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OBJECTIVE: To assess the real-world cardiovascular (CV) safety for sulfonylureas (SU), in comparison with dipeptidyl peptidase 4 inhibitors (DPP4i) and thiazolidinediones (TZD), through development of robust methodology for causal inference in a whole nation study. RESEARCH DESIGN AND METHODS: A cohort study was performed including people with type 2 diabetes diagnosed in Scotland before 31 December 2017, who failed to reach HbA1c 48 mmol/mol despite metformin monotherapy and initiated second-line pharmacotherapy (SU/DPP4i/TZD) on or after 1 January 2010. The primary outcome was composite major adverse cardiovascular events (MACE), including hospitalization for myocardial infarction, ischemic stroke, heart failure, and CV death. Secondary outcomes were each individual end point and all-cause death. Multivariable Cox proportional hazards regression and an instrumental variable (IV) approach were used to control confounding in a similar way to the randomization process in a randomized control trial. RESULTS: Comparing SU to non-SU (DPP4i/TZD), the hazard ratio (HR) for MACE was 1.00 (95% CI: 0.91–1.09) from the multivariable Cox regression and 1.02 (0.91–1.13) and 1.03 (0.91–1.16) using two different IVs. For all-cause death, the HR from Cox regression and the two IV analyses was 1.03 (0.94–1.13), 1.04 (0.93–1.17), and 1.03 (0.90–1.17). CONCLUSIONS: Our findings contribute to the understanding that second-line SU for glucose lowering are unlikely to increase CV risk or all-cause mortality. Given their potent efficacy, microvascular benefits, cost effectiveness, and widespread use, this study supports that SU should remain a part of the global diabetes treatment portfolio. [ABSTRACT FROM AUTHOR]

Objective: To investigate the association between visit-to-visit HbA1c variability and cardiovascular events and microvascular complications in patients with newly diagnosed type 2 diabetes.Research Design and Methods: This retrospective cohort study analyzed patients from Tayside and Fife in the Scottish Care Information-Diabetes Collaboration (SCI-DC) who were observable from the diagnosis of diabetes and had at least five HbA1c measurements before the outcomes were evaluated. We used the previously reported HbA1c variability score (HVS), calculated as the percentage of the number of changes in HbA1c >0.5% (5.5 mmol/mol) among all HbA1c measurements within an individual. The association between HVS and 10 outcomes was assessed using Cox proportional hazards models.Results: We included 13,111-19,883 patients in the analyses of each outcome. The patients with HVS >60% were associated with elevated risks of all outcomes compared with the lowest quintile (for example, HVS >80 to ≤100 vs. HVS ≥0 to ≤20, hazard ratio 2.38 [95% CI 1.61-3.53] for major adverse cardiovascular events, 2.4 [1.72-3.33] for all-cause mortality, 2.4 [1.13-5.11] for atherosclerotic cardiovascular death, 2.63 [1.81-3.84] for coronary artery disease, 2.04 [1.12-3.73] for ischemic stroke, 3.23 [1.76-5.93] for heart failure, 7.4 [3.84-14.27] for diabetic retinopathy, 3.07 [2.23-4.22] for diabetic peripheral neuropathy, 5.24 [2.61-10.49] for diabetic foot ulcer, and 3.49 [2.47-4.95] for new-onset chronic kidney disease). Four sensitivity analyses, including adjustment for time-weighted average HbA1c, confirmed the robustness of the results.Conclusions: Our study shows that higher HbA1c variability is associated with increased risks of all-cause mortality, cardiovascular events, and microvascular complications of diabetes independently of high HbA1c. [ABSTRACT FROM AUTHOR]

Objective: Progression to insulin therapy in clinically diagnosed type 2 diabetes is highly variable. GAD65 autoantibodies (GADA) are associated with faster progression, but their predictive value is limited. We aimed to determine if a type 1 diabetes genetic risk score (T1D GRS) could predict rapid progression to insulin treatment over and above GADA testing.Research Design and Methods: We examined the relationship between T1D GRS, GADA (negative or positive), and rapid insulin requirement (within 5 years) using Kaplan-Meier survival analysis and Cox regression in 8,608 participants with clinical type 2 diabetes (onset >35 years and treated without insulin for ≥6 months). T1D GRS was both analyzed continuously (as standardized scores) and categorized based on previously reported centiles of a population with type 1 diabetes (<5th [low], 5th-50th [medium], and >50th [high]).Results: In GADA-positive participants (3.3%), those with higher T1D GRS progressed to insulin more quickly: probability of insulin requirement at 5 years (95% CI): 47.9% (35.0%, 62.78%) (high T1D GRS) vs. 27.6% (20.5%, 36.5%) (medium T1D GRS) vs. 17.6% (11.2%, 27.2%) (low T1D GRS); P = 0.001. In contrast, T1D GRS did not predict rapid insulin requirement in GADA-negative participants (P = 0.4). In Cox regression analysis with adjustment for age of diagnosis, BMI, and cohort, T1D GRS was independently associated with time to insulin only in the presence of GADA: hazard ratio per SD increase was 1.48 (1.15, 1.90); P = 0.002.Conclusions: A T1D GRS alters the clinical implications of a positive GADA test in patients with clinical type 2 diabetes and is independent of and additive to clinical features. [ABSTRACT FROM AUTHOR]

Objective: The impact of taking oral glucose-lowering medicines intermittently, rather than as recommended, is unclear. We conducted a retrospective cohort study using community-acquired U.K. clinical data (Clinical Practice Research Database [CPRD] and GoDARTS database) to examine the prevalence of nonadherence to treatment for type 2 diabetes and investigate its potential impact on HbA1c reduction stratified by type of glucose-lowering medication.Research Design and Methods: Data were extracted for patients treated between 2004 and 2014 who were newly prescribed metformin, sulfonylurea, thiazolidinedione, or dipeptidyl peptidase 4 inhibitors and who continued to obtain prescriptions over 1 year. Cohorts were defined by prescribed medication type, and good adherence was defined as a medication possession ratio ≥0.8. Linear regression was used to determine potential associations between adherence and 1-year baseline-adjusted HbA1c reduction.Results: In CPRD and GoDARTS, 13% and 15% of patients, respectively, were nonadherent. Proportions of nonadherent patients varied by the oral glucose-lowering treatment prescribed (range 8.6% [thiazolidinedione] to 18.8% [metformin]). Nonadherent, compared with adherent, patients had a smaller HbA1c reduction (0.4% [4.4 mmol/mol] and 0.46% [5.0 mmol/mol] for CPRD and GoDARTs, respectively). Difference in HbA1c response for adherent compared with nonadherent patients varied by drug (range 0.38% [4.1 mmol/mol] to 0.75% [8.2 mmol/mol] lower in adherent group). Decreasing levels of adherence were consistently associated with a smaller reduction in HbA1c.Conclusions: Reduced medication adherence for commonly used glucose-lowering therapies among patients persisting with treatment is associated with smaller HbA1c reductions compared with those taking treatment as recommended. Differences observed in HbA1c responses to glucose-lowering treatments may be explained in part by their intermittent use. [ABSTRACT FROM AUTHOR]

Metformin is the most widely prescribed medication for the treatment of type 2 diabetes (T2D). However, gastrointestinal (GI) side effects develop in ~25% of patients treated with metformin, leading to the discontinuation of therapy in ~5% of cases. We hypothesized that reduced transport of metformin via organic cation transporter 1 (OCT1) could increase metformin concentration in the intestine, leading to increased risk of severe GI side effects and drug discontinuation. We compared the phenotype, carriage of reduced-function OCT1 variants, and concomitant prescribing of drugs known to inhibit OCT1 transport in 251 intolerant and 1,915 fully metformin-tolerant T2D patients. We showed that women and older people were more likely to be intolerant to metformin. Concomitant use of medications, known to inhibit OCT1 activity, was associated with intolerance (odds ratio [OR] 1.63 [95% CI 1.22-2.17], P = 0.001) as was carriage of two reduced-function OCT1 alleles compared with carriage of one or no deficient allele (OR 2.41 [95% CI 1.48-3.93], P < 0.001). Intolerance was over four times more likely to develop (OR 4.13 [95% CI 2.09-8.16], P < 0.001) in individuals with two reduced-function OCT1 alleles who were treated with OCT1 inhibitors. Our results suggest that reduced OCT1 transport is an important determinant of metformin intolerance. [ABSTRACT FROM AUTHOR]

The incretin hormone glucagon-like peptide 1 (GLP-1) promotes glucose homeostasis and enhances b-cell function. GLP-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, which inhibit the physiological inactivation of endogenous GLP-1, are used for the treatment of type 2 diabetes. Using the Metabochip, we identified three novel genetic loci with large effects (30-40%) on GLP-1--stimulated insulin secretion during hyperglycemic clamps in nondiabetic Caucasian individuals (TMEM114; CHST3 and CTRB1/ 2; n = 232; all P ≤ 8.8 x 10-7). rs7202877 near CTRB1/2, a known diabetes risk locus, also associated with an absolute 0.51 ± 0.16% (5.6 ± 1.7 mmol/mol) lower A1C response to DPP-4 inhibitor treatment in G-allele carriers, but there was no effect on GLP-1 RA treatment in type 2 diabetic patients (n = 527). Furthermore, in pancreatic tissue, we show that rs7202877 acts as expression quantitative trait locus for CTRB1 and CTRB2, encoding chymotrypsinogen, and increases fecal chymotrypsin activity in healthy carriers. Chymotrypsin is one of the most abundant digestive enzymes in the gut where it cleaves food proteins into smaller peptide fragments. Our data identify chymotrypsin in the regulation of the incretin pathway, development of diabetes, and response to DPP-4 inhibitor treatment. [ABSTRACT FROM AUTHOR]

Common variation in the Transcription factor 7-like 2 gene (TCF7L2) is strongly associated with type 2 diabetes. The function of TCF7L2 is poorly understood although some data suggests a role in beta-cell function. As sulfonylureas stimulate beta-cells we hypothesised that variation in TCF7L2 will influence glycemic response to sulfonylureas, but not to mefformin. Two independent data sets were used: GoDARTS1 (GD1) and the Wellcome Trust UK Type 2 diabetes case control consortium (GD2). Incident users of sulfonylureas (GD1 n=359; GD2 n=588) and metformin (GD1 n=253; GD2 n=735) with type 2 diabetes and HbA1c data 3-12 months from starting treatment between 1993 and 2004 were identified, and genotyped at TCF7L2 rs12255372. In GD1, only 36% of TT homozygotes were treated to a target hba1c <7% with sulfonylureas compared to 62% of G* (GT/GG) individuals (OR 0.35, p=0.003). In GD2, the equivalent OR was 0.65, p=0.1. Combining GD1 and GD2 gave an OR of 0.52, p=0.002. In the combined data set, a logistic regression model was used with the covariates: age of diabetes diagnosis, sex, bmi, diabetes duration and drug dose. In this model the OR for treatment success (TT vs G*) was 0.49, p=0.001, and this remained significant (OR 0.48, p=0.008) with addition of pre-treatment HbA1c to the model (n=515). By contrast in a similar model there was no effect of TCF7L2 genotype on metformin response (logistic regression OR 0.95, p=0.86). We conclude that variation in TCF7L2 predicts treatment response to sulfonylureas but not to metformin. This is a robust example of pharmacogenetics within a large Type 2 diabetic population. [ABSTRACT FROM AUTHOR]

Objective: To investigate the association between visit-to-visit HbA 1c variability and cardiovascular events and microvascular complications in patients with newly diagnosed type 2 diabetes., Research Design and Methods: This retrospective cohort study analyzed patients from Tayside and Fife in the Scottish Care Information-Diabetes Collaboration (SCI-DC) who were observable from the diagnosis of diabetes and had at least five HbA 1c measurements before the outcomes were evaluated. We used the previously reported HbA 1c variability score (HVS), calculated as the percentage of the number of changes in HbA 1c >0.5% (5.5 mmol/mol) among all HbA 1c measurements within an individual. The association between HVS and 10 outcomes was assessed using Cox proportional hazards models., Results: We included 13,111-19,883 patients in the analyses of each outcome. The patients with HVS >60% were associated with elevated risks of all outcomes compared with the lowest quintile (for example, HVS >80 to ≤100 vs. HVS ≥0 to ≤20, hazard ratio 2.38 [95% CI 1.61-3.53] for major adverse cardiovascular events, 2.4 [1.72-3.33] for all-cause mortality, 2.4 [1.13-5.11] for atherosclerotic cardiovascular death, 2.63 [1.81-3.84] for coronary artery disease, 2.04 [1.12-3.73] for ischemic stroke, 3.23 [1.76-5.93] for heart failure, 7.4 [3.84-14.27] for diabetic retinopathy, 3.07 [2.23-4.22] for diabetic peripheral neuropathy, 5.24 [2.61-10.49] for diabetic foot ulcer, and 3.49 [2.47-4.95] for new-onset chronic kidney disease). Four sensitivity analyses, including adjustment for time-weighted average HbA 1c , confirmed the robustness of the results., Conclusions: Our study shows that higher HbA 1c variability is associated with increased risks of all-cause mortality, cardiovascular events, and microvascular complications of diabetes independently of high HbA 1c ., (© 2019 by the American Diabetes Association.)