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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]

We sought to determine whether the use of sodium‐glucose cotransporter‐2 (SGLT‐2) inhibitors is associated with a decreased risk of incident lung cancers among patients with type 2 diabetes. We assembled a new‐user, active comparator cohort of SGLT‐2 inhibitor and dipeptidyl peptidase‐4 (DPP‐4) inhibitor users using the United Kingdom Clinical Practice Research Datalink. We fit Cox proportional hazards models with propensity score fine stratification weighting to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for incident lung cancer. Crude incidence rates were 0.94 per 1000 person‐years among 69 675 SGLT‐2 inhibitor users followed for a median of 2.4 years and 1.45 per 1000 person‐years among 151 495 DPP‐4 inhibitor users followed for a median of 3.7 years. No reduced short‐term risk of lung cancer was observed among SGLT‐2 inhibitor users after weighting (HR 0.96, 95% CI 0.77–1.21). Further research with a longer follow‐up period may be warranted. [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]

Aims: The contemporary prescription patterns of antidiabetic drugs following guideline changes recommending metformin as first‐line gestational diabetes (GDM) pharmacotherapy is underexplored. We aimed to examined use of metformin and insulin during pregnancy among women with GDM over 20 years in the United Kingdom. Methods: We conducted a population‐based cohort study using linked data from the Clinical Practice Research Datalink, its pregnancy register and Hospital Episode Statistics from 1998 to 2017. We included pregnancies of women without prior diabetes history who received GDM diagnosis or initiated an antidiabetic drug after 20 weeks gestation. Patient‐level and practice‐level characteristics were compared between metformin initiators and insulin initiators. We described trends of initiating metformin as first‐line treatment and described time to initiation of rescue insulin overall, and by body mass index among metformin initiators. Results: Our cohort included 5633 pregnancies from 5393 women with GDM, of whom 38.9% initiated pharmacotherapy (41% insulin, 59% metformin). Metformin prescriptions (as opposed to insulin) increased substantially, from <5% of pregnancies before 2007 to 42.5% in 2008. Over 85% of pregnancies that were prescribed pharmacotherapy were prescribed metformin as first‐line treatment in 2015. Among metformin initiators, 16% initiated rescue insulin, typically occurring within 40 days of metformin initiation. Choice of GDM pharmacotherapy varied by characteristics, including smoking, obesity, race/ethnicity and general practice regions. Conclusions: Metformin was the most prescribed medication for GDM, with large increases over the past 2 decades. The increasing use of oral‐antidiabetic drugs during pregnancy, consistent with other regions, highlights the need for future studies examining effectiveness and safety of antidiabetic drug use during pregnancy. [ABSTRACT FROM AUTHOR]

Aim: To determine whether the use of long‐acting insulin analogues is associated with an increased risk of incident diabetic retinopathy (DR) among patients with type 2 diabetes. Methods: Using data from the Clinical Practice Research Datalink Aurum, this retrospective, population‐based cohort study included patients with type 2 diabetes who initiated a long‐acting insulin analogue (glargine, detemir, degludec) or Neutral Protamine Hagedorn (NPH) insulin. The primary outcome was incident DR. We used Cox proportional hazards models with inverse probability of treatment weighting to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident DR with insulin analogues versus NPH insulin. Results: There were 66 280 new users of long‐acting insulin analogues and 66 173 new users of NPH insulin. The incidence rate of DR was 101.7 per 1000 person‐years (95% CI, 98.7‐104.8) for insulin analogues and 93.2 (95% CI, 90.0‐96.5) per 1000 person‐years for NPH insulin. Compared with the current use of NPH insulin, insulin analogues were not associated with the risk of incident DR (HR 1.04, 95% CI, 0.99‐1.09). The adjusted HRs were 0.84 (95% CI, 0.66‐1.07) for proliferative DR and 1.02 (95% CI, 0.97‐1.08) for non‐proliferative DR. Conclusions: Compared with NPH insulin, long‐acting insulin analogues were not associated with the risk of incident DR among patients with type 2 diabetes. This finding provides important reassurance regarding the safety of long‐acting insulin analogues with respect to incident DR. [ABSTRACT FROM AUTHOR]

Aim: To determine whether the use of sulphonylurea monotherapy, compared with metformin monotherapy, is associated with an increased risk of ventricular arrhythmia (VA) among patients initiating pharmacotherapy for type 2 diabetes. Research Design and Methods: We conducted a population‐based cohort study using electronic health data extracted from the UK's Clinical Practice Research Datalink Aurum. Using the active comparator, new‐user cohort design, we compared rates of VA among patients aged 18 years or older using sulphonylurea monotherapy with those using metformin monotherapy as their initial pharmacological treatment for type 2 diabetes from April 1998 to December 2019. We used a Cox proportional hazards model with inverse probability of treatment weighting by propensity score to estimate the adjusted hazard ratio (aHR) and a corresponding bootstrap 95% confidence interval (CI) for VA with sulphonylurea monotherapy versus metformin monotherapy. Results: The cohort included 92 638 new users of sulphonylurea and 506 882 new users of metformin. A total of 279 VA events occurred among sulphonylurea users (rate per 10 000 person‐years: 25.5, 95% CI: 22.7 to 28.7) and 1537 VA events occurred among metformin users (rate per 10 000 person‐years: 18.5, 95% CI: 17.6 to 19.5). Compared with metformin, sulphonylureas were associated with an increased risk of VA (aHR: 1.42, 95% CI: 1.18 to 1.69). Conclusions: Sulphonylureas are associated with an increased risk of VA when used as first‐line therapy for type 2 diabetes relative to metformin use. This increased risk should be considered when prescribing sulphonylureas as an initial treatment for type 2 diabetes. [ABSTRACT FROM AUTHOR]

Case reports and a pharmacovigilance analysis have linked glucagon-like peptide 1 receptor agonists (GLP-1 RAs) with anaphylactic reactions, but real-world evidence for this possible association is lacking. Using databases from the United Kingdom (Clinical Practice Research Datalink) and the United States (Medicare, Optum (Optum, Inc. Eden Prairie, Minnesota), and IBM MarketScan (IBM, Armonk, New York)), we employed a new-user, active comparator study design wherein initiators of GLP-1 RAs were compared with 2 different active comparator groups (initiators of dipeptidyl peptidase 4 (DPP-4) inhibitors and initiators of sodium-glucose cotransporter 2 (SGLT-2) inhibitors) between 2007 and 2019. Propensity score fine stratification weighted Cox proportional hazards models were fitted to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for an anaphylactic reaction. Database-specific HRs were pooled using random-effects models. Compared with the use of DPP-4 inhibitors (n  = 1,641,520), use of GLP-1 RAs (n  = 324,098) generated a modest increase in the HR for anaphylactic reaction, with a wide 95% CI (36.9 per 100,000 person-years vs. 32.1 per 100,000 person-years, respectively; HR = 1.15, 95% CI: 0.94, 1.42). Compared with SGLT-2 inhibitors (n  = 366,067), GLP-1 RAs (n  = 259,929) were associated with a 38% increased risk of anaphylactic reaction (40.7 per 100,000 person-years vs. 29.4 per 100,000 person-years, respectively; HR = 1.38, 95% CI: 1.02, 1.87). In this large, multisite population-based cohort study, GLP-1 RAs were associated with a modestly increased risk of anaphylactic reaction when compared with DPP-4 inhibitors and SGLT-2 inhibitors. [ABSTRACT FROM AUTHOR]

Background: There is some evidence that glucagon-like peptide 1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors have chemopreventive effects on prostate cancer cells but real-world evidence for this possible effect is lacking. Thus, the objective of this study was to estimate whether use of GLP-1 receptor agonists and DPP-4 inhibitors, separately, is associated with a decreased risk of prostate cancer among patients with type 2 diabetes.Methods: We assembled two new-user, active-comparator cohorts using the UK Clinical Practice Research Datalink (2007 to 2019). The first cohort included 5,063 initiators of GLP-1 receptor agonists and 112,955 of sulfonylureas. The second cohort included 53,529 initiators of DPP-4 inhibitors and 114,417 of sulfonylureas. We fit Cox proportional hazards models to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for prostate cancer. We weighted the models using propensity score fine stratification, which considered over 50 potential confounders.Results: GLP-1 receptor agonists were associated with a decreased risk of prostate cancer when compared with sulfonylureas (incidence rates = 156.4 vs. 232.0 per 100,000 person-years, respectively; HR = 0.65; 95% CI = 0.43, 0.99). DPP-4 inhibitors were also associated with a decreased risk of prostate cancer when compared with sulfonylureas (incidence rates = 316.2 vs. 350.5 events per 100,000 person-years, respectively; HR = 0.90; 95% CI = 0.81, 1.00).Conclusions: The results of this study are consistent with the hypothesis that the use of GLP-1 receptor agonists and DPP-4 inhibitors, separately, may decrease the risk of prostate cancer when compared with the use of sulfonylureas. [ABSTRACT FROM AUTHOR]

Previous studies have suggested an association between sulfonylureas and an increased risk of cardiovascular death among patients with type 2 diabetes. A potential mechanism involves sulfonylurea‐induced ventricular arrhythmias (VAs). We conducted a systematic review of observational studies to determine whether the use of sulfonylureas, compared with the use of other antihyperglycemic drugs, is associated with the risk of VA (ventricular tachycardia, ventricular fibrillation, and premature ventricular complexes), cardiac arrest, and sudden cardiac death among patients with type 2 diabetes. Two independent reviewers searched MEDLINE, EMBASE, CINAHL Plus, CENTRAL, and ClinicalTrials.gov from inception to July 2021 for observational studies comparing sulfonylureas vs. other antihyperglycemic therapies or intraclass comparisons of sulfonylureas. Our systematic review included 17 studies (1,607,612 patients). Per Risk Of Bias In Non‐randomized Studies of Interventions (ROBINS)‐I, there were few high‐quality studies (2 studies at moderate risk of bias; 4 at serious risk; and 11 at critical risk). All studies at a moderate or serious risk of bias reporting comparisons with other therapies were consistent with an increased risk of VA. Sulfonylureas were associated with a higher risk of arrhythmia vs. dipeptidyl peptidase‐4 inhibitors (adjusted hazard ratio (aHR): 1.52, 95% confidence interval (CI): 1.27–1.80) and of VA vs. metformin (aHR: 1.52, 95% CI: 1.10–2.13). One moderate quality study reported inconsistent results for a composite of cardiac arrest/VA in analyses of US Medicaid claims and Optum claims data. Our systematic review suggests that, among higher‐quality observational studies, sulfonylureas are associated with an increased risk of VA. However, we identified few methodologically rigorous studies, underscoring the need for additional real‐world studies. [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]

Aims: Aim of this study is to describe changes in the utilization of basal insulins (glargine, detemir, degludec, neutral protamine Hagedorn [NPH]) among individuals with type 2 diabetes between 2003 and 2018 in the United Kingdom (UK). Materials and Methods: Using the UK Clinical Practice Research Datalink (CPRD) Aurum, we created three study cohorts of individuals with type 2 diabetes: (1) all users of antidiabetic drugs (n = 686,170); (2) initiators of antidiabetic drugs (n = 382,247); and (3) initiators of basal insulins (n = 85,369). Trends in prescription rates were determined using Poisson regression overall and stratified by sex, cardiovascular disease history, and obesity. Crude and adjusted Cox proportional hazards models were used to obtain hazard ratios (HRs) and confidence intervals (CI) comparing rates of treatment change between classes of basal insulins, with an intention‐to‐treat exposure definition. Results: During the study period, prescription rates of insulin analogues increased in the all‐user cohort from 118.3 (95% CI: 116.4, 120.2) prescriptions per 1000 person‐years in 2003 to 579.4 (95% CI: 576.9, 582.0) in 2018. Prescription rates of NPH decreased from 770.5 (95% CI: 765.0, 775.3) in 2003 to 457.7 (95% CI: 455.5, 460.0) in 2018. Compared to initiators of NPH, initiators of detemir were more likely to change treatment (adjusted HR: 1.31, 95% CI: 1.25, 1.37) while glargine initiators were less likely to change treatment (adjusted HR: 0.85, 95% CI: 0.82, 0.88). Conclusions: Basal insulin prescription evolved between 2003 and 2018. Our study provides insight into the evolving use of basal insulin among individuals with type 2 diabetes in the UK. [ABSTRACT FROM AUTHOR]

Background: It has been proposed that the weight loss associated with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may improve detection of breast cancer in patients undergoing this treatment. We aimed to determine whether the weight-lowering effects of GLP-1 RAs are associated with an increased detection of breast cancer among obese women with type 2 diabetes.Methods: Using the UK Clinical Practice Research Datalink, we conducted a propensity score-matched cohort study among female obese patients with type 2 diabetes newly treated with antidiabetic drugs between 1 January 2007 and 31 January 2018. New users of GLP-1 RAs (n = 5,510) were matched to new users of second- to third-line noninsulin antidiabetic drugs (n = 5,510). We used time-dependent Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of breast cancer associated with different GLP-1 RA maximal weight loss categories (<5%, 5%-10%, >10%).Results: Breast cancer incidence gradually increased with GLP-1 RA maximal weight loss categories, with the highest HR observed for patients achieving at least 10% weight loss (HR = 1.8, 95% CI = 1.1, 2.8). In secondary analyses, the HR for >10% weight loss was highest in the 2-3 years since treatment initiation (HR = 2.9, 95% CI = 1.2, 6.9).Conclusions: In this population-based study, the detection of breast cancer gradually increased with GLP-1 RA weight loss categories, particularly among those achieving >10% weight loss. These results are consistent with the hypothesis that substantial weight loss with GLP-1 RAs may improve detection of breast cancer among obese patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

The association between the use of testosterone replacement therapy (TRT) and prostate cancer remains uncertain. Thus, we investigated whether TRT is associated with an increased risk of prostate cancer in men with late-onset hypogonadism. We used the UK Clinical Practice Research Datalink to assemble a cohort of 12,779 men who were newly diagnosed with hypogonadism between January 1, 1995, and August 31, 2016, with follow-up until August 31, 2017. Exposure to TRT was treated as a time-varying variable and lagged by 1 year to account for cancer latency, with nonuse as the reference category. During 58,224 person-years of follow-up, a total of 215 patients were newly diagnosed with prostate cancer, generating an incidence rate of 3.7 per 1,000 person-years. In time-dependent Cox proportional hazards models, use of TRT was not associated with an overall increased risk of prostate cancer (hazard ratio = 0.97; 95% confidence interval: 0.71, 1.32) compared with nonuse. Results remained consistent in secondary and sensitivity analyses, as well as in a propensity score–matched cohort analysis that further assessed the impact of residual confounding. Overall, the use of TRT was not associated with an increased risk of prostate cancer in men with late-onset hypogonadism. [ABSTRACT FROM AUTHOR]

Using pharmacovigilance data from VigiBase, Gérard and colleagues report the presence of a safety signal consistent with an increased risk of VAs among sulfonamide users relative to other drugs used to treat type 2 diabetes. We thank Gérard and colleagues for their interest in our systematic review of observational studies examining the association between sulfonylureas and the risk of ventricular arrhythmias (VAs) among patients with type 2 diabetes. We agree that, although there have been several studies on sulfonylureas' overall cardiovascular safety profile, this potential adverse drug effect has remained poorly understood. [Extracted from the article]