Management of Type 2 Diabetes Mellitus With Noninsulin Pharmacotherapy.

Type 2 diabetes mellitus is a chronic disease that is increasing in global prevalence. An individualized approach to pharmacotherapy should consider costs, benefits beyond glucose control, and adverse events. Metformin is the first-line therapy due to its low cost and effectiveness. Sulfonylureas and thiazolidinediones are additional low-cost oral hypoglycemic classes available in the United States; however, evidence shows variability in weight gain and hypoglycemia. Thiazolidinediones increase fluid retention and are not recommended in patients with New York Heart Association class III or IV heart failure. Newer medications, including glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors, have demonstrated weight loss, reduced cardiovascular events, decreased renal disease, and improved all-cause morbidity and mortality. Sodium-glucose cotransporter-2 inhibitors are recommended for people with known cardiovascular disease, heart failure, and chronic kidney disease but carry an increased risk of urinary tract and mycotic infections. Glucagon-like peptide-1 receptor agonists are contraindicated in patients with active multiple endocrine neoplasia type 2 or a personal or family history of medullary thyroid carcinoma; adverse effects include gastrointestinal upset and pancreatitis. Dipeptidyl-peptidase-4 inhibitors have a low risk of hypoglycemia but may increase the risk of pancreatitis and require a renal dose adjustment. Public and private programs to increase access to newer hypoglycemic medications are increasing; however, there are limitations to access, particularly for uninsured and underinsured people.

A loss-of-function mutation in KCNJ11 causing sulfonylurea-sensitive diabetes in early adult life.

AIMS/HYPOTHESIS: The ATP-sensitive potassium (KATP) channel couples beta cell electrical activity to glucose-stimulated insulin secretion. Loss-of-function mutations in either the pore-forming (inwardly rectifying potassium channel 6.2 [Kir6.2], encoded by KCNJ11) or regulatory (sulfonylurea receptor 1, encoded by ABCC8) subunits result in congenital hyperinsulinism, whereas gain-of-function mutations cause neonatal diabetes. Here, we report a novel loss-of-function mutation (Ser118Leu) in the pore helix of Kir6.2 paradoxically associated with sulfonylurea-sensitive diabetes that presents in early adult life. METHODS: A 31-year-old woman was diagnosed with mild hyperglycaemia during an employee screen. After three pregnancies, during which she was diagnosed with gestational diabetes, the patient continued to show elevated blood glucose and was treated with glibenclamide (known as glyburide in the USA and Canada) and metformin. Genetic testing identified a heterozygous mutation (S118L) in the KCNJ11 gene. Neither parent was known to have diabetes. We investigated the functional properties and membrane trafficking of mutant and wild-type KATP channels in Xenopus oocytes and in HEK-293T cells, using patch-clamp, two-electrode voltage-clamp and surface expression assays. RESULTS: Functional analysis showed no changes in the ATP sensitivity or metabolic regulation of the mutant channel. However, the Kir6.2-S118L mutation impaired surface expression of the KATP channel by 40%, categorising this as a loss-of-function mutation. CONCLUSIONS/INTERPRETATION: Our data support the increasing evidence that individuals with mild loss-of-function KATP channel mutations may develop insulin deficiency in early adulthood and even frank diabetes in middle age. In this case, the patient may have had hyperinsulinism that escaped detection in early life. Our results support the importance of functional analysis of KATP channel mutations in cases of atypical diabetes.

Outcomes of Various Classes of Oral Antidiabetic Drugs on Nonalcoholic Fatty Liver Disease.

Importance: Several oral antidiabetic drug (OAD) classes can potentially improve patient outcomes in nonalcoholic fatty liver disease (NAFLD) to varying degrees, but clinical data on which class is favored are lacking. Objective: To investigate which OAD is associated with the best patient outcomes in NAFLD and type 2 diabetes (T2D). Design, Setting, and Participants: This retrospective nonrandomized interventional cohort study used the National Health Information Database, which provided population-level data for Korea. This study involved patients with T2D and concomitant NAFLD. Exposures: Receiving either sodium-glucose cotransporter 2 (SGLT2) inhibitors, thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitors, or sulfonylureas, each combined with metformin for 80% or more of 90 consecutive days. Main Outcomes and Measures: The main outcomes were NAFLD regression assessed by the fatty liver index and composite liver-related outcome (defined as liver-related hospitalization, liver-related mortality, liver transplant, and hepatocellular carcinoma) using the Fine-Gray model regarding competing risks. Results: In total, 80 178 patients (mean [SD] age, 58.5 [11.9] years; 43 007 [53.6%] male) were followed up for 219 941 person-years, with 4102 patients experiencing NAFLD regression. When compared with sulfonylureas, SGLT2 inhibitors (adjusted subdistribution hazard ratio [ASHR], 1.99 [95% CI, 1.75-2.27]), thiazolidinediones (ASHR, 1.70 [95% CI, 1.41-2.05]), and DPP-4 inhibitors (ASHR, 1.45 [95% CI, 1.31-1.59]) were associated with NAFLD regression. SGLT2 inhibitors were associated with a higher likelihood of NAFLD regression when compared with thiazolidinediones (ASHR, 1.40 [95% CI, 1.12-1.75]) and DPP-4 inhibitors (ASHR, 1.45 [95% CI, 1.30-1.62]). Only SGLT2 inhibitors (ASHR, 0.37 [95% CI, 0.17-0.82]), not thiazolidinediones or DPP-4 inhibitors, were significantly associated with lower incidence rates of adverse liver-related outcomes when compared with sulfonylureas. Conclusions and Relevance: The results of this cohort study suggest that physicians may lean towards prescribing SGLT2 inhibitors as the preferred OAD for individuals with NAFLD and T2D, considering their potential benefits in NAFLD regression and lower incidences of adverse liver-related outcomes. This observational study should prompt future research to determine whether prescribing practices might merit reexamination.

No association between metformin initiation and incident dementia in older adults newly diagnosed with diabetes.

BACKGROUND: Metformin has been suggested to reduce dementia risk; however, most epidemiologic studies have been limited by immortal time bias or confounding due to disease severity. OBJECTIVES: To investigate the association of metformin initiation with incident dementia using strategies that mitigate these important sources of bias. METHODS: Residents of Ontario, Canada ≥66 years newly diagnosed with diabetes from January 1, 2008 to December 31, 2017 entered this retrospective population-based cohort. To consider the indication for metformin monotherapy initiation, people with hemoglobin A1c of 6.5%-8.0% and estimated glomerular filtration rate ≥45 mL/min/1.73 m2 were selected. Using the landmark method to address immortal time bias, exposure was grouped into "metformin monotherapy initiation within 180 days after new diabetes diagnosis" or "no glucose-lowering medications within 180 days." To address disease latency, 1-year lag time was applied to the end of the 180-day landmark period. Incident dementia was defined using a validated algorithm for Alzheimer's disease and related dementias. Adjusted hazard ratios (aHR) and confidence intervals (CIs) were estimated from propensity-score weighted Cox proportional hazard models. RESULTS: Over mean follow-up of 6.77 years from cohort entry, metformin initiation within 180 days after new diabetes diagnosis (N = 12,331; 978 events; 65,762 person-years) showed no association with dementia risk (aHR [95% CI] = 1.05 [0.96-1.15]), compared to delayed or no glucose-lowering medication initiation (N = 22,369; 1768 events; 117,415 person-years). CONCLUSION: Early metformin initiation was not associated with incident dementia in older adults newly diagnosed with diabetes. The utility of metformin to prevent dementia was not supported.

An observational multi-center study on type 2 diabetes treatment prescribing pattern and patient adherence to treatment.

In 2021, the International Diabetes Federation (IDF) reported that the prevalence of diabetes in Pakistan was 9.6%, higher than the global average. However, adherence to treatment guidelines, e.g., American Diabetes Association and Pakistan Endocrine Society and prescription patterns for Oral anti-diabetes (OAD), is poorly understood in Pakistan. Therefore, this study aimed to examine the prescribing practices of anti-diabetic medications, an association of lifestyle modification with drugs prescribed, and their effectiveness in preserving ideal glycemic levels in diabetic patients undergoing treatment in tertiary care teaching hospitals in rural and urban Pakistan. In this cross-sectional study, data were collected from prescriptions of outpatient diabetic patients from different rural and urban tertiary care hospitals between October 2021 and February 2022. 388 participants were enrolled in the study for a detailed interview on prescription evaluation and glycemic control. The coinvestigators conducted an interview with the patient and used a pre-validated questionnaire to collect the data. The relationship between following treatment guidelines and clinical and demographic factors was found using chi-square tests for bivariate analyses. The study reported that out of 388, the mean ages of the patients were 48 ± 12.4, and the majority were female. It was observed that 60.1% and 66.5% have uncontrolled fasting and random blood glucose, respectively. The education level of the study participants was also below par to have a complete understanding of the medical condition and self-management therapy. Even though they were taking the right medications-an average prescription regimen included 5.08 medications-52.1% of the studied people had glycated haemoglobin (HbA1c) levels higher than the therapeutic threshold set by the International Diabetes Federation. In this modern era, it was observed that the prescribing trend was still focused on traditional therapeutic options Biguanides, sulfonylureas, and dipeptidyl peptidase-4 inhibitors were prescribed in 64.6% of the patients. A significant association was found between glycemic control and body mass index, adherence to lifestyle modifications, and the number of medications prescribed (p-value < 0.05). The study reveals that Pakistan's prescribing practices do not align with international and national guidelines, leading to a high prevalence of uncontrolled diabetes and widespread use of polypharmacy among patients. To address this issue, policymakers should prioritize establishing a comprehensive national diabetes action plan. Additionally, there is a pressing need to develop diabetes education and awareness programs emphasizing the importance of lifestyle modifications for effective diabetes management.

Fine-tuned photochromic sulfonylureas for optical control of beta cell Ca2+ fluxes.

We previously developed, synthesized and tested light-activated sulfonylureas for optical control of KATP channels and pancreatic beta cell activity in vitro and in vivo. Such technology relies on installation of azobenzene photoswitches onto the sulfonylurea backbone, affording light-dependent isomerization, alteration in ligand affinity for SUR1 and hence KATP channel conductance. Inspired by molecular dynamics simulations and to further improve photoswitching characteristics, we set out to develop a novel push-pull closed ring azobenzene unit, before installing this on the sulfonylurea glimepiride as a small molecule recipient. Three fine-tuned, light-activated sulfonylureas were synthesized, encompassing azetidine, pyrrolidine and piperidine closed rings. Azetidine-, pyrrolidine- and piperidine-based sulfonylureas all increased beta cell Ca2+ -spiking activity upon continuous blue light illumination, similarly to first generation JB253. Notably, the pyrrolidine-based sulfonylurea showed superior switch OFF performance to JB253. As such, third generation sulfonylureas afford more precise optical control over primary pancreatic beta cells, and showcase the potential of pyrrolidine-azobenzenes as chemical photoswitches across drug classes.

Diabetes, metformin use, and survival in esophageal cancer: a population-based cohort study.

BACKGROUND: It is unclear how diabetes and metformin use is associated with survival of esophageal cancer. METHODS: This population-based cohort study included new cases of esophageal cancer reported in Sweden from 2006 to 2018 with follow-up through 2019. Diabetes status and metformin use were analyzed in relation to all-cause and disease-specific mortality using multivariable Cox regression. The hazard ratios (HRs) with 95% confidence intervals (CIs) were adjusted for age, sex, calendar year, obesity, comorbidity, and use of nonsteroidal anti-inflammatory drugs or statins. For comparison reasons, 3 other antidiabetic medications were also analyzed (ie, sulfonylureas, insulin, and thiazolidinedione). RESULTS: Among 4851 esophageal cancer patients (8404 person-years), 4072 (84%) died during follow-up. Compared with esophageal cancer patients with diabetes but not using metformin, decreased all-cause mortality was indicated among nondiabetic patients (without metformin) (HR = 0.86, 95% CI = 0.77 to 0.96) and diabetic patients who used metformin (HR = 0.86, 95% CI = 0.75 to 1.00). The hazard ratios of all-cause mortality decreased with a higher daily dose of metformin (Ptrend = .04). The corresponding hazard ratios for disease-specific mortality were similar but slightly attenuated. The results were also similar in separate analyses of esophageal cancer patients with adenocarcinoma or squamous cell carcinoma, with tumor stage I-II or III-IV, and in those who had or had not undergone surgery. No associations with mortality outcomes were found for use of sulfonylureas, insulin, or thiazolidinedione. CONCLUSIONS: Diabetes was associated with an increased all-cause mortality, whereas metformin use was associated with decreased all-cause mortality among esophageal cancer patients. More research is needed to determine if metformin affects survival in esophageal cancer.

Meta-analysis of factors associated with antidiabetic drug prescribing for type 2 diabetes mellitus.

BACKGROUND: There is a lack of consensus on prescribing alternatives to initial metformin therapy and intensification therapy for type 2 diabetes mellitus (T2DM) management. This review aimed to identify/quantify factors associated with prescribing of specific antidiabetic drug classes for T2DM. METHODS: Five databases (Medline/PubMed, Embase, Scopus, Web of Science) were searched using the synonyms of each concept (patients with T2DM, antidiabetic drugs and factors influencing prescribing) in both free text and Medical Subject Heading (MeSH) forms. Quantitative observational studies evaluating factors associated with antidiabetic prescribing of metformin, sulfonylurea, thiazolidinedione, Dipeptidyl-peptidase 4 inhibitors (DPP4-I), sodium glucose transporter 2 inhibitors (SGLT2-I), Glucagon-Like peptide receptor agonist (GLP1-RA) and insulin in outpatient settings and published from January 2009 to January 2021 were included. Quality assessment was performed using a Newcastle-Ottawa scale. The validation was done for 20% of identified studies. The pooled estimate was measured using a three-level random-effect meta-analysis model based on odds ratio [95% confidence interval]. Age, sex, body mass index (BMI), glycaemic control (HbA1c) and kidney-related problems were quantified. RESULTS: Of 2331 identified studies, 40 met the selection criteria. Of which, 36 and 31 studies included sex and age, respectively, while 20 studies examined baseline BMI, HbA1c and kidney-related problems. The majority of studies (77.5%, 31/40) were rated as good and despite that the overall heterogeneity for each studied factor was more than 75%, it is mostly related to within-study variance. Older age was significantly associated with higher sulfonylurea prescription (1.51 [1.29-1.76]), yet lower prescribing of metformin (0.70 [0.60-0.82]), SGLT2-I (0.57 [0.42-0.79]) and GLP1-RA (0.52 [0.40-0.69]); while higher baseline BMI showed opposite significant results (sulfonylurea: 0.76 [0.62-0.93], metformin: 1.22 [1.08-1.37], SGLT2-I: 1.88 [1.33-2.68], and GLP1-RA: 2.35 [1.54-3.59]). Both higher baseline HbA1c and having kidney-related problems were significantly associated with lower metformin prescription (0.74 [0.57-0.97], 0.39 [0.25-0.61]), but more insulin prescriptions (2.41 [1.87-3.10], 1.52 [1.10-2.10]). Also, DPP4-I prescriptions were higher for patients with kidney-related problems (1.37 [1.06-1.79]) yet lower among patients with higher HbA1c (0.82 [0.68-0.99]). Sex was significantly associated with GLP1-RA and thiazolidinedione prescribing (F:M; 1.38 [1.19-1.60] and 0.91 [0.84-0.98]). CONCLUSION: Several factors were identified as potential determinants of antidiabetic drug prescribing. The magnitude and significance of each factor differed by antidiabetic class. Patient's age and baseline BMI had the most significant association with the choice of four out of the seven studied antidiabetic drugs followed by the baseline HbA1c and kidney-related problems which had an impact on three studied antidiabetic drugs, whereas sex had the least impact on prescribing decision as it was associated with GLP1-RA and thiazolidinedione only.

Sulfonylurea Use in Patients with Type 2 Diabetes and COPD: A Nationwide Population-Based Cohort Study.

We conducted this study to investigate the long-term outcomes of sulfonylurea (SU) use in patients with chronic obstructive pulmonary disease (COPD) and type 2 diabetes (T2D). We used propensity-score matching to identify 6008 pairs of SU users and nonusers from Taiwan's National Health Insurance Research Database from 1 January 2000 to 31 December 2017. Cox proportional hazard models were used to compare the risks of mortality, cardiovascular events, non-invasive positive pressure ventilation, invasive mechanical ventilation, bacterial pneumonia, lung cancer, and hypoglycemia between SU users and nonusers. In the matched cohorts, the mean follow-up time for SU users and nonusers was 6.57 and 5.48 years, respectively. Compared with nonusers, SU users showed significantly lower risks of mortality [aHR 0.53(0.48-0.58)], cardiovascular events [aHR 0.88(0.81-0.96)], non-invasive positive pressure ventilation [aHR 0.74(0.6-0.92)], invasive mechanical ventilation [aHR 0.57(0.5-0.66)], and bacterial pneumonia [aHR 0.78(0.7-0.87)]. A longer cumulative duration of SU use was associated with a lower risk of these outcomes. This nationwide cohort study demonstrated that SU use was associated with significantly lower risks of cardiovascular events, ventilation use, bacterial pneumonia, and mortality in patients with COPD and T2D. SU may be a suitable option for diabetes management in these patients.

Factor analysis as a tool to explore the heterogeneity of type 2 diabetes: A feasibility study.

AIM: Diabetes is currently classified based on pathogenetic mechanisms and Type 2 diabetes (T2DM) can be considered a residual heterogeneous category. Factor analysis (FA) identifies a limited number of calculated variables related to a larger number of measured parameters, capable of explaining most of their variance. Aim of the present study was to verify the feasibility of the application of FA for the development of pathogenetic models of individual cases of T2DM, using three available databases. METHODS: Firstly, a model of FA was applied to an existing dataset of non-diabetic patients, identifying three factors associated with fasting or post-prandial hyperglycemia. These factors were then calculated in: - patients enrolled in a retrospective observational study, assessing time to failure to diabetes treatment in three cohorts of patients (metformin or sulfonylurea monotherapy, or no pharmacological therapy); - in a retrospective cohort of patients failing to dual oral therapy and initiating treatment with DPP4 inhibitors; - in patients enrolled in a case-control study onincident cancer in T2DM subjects initiating insulin treatment. RESULTS AND CONCLUSIONS: Despite limitations, our results confirm the feasibility of approaching the characterization of T2DM through the identification of dimensional factors, providing additional and complementary information to that obtained with cluster analysis.

The Effect of Dual Bioactive Compounds Artemisinin and Metformin Co-loaded in PLGA-PEG Nano-particles on Breast Cancer Cell lines: Potential Apoptotic and Anti-proliferative Action.

The most prevalent malignancy among women is breast cancer. Phytochemicals and their derivatives are rapidly being recognized as possible cancer complementary therapies because they can modify signaling pathways that lead to cell cycle control or directly alter cell cycle regulatory molecules. The phytochemicals' poor bioavailability and short half-life make them unsuitable as anticancer drugs. Applying PLGA-PEG NPs improves their solubility and tolerance while also reducing drug adverse effects. According to the findings, combining anti-tumor phytochemicals can be more effective in regulating several signaling pathways linked to tumor cell development. The point of the study was to compare the anti-proliferative impacts of combined artemisinin and metformin on cell cycle arrest and expression of cyclin D1 and apoptotic genes (bcl-2, Bax, survivin, caspase-7, and caspase-3), and also hTERT genes in breast cancer cells. T-47D breast cancer cells were treated with different concentrations of metformin (MET) and artemisinin (ART) co-loaded in PLGA-PEG NPs and free form. The MTT test was applied to assess drug cytotoxicity in T47D cells. The cell cycle distribution was investigated using flow cytometry and the expression levels of cyclin D1, hTERT, Bax, bcl-2, caspase-3, and caspase-7, and survivin genes were then determined using real-time PCR. The findings of the MTT test and flow cytometry revealed that each state was cytotoxic to T47D cells in a time and dose-dependent pattern. Compared to various state of drugs (free and nano state, pure and combination state) Met-Art-PLGA/PEG NPs demonstrated the strongest anti-proliferative impact and considerably inhibited the development of T-47D cells; also, treatment with nano-formulated forms of Met-Art combination resulted in substantial downregulation of hTERT, Bcl-2, cyclin D1, survivin, and upregulation of caspase-3, caspase-7, and Bax, in the cells, as compared to the free forms, as indicated by real-time PCR findings. The findings suggested that combining an ART/MET-loaded PLGA-PEG NP-based therapy for breast cancer could significantly improve treatment effectiveness.

Clinical course of adolescents with type 2 diabetes mellitus: A nationwide cohort study in Taiwan.

AIMS/INTRODUCTION: The global incidence of adolescents with type 2 diabetes mellitus is increasing. This cohort study was conducted aiming to describe the characteristics, drug-use condition, and long-term outcomes of adolescents with type 2 diabetes mellitus. MATERIALS AND METHODS: Two thousand seven hundred fifty-five newly diagnosed adolescents with type 2 diabetes mellitus (using ICD-9-CM: 250.x and having ≥3 clinic visits) were identified from the national health insurance dataset during 2000-2014. Treatments were classified into four groups: metformin, sulfonylurea (SU), metformin plus SU, and insulin with or without oral antidiabetic drugs. The multiple Cox regression model was used to compare the risks of mortality and hospitalization among these four groups. RESULTS: The mean follow-up period was 5.4 years. After 1 year of antidiabetic treatment, they gradually needed intensified therapy, and at 3 years, half of them showed treatment failure. The mortality rate was 2.08 per 1,000 person-years. Respiratory diseases (36.2%) and dysglycemia (16.4%) were the most common causes of hospitalization among these adolescents. Compared with persons taking metformin plus SU, metformin users were associated with a lower risk of all-cause hospitalization [0.82 (0.67-0.99)]; insulin users were associated with a higher risk of dysglycemia [4.38 (2.14-8.96)], cancer [3.76 (1.39-10.1)], and respiratory hospitalization [1.66 (1.14-2.41)]; and SU users were associated with a higher risk of hospitalization for respiratory diseases [1.91 (1.13-3.23)]. CONCLUSIONS: This nationwide cohort study demonstrated that adolescents with type 2 diabetes mellitus were prone to treatment failure. Furthermore, respiratory diseases and dysglycemia were the most common causes of hospitalization.

Incretin-Based Drugs and the Incidence of Prostate Cancer Among Patients With Type 2 Diabetes.

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.

The impact of oral hypoglycemics and statins on outcomes in myelodysplastic syndromes.

Observational studies suggest an anti-neoplastic effect associated with statins, metformin, and dipeptidyl peptidase-4 inhibitors (DPP4i), while sulfonylureas may have a neutral or detrimental effect. We linked the Ontario subset of a prospective Canadian myelodysplastic syndromes (MDS) registry with provincial administrative databases. We assessed the impact of statin/oral hypoglycemic medication exposure on overall survival (OS) using Cox regression analysis, controlling for comorbidities and sociodemographic factors. Five hundred thirty-three patients aged ≥ 66 years were included: 49.3% used statins, 18.9% used metformin, 9.0% used sulfonylureas, and 6.4% used DPP4i. Three hundred ninety-five patients were lower-risk based on the International Prognostic Scoring System. On univariate analysis, we identified a marginal improvement in OS in the lower-risk group using DPP4i (HR 0.98, 95% CI 0.95-1.00, P = 0.05), while there was no impact on mortality for higher-risk DPP4i users (HR 1.03, CI 0.99-1.07, P = 0.21). There was no mortality difference for statins (HR 1.00, CI 1.00-1.01, P = 0.93), metformin (HR 1.00, CI 0.99-1.01, P = 0.81), or sulfonylureas (HR 1.00, CI 0.99-1.02, P = 0.43) in the entire cohort, as well as when stratified into lower/higher-risk groups. On multivariable analysis in the lower-risk group, there was no association between DPP4i and OS (HR 0.98, CI 0.95-1.00, P = 0.06). Prospective studies with larger cohorts of patients and longer follow-up are required to further study the impact of DPP4i in MDS.

Cardioprotective effects of dipeptidyl peptidase-4 inhibitors versus sulfonylureas in addition to metformin: A nationwide cohort study of patients with type 2 diabetes.

AIMS: Cardiovascular effects of dipeptidyl peptidase-4 inhibitors (DPP4i) versus sulfonylureas (SU) remain controversial in observational studies. This study aimed to evaluate the influence of DPP4i on major adverse cardiovascular events (MACEs), including acute myocardial infarction, cerebrovascular disease, heart failure, cardiogenic shock, malignant dysrhythmia, and revascularisation. MATERIALS AND METHODS: We conducted a nationwide cohort study using claims data from the National Health Insurance in Taiwan from 2007 to 2013. We enrolled type 2 diabetes patients who received DPP4i or SU in addition to metformin. DPP4i users were matched to SU users using propensity scores at a ratio of 1:1. The study outcomes were hospitalisation for MACE, heart failure, acute myocardial infarction, cerebrovascular disease, coronary revascularisation, and hypoglycaemia. RESULTS: There were 37,317 matched pairs of DPP4i and SU users with a mean follow-up of 2.1 years. Compared with SU users, DPP4i users showed a significantly lower risk of hospitalisation for MACE (HR 0.79 [95% CI 0.75-0.82]), heart failure (0.86 [0.79-0.93]), acute myocardial infarction (0.76 [0.68-0.92]), and cerebrovascular disease (0.72 [0.67-0.77]). Both sitagliptin (0.89 [0.85-0.94]) and vildagliptin ([0.77 [0.60-0.99]) showed a significantly lower risk of hospitalisation for MACE, but saxagliptin showed a borderline significantly higher risk of hospitalisation for heart failure (1.59 [1.00-2.55]). CONCLUSIONS: DPP4i showed better cardioprotective effects than SU, especially among patients receiving sitagliptin or vildagliptin.

Cardiovascular outcomes of type 2 diabetic patients treated with DPP­4 inhibitors versus sulphonylureas as add-on to metformin in clinical practice.

DPP-4 inhibitors (DPP-4i) and sulphonylureas remain the most widely prescribed add-on treatments after metformin. However, there is limited evidence from clinical practice comparing major adverse cardiovascular events (MACE) in patients prescribed these treatments, particularly among those without prior history of MACE and from vulnerable population groups. Using electronic health records from UK primary care, we undertook a retrospective cohort study with people diagnosed type-2 diabetes mellitus, comparing incidence of MACE (myocardial infarction, stroke, major cardiovascular surgery, unstable angina) and all-cause mortality among those prescribed DPP-4i versus sulphonylureas as add-on to metformin. We stratified analysis by history of MACE, age, social deprivation and comorbidities and adjusted for HbA1c, weight, smoking-status, comorbidities and medications. We identified 17,570 patients prescribed sulphonylureas and 6,267 prescribed DPP-4i between 2008-2017. Of these, 16.3% had pre-existing MACE. Primary incidence of MACE was similar in patients prescribed DPP-4i and sulphonylureas (10.3 vs 8.5 events per 1000 person-years; adjusted Hazard Ratio (adjHR): 0.94; 95%CI 0.80-1.14). For those with pre-existing MACE, rates for recurrence were higher overall, but similar between the two groups (21.8 vs 17.2 events per 1000 person-years; adjHR: 0.93; 95%CI 0.69-1.24). For those aged over 75 and with BMI less than 25 kg/m2 there was a protective effect for DPP-I, warranting further investigation. Patients initiating a DPP-4i had similar risk of cardiovascular outcomes to those initiating a sulphonylurea. This indicates the choice should be based on safety and cost, not cardiovascular prognosis, when deciding between a DPP-4i or sulphonylurea as add-on to metformin.

Genome-Wide Meta-analysis Identifies Genetic Variants Associated With Glycemic Response to Sulfonylureas.

OBJECTIVE: Sulfonylureas, the first available drugs for the management of type 2 diabetes, remain widely prescribed today. However, there exists significant variability in glycemic response to treatment. We aimed to establish heritability of sulfonylurea response and identify genetic variants and interacting treatments associated with HbA1c reduction. RESEARCH DESIGN AND METHODS: As an initiative of the Metformin Genetics Plus Consortium (MetGen Plus) and the DIabetes REsearCh on patient straTification (DIRECT) consortium, 5,485 White Europeans with type 2 diabetes treated with sulfonylureas were recruited from six referral centers in Europe and North America. We first estimated heritability using the generalized restricted maximum likelihood approach and then undertook genome-wide association studies of glycemic response to sulfonylureas measured as HbA1c reduction after 12 months of therapy followed by meta-analysis. These results were supported by acute glipizide challenge in humans who were naïve to type 2 diabetes medications, cis expression quantitative trait loci (eQTL), and functional validation in cellular models. Finally, we examined for possible drug-drug-gene interactions. RESULTS: After establishing that sulfonylurea response is heritable (mean ± SEM 37 ± 11%), we identified two independent loci near the GXYLT1 and SLCO1B1 genes associated with HbA1c reduction at a genome-wide scale (P < 5 × 10-8). The C allele at rs1234032, near GXYLT1, was associated with 0.14% (1.5 mmol/mol), P = 2.39 × 10-8), lower reduction in HbA1c. Similarly, the C allele was associated with higher glucose trough levels (ß = 1.61, P = 0.005) in healthy volunteers in the SUGAR-MGH given glipizide (N = 857). In 3,029 human whole blood samples, the C allele is a cis eQTL for increased expression of GXYLT1 (ß = 0.21, P = 2.04 × 10-58). The C allele of rs10770791, in an intronic region of SLCO1B1, was associated with 0.11% (1.2 mmol/mol) greater reduction in HbA1c (P = 4.80 × 10-8). In 1,183 human liver samples, the C allele at rs10770791 is a cis eQTL for reduced SLCO1B1 expression (P = 1.61 × 10-7), which, together with functional studies in cells expressing SLCO1B1, supports a key role for hepatic SLCO1B1 (encoding OATP1B1) in regulation of sulfonylurea transport. Further, a significant interaction between statin use and SLCO1B1 genotype was observed (P = 0.001). In statin nonusers, C allele homozygotes at rs10770791 had a large absolute reduction in HbA1c (0.48 ± 0.12% [5.2 ± 1.26 mmol/mol]), equivalent to that associated with initiation of a dipeptidyl peptidase 4 inhibitor. CONCLUSIONS: We have identified clinically important genetic effects at genome-wide levels of significance, and important drug-drug-gene interactions, which include commonly prescribed statins. With increasing availability of genetic data embedded in clinical records these findings will be important in prescribing glucose-lowering drugs.

Weight change and risk of cardiovascular disease among adults with type 2 diabetes: more than 14 years of follow-up in the Tehran Lipid and Glucose Study.

BACKGROUND: To examine the impact of weight change on incident cardiovascular disease and coronary heart disease (CVD/CHD) among an Iranian population with type 2 diabetes mellitus (T2DM). METHODS: The study population included 763 participants with T2DM aged ≥ 30 years without a history of CVD and cancer at baseline. Two weight measurements done at baseline and about 3 years later. Based on their weight change, they categorized into: > 5% loss, 3-5% loss, stable (± < 3%), 3-5% gain, > 5% gain. Participants were then followed for incident CVD/CHD annually up to 20 March 2018. Multivariable Cox proportional hazard models, adjusted for age, sex, body mass index, educational level, current smoking, glucose-lowering drug use, family history of CVD, hypertension, hypercholesterolemia, chronic kidney disease, and fasting plasma glucose (FPG) were applied to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of weight change categories for incident CVD/CHD, considering stable weight as reference. RESULTS: After the weight change measurement, during a median follow-up of 14.4 years, 258 CVD and 214 CHD occurred. Over 5% weight gain was associated with reduced risks of CVD and CHD development by the HRs of 0.70 [95% CI 0.48-1.01; P-value: 0.058] and 0.61 [0.40-0.93], respectively, in multivariable analysis. After further adjustment for FPG change, the HRs of weight gain > 5% were attenuated to 0.75 [0.51-1.10; P-value: 0.138] and 0.66 [043-1.01; P-value: 0.053] for incident CVD and CHD, respectively. The effect of weight loss > 5% was in opposite direction among those older versus younger than 60 years; with suggestive increased risk (not statistically significant) of incident CHD/CVD for the older group. Moreover, weight gain > 5% significantly reduced the risk of CHD only among those older than 60 years (P-value for interaction < 0.2). Furthermore, weight gain > 5% had an association with lower risk of CVD and CHD among sulfonylurea users (0.56 [0.32-0.98] for CVD and 0.54 [0.29-0.99] for CHD). CONCLUSIONS: Our results with a long-term follow-up showed that weight gain > 5% was associated with better CVD/CHD outcomes among Iranian participants with T2DM, especially older ones. Moreover, we did not find an unfavorable impact on incident CVD/CHD for sulfonylurea-induced weight gain.

Use of incretin-based drugs and risk of cholangiocarcinoma: Scandinavian cohort study.

AIMS/HYPOTHESIS: Concerns have been raised regarding a potential association of use of the incretin-based drugs dipeptidyl peptidase 4 (DPP4) inhibitors and glucagon-like peptide-1 (GLP-1)-receptor agonists with risk of cholangiocarcinoma. We examined this association in nationwide data from three countries. METHODS: We used data from nationwide registers in Sweden, Denmark and Norway, 2007-2018, to conduct two cohort studies, one for DPP4 inhibitors and one for GLP-1-receptor agonists, to investigate the risk of incident cholangiocarcinoma compared with an active-comparator drug class (sulfonylureas). The cohorts included patients initiating treatment episodes with DPP4 inhibitors vs sulfonylureas, and GLP-1-receptor agonists vs sulfonylureas. We used Cox regression models, adjusted for potential confounders, to estimate hazard ratios from day 366 after treatment initiation to account for cancer latency. RESULTS: The main analyses of DPP4 inhibitors included 1,414,144 person-years of follow-up from 222,577 patients receiving DPP4 inhibitors (median [IQR] follow-up time, 4.5 [2.6-7.0] years) and 123,908 patients receiving sulfonylureas (median [IQR] follow-up time, 5.1 [2.9-7.8] years) during which 350 cholangiocarcinoma events occurred. Use of DPP4 inhibitors, compared with sulfonylureas, was not associated with a statistically significant increase in risk of cholangiocarcinoma (incidence rate 26 vs 23 per 100,000 person-years; adjusted HR, 1.15 [95% CI 0.90, 1.46]; absolute rate difference 3 [95% CI -3, 10] events per 100,000 person-years). The main analyses of GLP-1-receptor agonists included 1,036,587 person-years of follow-up from 96,813 patients receiving GLP-1-receptor agonists (median [IQR] follow-up time, 4.4 [2.4-6.9] years) and 142,578 patients receiving sulfonylureas (median [IQR] follow-up time, 5.5 [3.2-8.1] years) during which 249 cholangiocarcinoma events occurred. Use of GLP-1-receptor agonists was not associated with a statistically significant increase in risk of cholangiocarcinoma (incidence rate 26 vs 23 per 100,000 person-years; adjusted HR, 1.25 [95% CI 0.89, 1.76]; absolute rate difference 3 [95% CI -5, 13] events per 100,000 patient-years). CONCLUSIONS/INTERPRETATION: In this analysis using nationwide data from three countries, use of DPP4 inhibitors and GLP-1-receptor agonists, compared with sulfonylureas, was not associated with a significantly increased risk of cholangiocarcinoma.

Thiazolidinediones and Glucagon-Like Peptide-1 Receptor Agonists and the Risk of Nonalcoholic Fatty Liver Disease: A Cohort Study.

BACKGROUND AND AIMS: Thiazolidinediones (TZDs) and glucagon-like peptide-1 (GLP-1) receptor agonists are potential pharmacological treatment options for patients at risk of NAFLD. Therefore, we examined the association between the risk of NAFLD and the use of TZDs and GLP-1 receptor agonists compared with the use of sulfonylureas (SUs) and insulins. Additionally, we calculated the incidence of HCC in users of TZDs and GLP-1 receptor agonists. APPROACH AND RESULTS: We conducted a population-based cohort study using primary care data from the Clinical Practice Research Datalink database (2007-2018). All patients aged ≥18 with a prescription of an oral glucose-lowering agent or GLP-1 receptor agonist were included. The first prescription defined the start of follow-up. The primary outcome was a new diagnosis of NAFLD. Cox proportional hazards regression was used to estimate HRs and 95% CIs of the primary outcome. Incidence rates of HCC were determined per 1,000 person-years for all exposures. The study identified 207,367 adults with a prescription for a glucose-lowering agent. The risk of NAFLD was lower in patients prescribed a TZD than in those prescribed an SU (adjusted HR [aHR], 0.32; 95% CI, 0.20-0.51). No difference in risk of NAFLD was observed comparing GLP-1 receptor agonist use with insulin use (aHR, 1.22; 95% CI, 0.91-1.63). CONCLUSIONS: Results of our study endorse the use of TZDs for selected patients at risk of NAFLD but do not support previous findings regarding the beneficial effect of GLP-1 receptor agonists. The low number of events in several subgroups may affect the generalizability of the current findings.