals (CI). Results: Based on 159,177 eligible person‐trials (5781 women), the matched cohort included 181 initiators and 640 non‐initiators of levothyroxine, with 57 pregnancy losses occurring during follow‐up. Overall, the mean age of women was 32.2 years (SD 5.4), 25% were obese, 8% had type 2 diabetes and about 50% were nulliparous. After matching, women who initiated levothyroxine versus not had higher thyroid‐stimulating levels during pregnancy and were more likely to have a history of hypothyroidism. The cumulative incidence of pregnancy loss was lower in initiators versus non‐initiators of levothyroxine. The adjusted HR for pregnancy loss was 0.87 (95% CI 0.22, 1.56). Conclusions: Although our assessment of the effect of initiation of levothyroxine for SCH in pregnancy precludes any definitive conclusions due to wide confidence intervals, this study illustrates the feasibility of using the target trial emulation framework to examine the effectiveness of medication use in pregnancy. [ABSTRACT FROM AUTHOR]

Aims: The objective of this study was to determine whether the use of glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) is associated with an increased risk of melanoma and nonmelanoma skin cancer, separately, compared with the use of sulfonylureas among patients with type 2 diabetes. Methods: Using the United Kingdom Clinical Practice Research Datalink (2007–2019), we assembled two new‐user active comparator cohorts. In the first cohort assessing melanoma as the outcome, 11,786 new users of GLP‐1 RAs were compared with 208,519 new users of sulfonylureas. In the second cohort assessing nonmelanoma skin cancer as the outcome, 11,774 new users of GLP‐1 RAs were compared with 207,788 new users of sulfonylureas. Cox proportional hazards models weighted using propensity score fine stratification were fit to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of melanoma and nonmelanoma skin cancer, respectively. Results: Compared with sulfonylureas, GLP‐1 RAs were not associated with an increased risk of either melanoma (42.6 vs. 43.9 per 100,000 person‐years, respectively; HR 0.96, 95% CI 0.53–1.75) or nonmelanoma skin cancer (243.9 vs. 229.9 per 100,000 person‐years, respectively; HR 1.03, 95% CI 0.80–1.33). There was no evidence of an association between cumulative duration of use with either melanoma or nonmelanoma skin cancer. Consistent results were observed in secondary and sensitivity analyses. Conclusions: In this population‐based cohort study, GLP‐1 RAs were not associated with an increased risk of melanoma or nonmelanoma skin cancer, compared with sulfonylureas. [ABSTRACT FROM AUTHOR]

Aim: The results from the SUSTAIN‐6 trial generated some uncertainty regarding the association between incretin‐based drugs [dipeptidyl peptidase‐4 (DPP‐4) inhibitors and glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs)] and the risk of diabetic retinopathy. Our objective was to synthesize the available evidence from observational studies regarding the use of incretin‐based drugs and the risk of diabetic retinopathy among individuals with type 2 diabetes. Materials and Methods: We systemically searched Cochrane Library, Embase and Medline to identify observational studies of interest. Risk of bias was assessed using the ROBINS‐I tool. Data from included studies were pooled using the DerSimonian and Laird random‐effect model with the Hartung‐Knapp extension. Results: We included 14 studies in the systematic review, with 10 examining DPP‐4 inhibitors and seven examining GLP‐1 RAs. Nine studies investigated incident diabetic retinopathy, six investigated diabetic retinopathy progression and two investigated both outcomes. Seven studies were at moderate risk of bias, four at serious risk of bias and three at critical risk of bias. Data pooled across studies showed no association between the use of DPP‐4 inhibitors (risk ratio: 0.98, 95% confidence interval: 0.83, 1.17) or GLP‐1 RAs (risk ratio: 0.87, 95% confidence interval: 0.56, 1.34) and the risk of diabetic retinopathy. Conclusion: This study suggests that the use of incretin‐based drugs is not associated with the risk of diabetic retinopathy among individuals with type 2 diabetes. However, these findings should be interpreted with caution considering the limited quality of some of the available evidence. [ABSTRACT FROM AUTHOR]

Aim: To assess the risk of amputation associated with sodium‐glucose co‐transporter‐2 inhibitors (SGLT2is) among patients with type 2 diabetes, across categories of baseline cardiovascular disease (CVD) and diuretic use (DU). Materials and Methods: We conducted an active comparator, new‐user cohort study using Korea's nationwide claims data (2015‐2020). The study cohort consisted of patients with type 2 diabetes who initiated SGLT2is or dipeptidyl peptidase‐4 inhibitors (DPP4is). Cohort entry was defined by first prescription date. We then classified patients into four discrete subcohorts based on their baseline status of CVD and DU as (1) CVD+/DU+, (2) CVD+/DU‐, (3) CVD‐/DU+ and (4) CVD‐/DU‐. We performed 1:1 propensity score (PS) matching within each cohort and estimated hazard ratios (HRs) with 95% confidence intervals (CIs) for the risk of amputation with SGLT2is versus DPP4is using Cox models. Results: We identified 219 900 PS‐matched pairs of SGLT2is and DPP4is (CVD+/DU+, n = 11 719; CVD+/DU‐, n = 26 092; CVD‐/DU+, n = 26 894; and CVD‐/DU‐, n = 155 195), with well‐balanced baseline covariates across all cohorts. Significantly lower risks of amputation with SGLT2is versus DPP4is were found in CVD+/DU+ (HR 0.36, 95% CI 0.14‐0.90), CVD+/DU‐ (0.45, 0.21‐0.99) and CVD‐/DU‐ (0.48, 0.33‐0.70), but not in CVD‐/DU+ (0.54, 0.26‐1.12). Consistent trends in estimates were found across various sensitivity analyses. Conclusions: Initiating SGLT2is against DPP4is did not increase the risk of amputation across patient populations of varying vulnerability. These findings based on routine practice will reassure clinicians of the safety of SGLT2is with regard to amputation risk in selected high‐risk patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Aims: The cardiovascular benefits of sodium‐glucose cotransporter 2 inhibitors (SGLT2Is) result from their complex impact on coronary and arterial vessels. However, their effect on veins and the risk of venous thromboembolism (VTE) remains unclear. Meta‐analysis of trials has suggested no significant change in risk, but observational studies on the topic are scarce. Our objective was to determine if the use of SGLT2Is, compared to the use of dipeptidyl peptidase 4 inhibitors (DPP‐4Is), is associated with the risk of VTE among patients with type 2 diabetes. Methods: Using the Clinical Practice Research Datalink linked to hospitalization and vital statistics databases, we conducted a retrospective cohort study using a prevalent new‐user design. SGLT2Is were matched to DPP‐4I users on calendar time, diabetes treatment intensity, duration of previous DPP‐4I use and time‐conditional high‐dimensional propensity score. Cox proportional hazard models estimated the hazard ratio (HR) for VTE with SGLT2Is versus DPP‐4Is. Results: SGLT2I use was not associated with an increased risk of VTE (HR 0.65, 95% confidence interval [CI] 0.34 to 1.25). This finding was consistent among prevalent (HR 0.47, 95% CI 0.16 to 1.42) and incident (HR 0.75, 95% CI 0.33 to 1.72) new users. Conclusions: We found that SGLT2Is were not associated with an increased risk of VTE compared to DPP‐4Is. Although we observed a numerically decreased risk of VTE with SGLT2Is, estimates were accompanied by wide 95% CIs. Nonetheless, given the morbidity associated with VTE, our results provide some reassurance regarding the safety of SGLT2Is with respect to VTE. [ABSTRACT FROM AUTHOR]

Glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) and dipeptidyl peptidase‐4 (DPP‐4) inhibitors might increase the risk of intestinal obstruction, but real‐world evidence for this severe adverse event is lacking. Thus, the objective of this study was to determine whether GLP‐1 RAs and DPP‐4 inhibitors are associated with an increased risk of intestinal obstruction compared with sodium‐glucose cotransporter‐2 (SGLT‐2) inhibitors. We used the United Kingdom Clinical Practice Research Datalink and linked databases to assemble two new‐user, active comparator cohorts (2013–2019). The first included 25,617 and 67,261 GLP‐1 RA and SGLT‐2 inhibitor users, respectively. The second included 131,927 and 40,615 DPP‐4 inhibitor and SGLT‐2 inhibitor users, respectively. Propensity score fine stratification weighted Cox proportional hazards models were fit to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of intestinal obstruction requiring hospitalization. GLP‐1 RAs were associated with an increased risk of intestinal obstruction compared with SGLT‐2 inhibitors (1.9 vs. 1.1 per 1,000 person‐years, respectively; HR: 1.69, 95% CI: 1.04–2.74). The highest HR was observed after 1.6 years of use (HR: 3.48, 95% CI: 1.79–6.79). DPP‐4 inhibitors were also associated with an increased risk (2.7 vs. 1.0 per 1,000 person‐years; HR: 2.59, 95% CI: 1.52–4.42), with the highest HR observed after 1.8 years of use (HR: 9.53, 95% CI: 4.47–20.30). The number needed to harm after 1 year of use was 1,223 and 603 for GLP‐1 RAs and DPP‐4 inhibitors, respectively. In this large real‐world study, GLP‐1 RAs and DPP‐4 inhibitors were associated with an increased risk of intestinal obstruction. [ABSTRACT FROM AUTHOR]

Our study aimed to describe levothyroxine prescription patterns and trends over time among pregnant women with subclinical hypothyroidism (SCH) in the United Kingdom. We used data from the Clinical Practice Research Datalink linked to its Pregnancy Register and the Hospital Episode Statistics database from 1998 to 2017. The study population included women with a diagnosis of SCH or an abnormal thyroid-simulated hormone (TSH) level one year prior to or during pregnancy. We compared characteristics between women who received a prescription for levothyroxine during pregnancy and those who did not. We further described the timing, dose, duration, and temporal trends of levothyroxine prescriptions. Our cohort included 6,757 pregnancies from 6,287 women with SCH, of whom 10% received levothyroxine during pregnancy. Among women who received levothyroxine, most received their first prescription during the first trimester (median gestational age: 7 weeks; interquartile range [IQR]: 0, 16) with a median daily dosage of 50 mcg (IQR: 50, 73). Levothyroxine prescription varied over time, decreasing from 23% of pregnant women in 1998 to 7.5% in 2003, remaining stable until 2014, and increasing to 12.5% in 2016. Smoking, diabetes, polycystic ovary syndrome, infertility, timing of SCH diagnosis, age, TSH level at diagnosis, and general practice regions were associated with prescription. Few women with SCH received levothyroxine during pregnancy, and treatment varied by patient characteristics and geographical regions. These results highlight the need to increase awareness among healthcare providers and will guide future studies that explore barriers to initiating levothyroxine treatment for women with SCH during pregnancy. [ABSTRACT FROM AUTHOR]

Background: Recent randomized controlled trials (RCTs) have investigated glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual or triple co-agonists for weight loss among adults with overweight or obesity and without diabetes., Purpose: To assess the efficacy and safety of GLP-1 RAs and co-agonists for the treatment of obesity among adults without diabetes., Data Sources: MEDLINE, Embase, and Cochrane CENTRAL from inception to 4 October 2024., Study Selection: Placebo-controlled RCTs in otherwise healthy participants with overweight or obesity., Data Extraction: The primary outcome was change in relative or absolute body weight from baseline to maximum on-treatment follow-up. Safety outcomes included death, serious adverse events (SAEs), any adverse events (AEs), and gastrointestinal AEs., Data Synthesis: A total of 26 RCTs comprising 15 491 participants (72% female; mean body mass index, 30 to 41 kg/m 2 ; mean age, 34 to 57 years) and 12 agents (3 commercially available agents [liraglutide, semaglutide, and tirzepatide] and 9 premarket agents for long-term weight management) were included. Treatment ranged from 16 to 104 weeks (median, 43 weeks). Compared with placebo, tirzepatide (15 mg once weekly) resulted in weight loss of up to 17.8% (95% CI, 16.3% to 19.3%) after 72 weeks of therapy; semaglutide (2.4 mg once weekly), up to 13.9% (CI, 11.0% to 16.7%) after 68 weeks; and liraglutide (3.0 mg once daily), up to 5.8% (CI, 3.6% to 8.0%) after 26 weeks. Retatrutide (12 mg once weekly) produced greater weight loss of up to 22.1% (CI, 19.3% to 24.9%) after 48 weeks; other novel single and combination GLP-1 agents were also efficacious to varying degrees. Although AEs were frequent (GLP-1 RA vs. placebo: 80% to 97% vs. 63% to 100%), the majority were gastrointestinal-related (47% to 84% vs. 13% to 63%, respectively), most commonly nausea, vomiting, diarrhea, and constipation. AEs requiring treatment discontinuation (0% to 26% vs. 0% to 9%, respectively) and SAEs (0% to 10% vs. 0% to 12%, respectively) were rare., Limitations: No head-to-head RCTs were available. Heterogeneity prevented meta-analysis., Conclusion: GLP-1 RAs and co-agonists are efficacious for weight loss, with reported safety concerns predominantly gastrointestinal in nature, when used among adults with overweight or obesity and without diabetes., Primary Funding Source: None. (PROSPERO: CRD42024505558)., Competing Interests: Disclosures: Disclosure forms are available with the article online.

Objective: To determine whether sodium-glucose cotransporter 2 (SGLT2) inhibitors, compared with glucagon-like peptide 1 receptor agonists (GLP-1RAs) or dipeptidyl peptidase 4 (DPP-4) inhibitors, are associated with an increased risk of early bladder cancer events., Research Design and Methods: We conducted a multisite, population-based, new-user, active comparator cohort study using the U.K. Clinical Practice Research Datalink, Medicare fee-for-service, Optum's de-identifed Clinformatics Data Mart Database (CDM), and MarketScan Health databases from January 2013 through December 2020. We assembled two cohorts of adults with type 2 diabetes initiating 1) SGLT2 inhibitors or GLP-1RAs and 2) SGLT2 inhibitors or DPP-4 inhibitors. Cox proportional hazards models were fit to estimate hazard ratios (HRs) and 95% CIs of incident bladder cancer. The models were weighted using propensity score fine stratification. Site-specific HRs were pooled using random-effects models., Results: SGLT2 inhibitor (n = 453,560) and GLP-1RA (n = 375,997) users had a median follow-up ranging from 1.5 to 2.2 years. Overall, SGLT2 inhibitors were not associated with an increased risk of bladder cancer compared with GLP-1RAs (HR 0.90, 95% CI 0.81-1.00). Similarly, when compared with DPP-4 inhibitors (n = 853,186), SGLT2 inhibitors (n = 347,059) were not associated with an increased risk of bladder cancer (HR 0.99, 95% CI 0.91-1.09) over a median follow-up ranging from 1.6 to 2.6 years. Results were consistent across sensitivity analyses., Conclusions: Contrary to previous randomized controlled trials, these findings indicate that the use of SGLT2 inhibitors is not associated with an increased risk of bladder cancer compared with GLP-1RAs or DPP-4 inhibitors. This should provide reassurance on the short-term effects of SGLT2 inhibitors on bladder cancer incidence., (© 2022 by the American Diabetes Association.)

Objective: To determine whether the use of dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1 RAs), separately, is associated with an increased risk of acute liver injury compared with the use of sodium-glucose cotransporter 2 (SGLT-2) inhibitors., Research Design and Methods: We used the U.K. Clinical Practice Research Datalink linked with the Hospital Episode Statistics Admitted Patient Care and the Office for National Statistics databases to assemble two new-user, active-comparator cohorts. The first included 106,310 initiators of DPP-4 inhibitors and 27,277 initiators of SGLT-2 inhibitors, while the second included 9,470 initiators of GLP-1 RAs and 26,936 initiators of SGLT-2 inhibitors. Cox proportional hazards models with propensity score fine stratification weighting were used to estimate hazard ratios (HRs) and 95% CIs of acute liver injury., Results: Compared with SGLT-2 inhibitors, DPP-4 inhibitors were associated with a 53% increased risk of acute liver injury (HR 1.53, 95% CI 1.02-2.30). In contrast, GLP-1 RAs were not associated with an overall increased risk of acute liver injury (HR 1.11, 95% CI 0.57-2.16). However, an increased risk was observed among female users of both DPP-4 inhibitors (HR 3.22, 95% CI 1.67-6.21) and GLP-1 RAs (HR 3.23, 95% CI 1.44-7.25)., Conclusions: In this population-based study, DPP-4 inhibitors were associated with an increased risk of acute liver injury compared with SGLT-2 inhibitors in patients with type 2 diabetes. In contrast, an increased risk of acute liver injury was observed only among female GLP-1 RA users., (© 2022 by the American Diabetes Association.)