Metformin Therapy In Patients Research Articles

Efficacy and safety of dapagliflozin add-on to evogliptin plus metformin therapy in patients with type 2 diabetes: A randomized, double-blind, placebo-controlled study.

To evaluate the efficacy and safety of dapagliflozin versus placebo as an add-on in patients with type 2 diabetes who did not achieve adequate glycaemic control with evogliptin and metformin combination. In this multicentre, randomized, double-blind, placebo-controlled Phase 3 trial, patients with glycated haemoglobin (HbA1c) levels ≥7.0% (≥53 mmol/mol) and ≤10.5% (≤91 mmol/mol) who had received stable-dose metformin (≥1000 mg) and evogliptin (5 mg) for at least 8 weeks were randomized to receive dapagliflozin 10 mg or placebo once daily for 24 weeks. Participants continued treatment with metformin and evogliptin. The primary endpoint was change in HbA1c level after 24 weeks of treatment from baseline level. In total, 198 patients were randomized, and 195 patients were included in the efficacy analyses (dapagliflozin: 96, placebo: 99). At Week 24, dapagliflozin significantly reduced HbA1c levels. The least squares mean difference in HbA1c level change from baseline after 24 weeks of treatment was -0.70% (-7.7 mmol/mol)(p < 0.0001). The proportion of participants achieving HbA1c <7.0% (≥53 mmol/mol)was higher in the dapagliflozin group than in the placebo group. Compared to placebo, dapagliflozin significantly reduced fasting plasma glucose, mean daily glucose, 2-h postprandial plasma glucose, fasting insulin, uric acid and gamma-glutamyl transferase levels, homeostatic model assessment for insulin resistance index, body weight, hepatic steatosis index, and albuminuria. Adiponectin level significantly increased from baseline level after 24 weeks of dapagliflozin treatment. Adverse event rates were similar in the two groups. Dapagliflozin add-on to evogliptin plus metformin improved glycaemic control and was well tolerated by the target patients.

Metformin Therapy for Acne Vulgaris: A Meta-Analysis.

Acne vulgaris is a common disease, which occurs in adolescents as well as adults and has a significant influence on the patient's quality of life (QoL) in every aspect. Due to resistance to standard therapies, it has become necessary to prospect for new treatment strategies. It is important to highlight that the diagnosis and treatment of the underlying cause of acne such as metabolic and hormonal disorders may significantly improve the effectiveness of acne treatment. The correlation between Insulin Resistance (IR) and acne has been proven. Both disorders share many common occurrence factors and activation pathways. Metformin, an antihyperglycemic agent, seems to be a possible therapy option, not only because of its insulin sensitizing ability but also via plenty of additional effects of this medicine. While the efficiency of metformin therapy in patients with acne and Polycystic Ovary Syndrome (PCOS) is well explored, it is still necessary to evaluate it in patients without any endocrinopathies. This meta-analysis aimed to estimate the effectiveness of oral metformin as a monotherapy in acne patients without PCOS or other endocrinopathies. Study selection was performed with included criteria such as no PCOS and other endocrinopathies diagnosed, oral administration of metformin, and metformin in monotherapy. Selected studies contained comparisons in the Global Acne Grading System (GAGS) before and after metformin therapy. Statistical analysis detected significant improvement in skin condition after treatment with metformin.

Metformin increases 3-hydroxy medium chain fatty acids in patients with type 2 diabetes: a cross-sectional pharmacometabolomic study.

Metformin is a drug with a long history of providing benefits in diabetes management and beyond. The mechanisms of action of metformin are complex, and continue to be actively debated and investigated. The aim of this study is to identify metabolic signatures associated with metformin treatment, which may explain the pleiotropic mechanisms by which metformin works, and could lead to an improved treatment and expanded use. This is a cross-sectional study, in which clinical and metabolomic data for 146 patients with type 2 diabetes were retrieved from Qatar Biobank. Patients were categorized into: Metformin-treated, treatment naïve, and non-metformin treated. Orthogonal partial least square discriminate analysis and linear models were used to analyze differences in the level of metabolites between the metformin treated group with each of the other two groups. Patients on metformin therapy showed, among other metabolites, a significant increase in 3-hydroxyoctanoate and 3-hydroxydecanoate, which may have substantial effects on metabolism. This is the first study to report an association between 3-hydroxy medium chain fatty acids with metformin therapy in patients with type 2 diabetes. This opens up new directions towards repurposing metformin by comprehensively understanding the role of these metabolites.

Serum Irisin in Polycystic Ovary Syndrome and its Alteration with Metformin Intervention.

Studies investigating the alterations of serum irisin and its change with metformin therapy in patients with polycystic ovary syndrome (PCOS) are conflicting. Our aim is to study serum irisin in PCOS patients and the change of irisin levels with metformin therapy over 6 months. This is a randomized control study conducted in 187 PCOS cases and 94 age-matched controls aged 18-40 years. Detailed evaluation of anthropometric, biochemical, and hormonal parameters was performed. A subset of 99 overweight/obese patients with body mass index (BMI) ≥23 kg/m2 were stratified into a metformin group (n = 67) receiving 500 mg thrice daily and a lifestyle intervention-only group (n = 32). The effect of metformin therapy on serum irisin levels was measured at the end of 6 months. Statistical analyses were performed with SPSS version 26.0 Software. Serum irisin was higher in PCOS patients than in controls [12.47 (8.1-17.7) vs 8.3 (7.0-9.6) ng/ml, P < 0.001], independent of BMI. Serum irisin showed a significant positive association with BMI (β =0.168), waist-to-hip ratio (β =0.166), leutinizing hormone (β =0.225), TG (β =0.305), FAI (β =0.151), and testosterone (β =0.135). Serum irisin showed a significant positive association with homeostatic model assessment of insulin resistance (HOMA-IR) (β =0.14, P = 0.04) in overweight/obese PCOS patients only (n = 146) but not in the whole PCOS cohort (n = 187). Metformin reduced the median serum irisin levels significantly (13.9 to 12.1 ng/ml, P < 0.001), and the delta change in irisin levels was associated with HOMA-IR in the metformin group. Serum irisin is increased in PCOS patients independent of BMI. Metformin therapy reduced serum irisin levels in overweight/obese PCOS patients by improving insulin resistance.

Revisiting metformin therapy for the mitigation of diabetic foot ulcer in patients with diabetic kidney disease from real-world evidence.

Diabetic foot ulcer and diabetic kidney disease are diabetes-related chronic vascular complications that strongly correlate with high morbidity and mortality. Although metformin potentially confers a wound-healing advantage, no well-established clinical evidence supports the benefit of metformin for diabetic foot ulcer. Thus, this study investigated the effect of metformin on diabetic foot ulcer from a large diabetic kidney disease cohort for the first time. This retrospective cohort study enrolled 10 832 patients who visited the nephrology department more than twice at two South Korean tertiary-referral centers between 2001 and 2016. The primary outcome was diabetic foot ulcer events; secondary outcomes included hospitalization, amputation, a composite of amputation or vascular intervention, and Wagner Grade ≥ 3. Multivariate Cox analysis and propensity score matching (PSM) were used to balance baseline intergroup differences between metformin users and non-users. In total, 4748 patients were metformin users, and 6084 patients were metformin non-users. Over a follow-up period of 117.5 ± 66.9 months, the diabetic foot ulcer incidence was 5.2%. After PSM, metformin users showed a lower incidence of diabetic foot ulcer events than metformin non-users (adjusted hazard ratio 0.41; p < 0.001). In a sensitivity analysis of 563 patients with diabetic foot ulcer, metformin usage was associated with lower severity in all four secondary outcomes: hospitalization (adjusted hazard ratio 0.33; p < 0.001); amputation (adjusted hazard ratio 0.44; p = 0.001); composite of amputation or vascular intervention (adjusted hazard ratio 0.47; p < 0.001); and Wagner Grade ≥ 3 (adjusted hazard ratio 0.39; p < 0.001). In conclusion, metformin therapy in patients with diabetic kidney disease can lower diabetic foot ulcer incidence and progression.

A randomized, double-blind, placebo controlled, phase 3 trial to evaluate the efficacy and safety of cetagliptin added to ongoing metformin therapy in patients with uncontrolled type 2 diabetes with metformin monotherapy.

This trial was designed to assess the efficacy and safety of cetagliptin added to metformin in Chinese patients with type 2 diabetes who had inadequate glycaemic control with metformin monotherapy. In total, 446 patients with type 2 diabetes on metformin monotherapy were randomized to receive the addition of once-daily cetagliptin 100 mg, cetagliptin 50 mg and placebo in a 2:2:1 ratio for 24-week double-blind treatment. At week 24, patients initially randomized to cetagliptin 50 mg and placebo were switched to cetagliptin 100 mg for 28 weeks open-label treatment. The primary endpoint was the change in haemoglobin A1c (HbA1c) from baseline, and the efficacy analyses were based on an all-patients-treated population using an analysis of co-variance. After 24 weeks, both add-on therapies led to greater glycaemic control. Reductions in HbA1c from baseline were -1.17 ± 0.794%, -1.23 ± 0.896% in cetagliptin 100 mg and 50 mg plus metformin group, respectively. No difference was observed between the cetagliptin 100 mg and 50 mg plus metformin group. Patients with higher baseline HbA1c levels (≥8.5%) experienced greater reductions in HbA1c. A significantly greater proportion of patients achieved an HbA1c <7.0% with cetagliptin 100 mg (49.4%) and cetagliptin 50 mg (51.1%) plus metformin than metformin monotherapy (14.4%). Both combination therapies also improved the homeostasis model assessment β-function index and decreased systolic blood pressure. There was no increased risk of adverse effects with combination therapy, and both combination therapies were generally well tolerated. The addition of cetagliptin once daily to metformin was more efficacious and well tolerated than metformin monotherapy in Chinese patients with type 2 diabetes who had inadequate glycaemic control with metformin monotherapy.

Efficacy of metformin therapy in patients with cancer: a meta-analysis of 22 randomised controlled trials

BackgroundTo investigate whether metformin monotherapy or adjunctive therapy improves the prognosis in patients with any type of cancer compared to non-metformin users (age ≥18).MethodsDatabases (Medline, Embase, and the Cochrane Central Register of Controlled Trials) and clinical trial registries (ClinicalTrials.gov; the World Health Organization International Clinical Trials Registry Platform) were screened for randomized, controlled trials (RCT) reporting at least progression-free survival (PFS) and/or overall survival (OS). Main outcome measures included hazard ratios (HR), and combined HRs and 95% confidence intervals (CI) were calculated using random-effects models.ResultsOf the 8419 records screened, 22 RCTs comprising 5943 participants were included. Pooled HRs were not statistically significant in both PFS (HR 0.97, 95% CI 0.82–1.15, I2 = 50%) and OS (HR 0.98, 95% CI 0.86–1.13, I2 = 33%) for patients with cancer between the metformin and control groups. Subgroup analyses demonstrated that metformin treatment was associated with a marginally significant improvement in PFS in reproductive system cancers (HR 0.86, 95% CI 0.74–1.00) and a significantly worse PFS in digestive system cancers (HR 1.45, 95% CI 1.03–2.04). The PFS or OS was observed consistently across maintenance dose, diabetes exclusion, median follow-up, risk of bias, and combined antitumoral therapies.ConclusionMetformin treatment was not associated with cancer-related mortality in adults compared with placebo or no treatment. However, metformin implied beneficial effects in the PFS of the patients with reproductive system cancers but was related to a worse PFS in digestive system cancers.Systematic review registrationPROSPERO registration number CRD42022324672.

A Randomized Controlled Trial of R-Form Verapamil Added to Ongoing Metformin Therapy in Patients with Type 2 Diabetes

ContextThere is a medical need for effective insulin-independent antidiabetic drugs that can promote pancreatic β-cell function and have a low risk of hypoglycemia in type 2 diabetes mellitus (T2DM) patients. R-form verapamil (R-Vera), which is able to enhance the survival of β-cells and has higher cardiovascular safety margin compared with racemic verapamil, was developed as a novel approach for T2DM treatment.ObjectiveThis randomized, double-blind, placebo-controlled clinical trial was designed to evaluate the efficacy and safety of 3 dosages of R-Vera added to ongoing metformin therapy in T2DM patients who had inadequate glycemic control on metformin alone.MethodsParticipants were randomly assigned in an equal ratio to receive R-Vera 450, 300, or 150 mg per day, or matching placebo, in combination with metformin. The primary endpoint was change in hemoglobin A1c (HbA1c) after 12 weeks of treatment.ResultsA total of 184 eligible participants were randomized to receive either R-Vera or placebo plus metformin. At week 12, significant reductions in HbA1c were observed for R-Vera 300 mg/day (−0.36, P = 0.0373) and 450 mg/day (−0.45, P = 0.0098) compared with placebo. The reduction in HbA1c correlated with decreasing fasting plasma glucose levels and improved HOMA2-β score. Treatment with R-Vera was well tolerated with no hypoglycemic episodes occurring during the trial.ConclusionAddition of R-Vera twice daily to ongoing metformin therapy significantly improved glycemic control in T2DM patients. The favorable efficacy and safety profile of R-Vera 300 mg/day can be considered as the appropriate dose for clinical practice.

Genetic and Phenotypic Factors Affecting Glycemic Response to Metformin Therapy in Patients with Type 2 Diabetes Mellitus.

Metformin is an oral hypoglycemic agent widely used in clinical practice for treatment of patients with type 2 diabetes mellitus (T2DM). The wide interindividual variability of response to metformin therapy was shown, and recently the impact of several genetic variants was reported. To assess the independent and combined effect of the genetic polymorphism on glycemic response to metformin, we performed an association analysis of the variants in ATM, SLC22A1, SLC47A1, and SLC2A2 genes with metformin response in 299 patients with T2DM. Likewise, the distribution of allele and genotype frequencies of the studied gene variants was analyzed in an extended group of patients with T2DM (n = 464) and a population group (n = 129). According to our results, one variant, rs12208357 in the SLC22A1 gene, had a significant impact on response to metformin in T2DM patients. Carriers of TT genotype and T allele had a lower response to metformin compared to carriers of CC/CT genotypes and C allele (p-value = 0.0246, p-value = 0.0059, respectively). To identify the parameters that had the greatest importance for the prediction of the therapy response to metformin, we next built a set of machine learning models, based on the various combinations of genetic and phenotypic characteristics. The model based on a set of four parameters, including gender, rs12208357 genotype, familial T2DM background, and waist–hip ratio (WHR) showed the highest prediction accuracy for the response to metformin therapy in patients with T2DM (AUC = 0.62 in cross-validation). Further pharmacogenetic studies may aid in the discovery of the fundamental mechanisms of type 2 diabetes, the identification of new drug targets, and finally, it could advance the development of personalized treatment.

Lipocalin-2 Level in Patients with Polycystic Ovary Syndrome: Association with Insulin Resistance and Metformin Therapy

Abstract Background PCOS appears to be associated with an increased risk of metabolic aberrations, including insulin resistance and hyperinsulinemia, type 2 diabetes mellitus, dyslipidemia, and cardiovascular disease throughout womens’ lifespan. Obesity is a state of chronic low-grade systemic inflammation. This chronic inflammation is characterized by abnormal cytokine production and activation of inflammatory signaling pathways in adipose tissues, which contributes to insulin resistance and its related diseases such as PCOS and metabolic syndrome. Objective To evaluate Lipocalin-2 level in a sample of Egyptian females with PCOS and study the effect of metformin therapy on Lipocalin-2 level in patients with PCOS. Methods This case control study was conducted on 52 females, collected from the outpatient obstetrics and gynaecology clinics of Ain Shams University Hospitals from June 2018 to March 2019, their age ranged between 17-43 years old. divided into 2 groups: Group (I) 32 women with polycystic ovary syndrome According to the Rotterdam diagnostic criteria of PCOS, and Group (II) 20 healthy women old with normal ovulatory cycle as a control group. All subjects were subjected to full medical history taking, thorough physical examination including BMI and waist circumference. Fasting plasma glucose, Fasting s.insulin, HOMA-IR, lipocalin-2 level were assessed. Results Serum lipocalin-2 levels did not differ between patients with PCOS and BMI-matched healthy controls (P-value 0.193), and there was no significant difference between the 2 studied groups as regard HOMA-IR (p = 0.375). Metformin therapy for 3 months in patients with PCOS in the present study, resulted in significant reduction in lipocalin-2 level (p-value&amp;lt;0.01), (mean 54.2±15.3ng/ml before metformin therapy vs 42.9±14.2 ng/ml after metformin therapy). Moreover, metformin therapy in PCOS group resulted in significant reduction in weight, BMI, waist circumference and HOMA-IR. Furthermore, linear regression analysis for the parameters affecting lipocalin level in our study, showed that BMI was the only significant confounder affecting lipocalin level. So, the reduction in lipocalin level following metformin therapy in PCOS group in our study may be due to weight reduction perse. Conclusion PCOS per se is not associated with elevated serum lipocalin-2 levels. Metformin therapy induces a significant reduction in serum lipocalin-2 levels, weight, BMI, waist circumference and HOMA-IR in patients with PCOS. Reduction of BMI was the only significant confounder affecting lipocalin level after metformin therapy. So the reduction in lipocalin level following metformin therapy in patients with PCOS in our study may be due to weight reduction perse.

Genetic Association of Solute Carrier Transporter Gene Variants with Metformin Response.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by elevated blood glucose levels and is influenced by both genetic and environmental factors. It is treated with various classes of oral antidiabetic drugs, however, response to treatment is highly variable with patients failing to achieve adequate glycemic control. Treatment response variability has been associated with single nucleotide polymorphisms (SNPs) which influence the pharma-cokinetics and pharmacodynamics of drug(s). The aim of this study was to evaluate the genetic association of 17 SNPs and the response to metformin therapy in patients diagnosed with diabetes from the indigenous Nguni population of South Africa. One hundred and forty indigenous African patients diagnosed with T2DM were recruited and genotyped using the MassARRAY® system. Therapeutic response of patients was ascertained by a change in Hb A1c. Two SNPs (rs1801282 and rs6265) were monomorphic. All other variants were within the Hardy-Weinberg equilibrium (HWE). The T allele of the SLC variant rs316009 [odds ratio (OR) = 0.25, 95% confidence interval (95% CI) = 0.01-0.09, p value = 0.044] and the CT genotype of the PCK1 variant rs4810083 (OR = 2.80, 95% CI = 1.01-7.79, p value = 0.049) were associated with an improved response to treatment after adjustment. No association was observed with post Bonferroni correction. Moreover, this study provides important additional data regarding possible associations between genetic variants and metformin therapy outcomes. In addition, this is one of the first studies providing genetic data from the understudied indigenous sub-Saharan African populations.

Metformin in patients with type 2 diabetes mellitus and heart failure: a review.

Diabetes mellitus is a major, global problem. Among the numerous complications of diabetes, there is increasing concern over the coexisting heart failure. Metformin is the most frequently used oral antidiabetic drug that is considered to be safe and effective in the management of type 2 diabetes mellitus. Since the publication of the UK Prospective Diabetes Study, it has been suggested that metformin might improve cardiovascular prognoses. Results from available studies have shown that metformin therapy in patients with type 2 diabetes mellitus and heart failure was associated with improved clinical outcomes when compared with other oral antidiabetic agents, insulin, or lifestyle management. However, there have been no randomized controlled trials evaluating the influence of metformin use on clinical outcomes in patients with type 2 diabetes mellitus and heart failure. New evidence from large cardiovascular outcome trials that showed a reduction in heart failure hospitalization for SGLT2 inhibitors caused changes in recommendations on the management of hyperglycaemia. Currently, the European Society of Cardiology recommends sodium-glucose co-transporter 2 inhibitors in patients with type 2 diabetes mellitus and heart failure or at high risk for heart failure, as a first choice in drug naïve patients, or as a second drug if the patient is already on metformin. The aim of our study is to review the current state of knowledge about the position of metformin in the treatment of patients with type 2 diabetes mellitus and heart failure.

Effect of metformin therapy on muscle mass and strength in patients with and without diabetes. Meta-analysis of 15 studies

Aim. To assess the parameters reflecting sarcopenia (body composition, muscle strength, muscle function) in order to determine the effectiveness of metformin in patients with sarcopenia.Material and methods. Systematic searches of clinical trials were carried out in MEDLINE databases through PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), ResearchGate from January 1990 to March 2019. For statistical processing, the R language with the RStudio software was used. The following packages were used: googlesheets4, tidyverse, meta, dmetar, metafor. The metaanalysis included 391 patients with both established for the first time and existing long-term type 2 diabetes (T2D), with prediabetes, impaired glucose tolerance (IGT), as well as patients without impaired glucose metabolism. In comparison groups (194 patients who received metformin and 197 patients who received placebo), the effect of metformin on lean body mass (LBM), fat mass, muscle strength and muscle function was assessed, which made it possible to indirectly evaluate the potential effect of metformin on sarcopenia.Results. The use of metformin in patients with different glucose metabolism (type 2 diabetes, IGT, prediabetes) did not lead to significant changes in body composition (on average, LBM increased by 0,9 kg (MD, 0,8815; CI (-0,11; 1,87), p=0,0818), fat mass decreased by 0,7% (MD, -0,6856; CI (-1,54; 0,17), p=0,1170), but muscle strength significantly increased by 0,5 kg (SMD, 0,5241, CI (0,2265; 0,8217), p=0,0006).Conclusion. Meta-analysis has confirmed that the use of metformin has an effect on muscle strength, which makes it possible to consider it for sarcopenia treatment. Unfortunately, a small number of studies have not allowed to analyze the effect of metformin on a number of characteristics: muscle strength, muscle function (walking speed, functional tests). At the moment, a much larger prospective study is needed to form a final opinion on the rationale of metformin therapy in patients with sarcopenia.

2140-PUB: Effect of Metformin on Incretin Secretion in Patients with Diabetes and Chronic Heart Failure

Aim: Metformin (MET) is a mainstay for treatment of type 2. diabetes (DM). Its use in patients with chronic heart failure (HF) patients is recent, associated with lower frequency of cardiovascular events and with better survival, but mechanisms of action are unclear. GLP-1 incretin is reported to have cardioprotective effects. Our aim was to assess the effects of MET on glucose metabolism, incretin secretion and cardiac function in patients with DM and HF. Methods: A randomized, double-blind, placebo-controlled, crossover study testing the effect of 3 - month usage of metformin vs. placebo. Treatment naive patients with DM and HF were randomized to metformin (2 g/day) or to placebo group. At the beginning and the end of each intervention period (baseline, after MET and after placebo) panel of various metabolic tests including meal test and cardiac function tests (echocardiography, cardiopulmonary exercise test) was done. Results: Metformin significantly reduced HbA1c. During meal test, metformin significantly reduced AUC of glucose, insulin and amylin; and increased GLP-1 and peptide YY. Details in Table. There was no change in cardiac function as assessed by echocardiography and spiroergometry. Conclusions: Metformin therapy in patients with HF improves diabetes compensation and has no significant effect on cardiac function. Improvement might be partly mediated by alteration of gut endocrine function. Disclosure J. Kopecky: None. E. Hošková: None. J. Veleba: None. V. Melenovsky: None. T. Pelikanova: None. Funding VZ 00023001 IKEM

Current status of metformin in addition to insulin therapy in adult patients with type 1 diabetes mellitus: An analysis from the Guangdong Type 1 Diabetes Mellitus Translational Medicine Study

Limited data on the efficacy of the additional metformin therapy in patients with type 1 diabetes mellitus (T1DM) under real-life conditions have been available so far. Patients aged ≥18 years with a duration of T1DM for at least 1 year were included in this multicenter observational study. Patients with insulin combined with metformin therapy (MET group) were compared with those with insulin therapy only (INS group). A total of 76 patients in the MET group were compared with 655 patients in the INS group. At baseline, patients with dyslipidemia were more prevalent in the MET group (17.6% vs 9.0%; P = .006), and they also had a higher body mass index (BMI) (21.7 ± 3.2 kg/m2 vs 20.4 ± 2.6 kg/m2 ; P < .001) than those in the INS group. But glycosylated hemoglobin (HbA1c) and daily insulin dose were not significantly different between the two groups. After 1-year follow-up, HbA1c decreased in both groups, while the daily insulin dose decreased in the MET group, but did not change in the INS group (-0.02 IU/kg [-0.16, 0.09] vs 0 IU/kg [-0.09, 0.09]; P = .029). The additional metformin therapy led to no change of BMI and weight in the MET group, while the body weight increased from 53.7 ± 8.6 kg to 55.0 ± 7.9 kg in the INS group (P < .001). Metformin is initiated more in T1DM patients with dyslipidemia or higher BMI in current practice in China. The addition of metformin is effective in maintaining weight and reducing the insulin dosage without improving glycemic control in patients with T1DM.

Metformin therapy in patients with diabetes mellitus is associated with a reduced risk of vasculopathy and cardiovascular mortality after heart transplantation

BackgroundCardiac allograft vasculopathy (CAV) is a major cause of morbidity and mortality following heart transplantation (HT). Reduced cardiovascular mortality and morbidity have been reported in non-HT patients treated with metformin. Given the high prevalence of type 2 diabetes mellitus (T2DM) in HT patients, we investigated the association between metformin therapy and cardiovascular outcomes after HT.MethodsThe study population comprised 103 DM patients who had undergone HT between 1994 and 2018 and were prospectively followed-up. We excluded from the study patients with type 1 diabetes mellitus. Fifty-five HT patients (53%) in the cohort were treated with metformin. Clinical data were recorded on prospectively designed forms. The primary outcomes included CAV, survival, and the combined end-point of CAV or cardiovascular mortality.ResultsKaplan–Meier survival analysis showed that the CAV rate at 20 years of follow-up was lower in DM patients treated with metformin than in those who were not (30 vs. 65%; log-rank p = 0.044). Similarly, the combined risk of CAV or cardiovascular mortality was lower in the metformin-treated patients than in those not receiving metformin (32 vs. 68%; log rank p = 0.01). Consistently, multivariate analysis adjusted for age and comorbidities showed that metformin therapy was independently associated with a significant 90% reduction (95% confidence interval 0.02–0.46, p = 0.003) in the risk for the development of CAV, and a 91% reduction (95% confidence interval 0.02–0.42; p = 0.003) in the risk for CAV or cardiovascular mortality.ConclusionsIn diabetic HT patients, metformin therapy is independently associated with a significant reduction in the long-term risk for CAV and the combined end-point of CAV or cardiovascular mortality after HT.

1226-P: Antifibrotic Effect of Combination Dapagliflozin and Metformin Therapy in Patients with Type 2 Diabetes Mellitus and Nonalcoholic Fatty Liver Disease

Objective: Evaluation of long-term results of combination therapy with dapagliflozin and metformin on fibrotic changes in the liver of patients with type 2 diabetes (DM) and nonalcoholic fatty liver disease (NAFLD). Materials and Methods: We recruited 45 DM patients with clinical NAFLD (27M, 18F) and in addition to dietary recommendations all received dapagliflozin 10 mg/daily plus metformin (max 2000 mg/daily); 7 patients required additional therapy with insulin. Results: As well documented in the literature, the efficacy of the dapagliflozin/metformin combination in the treatment of DM patients with NAFLD was shown in our series. Improvements in glycemic indices (HbA1c- 7.17 ± 0.16vs. 7.05 ± 0.18; FPG - 10.85 ± 0.48vs. 9.39 ± 0.46,р &amp;lt; 0.05), a reduction of BMI (31.04 ± 0.63kg/m2vs. 29.55 ± 0.50kg/m2, р &amp;lt; 0.05) and in liver function (AST/ALT 0.83 ± 0.05vs. 0.74 ± 0.05) observed during the long-term (16 months) administration of these drugs. The NAFLD, FIB-4 and APRI scales were used to determine the risk of liver fibrosis in this group of DM patients. After the start of the combination therapy, all scales showed decreases in the level of non-invasive liver fibrosis indices of these patients. The most sensitive method for the early diagnosis of liver fibrosis was the NAFLD scale, which decreased significantly (-0.941 ± 0.11 vs. -1.61 ± 0.12 points, р &amp;lt; 0,001). Following treatment, the number of patients with mild liver fibrosis increased from 8 (27.6%) to 21 (64.9%) and those in the "gray zone" also decreased from 29 (72.6%) to 13 (35.1%). Conclusion: In this non-randomized, single treatment arm group of DM patients study, we demonstrated that following combination therapy of dapagliflozin plus metformin for 16 months, better glycemic control is accompanied by simultaneous improvements in liver function tests and superior NAFLD scale values of liver fibrosis. Disclosure O. Lavrynenko: None. N. Kravchun: None. O. Zemlianitsyna: None. I. Dunaeva: None. R.A. DeFronzo: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc. E. Cersosimo: None. I. Karachentsev: None.

Augmented Mitophagy and Inflammasome Activation with Metformin therapy in patients with T2DM

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Maternal and Neonatal Outcomes in Patients of Gestational Diabetes Mellitus on Metformin Therapy

Present study carried out in a tertiary referral hospital in North India attempts to determine the maternal and neonatal outcomes of metformin therapy in patients of gestational diabetes mellitus. To evaluate maternal and neonatal outcomes in patients of GDM on metformin therapy and to study its adverse effects. In this prospective observational study, all women diagnosed with GDM not controlled by medical nutrition therapy were started on metformin therapy and the maternal and neonatal outcomes were studied. A total of 104 patients of GDM, not controlled on MNT and requiring pharmacotherapy, were enrolled for the study. An important clinical data from the study were that in 63.5% of patients there was no family history of diabetes mellitus. Average weight gain during pregnancy ranged from 6 to 10kg. Glycemic control was achieved in 96.2% of patients with varying doses of metformin therapy, and it reached statistical significance. Duration of metformin therapy ranged from a minimum of 2months to a maximum of 6months. No serious side effects were noted except for hypoglycemia in one patient. Patient acceptability toward metformin intake was good. Mean birth weight of newborns was 2972 ± 280g, and no case of fetal macrosomia was seen. Neonatal hypoglycemia was seen in 3.8% of the babies and 6.7% required NICU admission. No case of congenital malformation was reported. Metformin is a clinically effective, inexpensive and safe drug for treating gestational diabetes mellitus.

Review of the cardiovascular safety of dipeptidyl peptidase-4 inhibitors and the clinical relevance of the CAROLINA trial

BackgroundCardiovascular (CV) disease (CVD) is a well-recognized complication of type 2 diabetes mellitus (T2DM) and there is a clinical need for glucose-lowering therapies that do not further increase CV risk in this population. Although sulfonylureas (SUs) may be used as second-line therapy for patients requiring additional therapy after first-line metformin to improve glycemic control, their long-term effects on CV outcomes remain uncertain, and a wide range of alternative agents exist including dipeptidyl peptidase-4 (DPP-4) inhibitors.MethodsLiterature searches in PubMed (2013–2018) were conducted with terms for DPP-4 inhibitors combined with CV terms, with preference given to cardiovascular outcomes trials (CVOTs). Reference lists from retrieved articles and diabetes guidelines were also considered.ResultsThis narrative review discusses current evidence for the CV safety of these agents, describes the long-term CV effects of DPP-4 inhibitors, including effects on CV events, mortality, the risk for heart failure hospitalization, and highlights the need for further research into the CV effects of SU therapy. Although SUs remain a treatment option for T2DM, the long-term effects of these agents on CV outcomes are unclear, and further long-term studies are required. For DPP-4 inhibitors, uncertainties have been raised about their long-term effect on hospitalization for heart failure in light of the results of SAVOR-TIMI 53, although the findings of other DPP-4 inhibitor CVOTs in T2DM and data analyses have suggested these agents do not increase the occurrence of adverse CV outcomes.ConclusionsBased on recent CVOTs and guideline updates, the choice of add-on to metformin therapy for patients with T2DM and established CV disease should be a sodium-glucose co-transporter-2 inhibitor or a glucagon-like peptide-1 agonist with proven CV benefit. Additional treatment options for those individuals who require therapy intensification, as well as in patients with T2DM and without established CVD include DPP-4 inhibitors and SUs. Since few head-to-head trials have compared the effects of different oral glucose-lowering agents on CV outcomes in T2DM, with most CVOTs using placebo as a comparator, the CAROLINA trial will provide important information on the comparative CV safety of a commonly prescribed SU and a DPP-4 inhibitor.