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Metformin use is associated with a reduced risk of mortality in patients with diabetes hospitalised for COVID-19.
Lalau, JD, Al-Salameh, A, Hadjadj, S, Goronflot, T, Wiernsperger, N, Pichelin, M, Allix, I, Amadou, C, Bourron, O, Duriez, T, et al
Diabetes & metabolism. 2021;(5):101216
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Abstract
AIMS: Metformin exerts anti-inflammatory and immunosuppressive effects. We addressed the impact of prior metformin use on prognosis in patients with type 2 diabetes hospitalised for COVID-19. METHODS CORONADO is a nationwide observational study that included patients with diabetes hospitalised for COVID-19 between March 10 and April 10, 2020 in 68 French centres. The primary outcome combined tracheal intubation and/or death within 7 days of admission. A Kaplan-Meier survival curve was reported for death up to day 28. The association between metformin use and outcomes was then estimated in a logistic regression analysis after applying a propensity score inverse probability of treatment weighting approach. RESULTS Among the 2449 patients included, 1496 were metformin users and 953 were not. Compared with non-users, metformin users were younger with a lower prevalence of diabetic complications, but had more severe features of COVID-19 on admission. The primary endpoint occurred in 28.0% of metformin users (vs 29.0% in non-users, P = 0.6134) on day 7 and in 32.6% (vs 38.7%, P = 0.0023) on day 28. The mortality rate was lower in metformin users on day 7 (8.2 vs 16.1%, P < 0.0001) and on day 28 (16.0 vs 28.6%, P < 0.0001). After propensity score weighting was applied, the odds ratios for primary outcome and death (OR [95%CI], metformin users vs non-users) were 0.838 [0.649-1.082] and 0.688 [0.470-1.007] on day 7, then 0.783 [0.615-0.996] and 0.710 [0.537-0.938] on day 28, respectively. CONCLUSION Metformin use appeared to be associated with a lower risk of death in patients with diabetes hospitalised for COVID-19.
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Metabolic impact of current therapeutic strategies in Polycystic Ovary Syndrome: a preliminary study.
De Diego, MV, Gómez-Pardo, O, Groar, JK, López-Escobar, A, Martín-Estal, I, Castilla-Cortázar, I, Rodríguez-Zambrano, MÁ
Archives of gynecology and obstetrics. 2020;(5):1169-1179
Abstract
PURPOSE To investigate the metabolic impact of currently used therapies in polycystic ovary syndrome (PCOS). METHODS This is an observational, retrospective and transversal protocol. A small cohort of 133 patients, aged 14-48 years, diagnosed with PCOS was divided into four experimental groups: 1) untreated PCOS patients (n = 51); 2) PCOS patients treated with one of the following therapies (n = 82): a) combined oral contraceptives (COC, n = 35); b) metformin (n = 11); and c) inositols (n = 36). RESULTS Although only < 10% of patients included in this cohort can be strictly encompassed in the development of metabolic syndrome, approximately 20% had insulin resistance. In PCOS patients, COC treatment modified the hormonal profile and worsened lipid parameters (increasing cholesterol and triglyceride levels) and insulin resistance, whereas inositol therapies improved significantly insulin resistance and glycosylated hemoglobin, reducing cholesterol and triglyceride levels. In these women, obesity was associated with greater alterations in lipid and glycemic metabolism and with higher blood pressure levels. PCOS patients with phenotype A presented vaster alterations in lipid metabolism and higher values of glycosylated hemoglobin as well as blood pressure compared to other PCOS phenotypes. CONCLUSIONS Results in this paper suggest that inositol therapies (alone or combined with COC) are the most useful therapies with the best benefits against PCOS symptoms. Thus, integrative treatment may become a more efficient long-term choice to control PCOS symptoms. Furthermore, obesity can be considered as an adverse symptom and calorie restriction a key element of combined treatment in PCOS, not only for fertility management but also in long-term metabolic sequelae.
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Level of glycemic control among US type 2 diabetes mellitus patients on dual therapy of metformin and sodium-glucose cotransporter 2 inhibitor: a retrospective database study.
Lautsch, D, Iglay, K, Yang, L, Bansal, N, Markan, R, Kathe, N, Rajpathak, S
Current medical research and opinion. 2020;(10):1583-1589
Abstract
OBJECTIVE To assess the level of glycemic control among type 2 diabetes patients on sodium-glucose cotransporter 2 inhibitor (SGLT2i) and metformin dual therapy. METHODS Observational, retrospective database study in adult type 2 diabetes mellitus patients from the IQVIA Electronic Medical Record (EMR) database was conducted. The observation period was June 2015 to June 2018. Patient's earliest encounter in the observation period while on SGLT2i and metformin dual therapy served as the index date. Patients were required to have at least one HbA1c measure in the 12 months prior to the index date and be on SGLT2i and metformin dual therapy and no other antihyperglycemic treatment as of the HbA1c measurement date or any time during the 90 days prior. The associations between sociodemographic factors and clinical burden on achievement of HbA1c <8% were assessed using multivariable logistic regression with backward stepwise selection. RESULTS Of 3491 patients, 2176 (62.3%) achieved HbA1c <8%, with a median distance to goal of 1.1% (IQR 0.5-2.3%) for those not at glycemic target. Mean age was 56.5 years and 52.6% were male. At baseline, 28.3% of patients had established cardiovascular disease/chronic kidney disease, and of those 63.8% had HbA1c <8%. African American patients had lower odds of attaining HbA1c <8% when compared with white patients [OR 0.69], while older patients had marginally higher odds [OR 1.01]. CONCLUSION Approximately 3 out of 5 patients on metformin and SGLT2i dual therapy achieved HbA1c <8%, with African Americans having a lower likelihood of achieving this glycemic goal.
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Mortality and other adverse outcomes in patients with type 2 diabetes mellitus admitted for COVID-19 in association with glucose-lowering drugs: a nationwide cohort study.
Pérez-Belmonte, LM, Torres-Peña, JD, López-Carmona, MD, Ayala-Gutiérrez, MM, Fuentes-Jiménez, F, Jorge Huerta, L, Muñoz, JA, Rubio-Rivas, M, Madrazo, M, Garcia, MG, et al
BMC medicine. 2020;(1):359
Abstract
BACKGROUND Limited evidence exists on the role of glucose-lowering drugs in patients with COVID-19. Our main objective was to examine the association between in-hospital death and each routine at-home glucose-lowering drug both individually and in combination with metformin in patients with type 2 diabetes mellitus admitted for COVID-19. We also evaluated their association with the composite outcome of the need for ICU admission, invasive and non-invasive mechanical ventilation, or in-hospital death as well as on the development of in-hospital complications and a long-time hospital stay. METHODS We selected all patients with type 2 diabetes mellitus in the Spanish Society of Internal Medicine's registry of COVID-19 patients (SEMI-COVID-19 Registry). It is an ongoing, observational, multicenter, nationwide cohort of patients admitted for COVID-19 in Spain from March 1, 2020. Each glucose-lowering drug user was matched with a user of other glucose-lowering drugs in a 1:1 manner by propensity scores. In order to assess the adequacy of propensity score matching, we used the standardized mean difference found in patient characteristics after matching. There was considered to be a significant imbalance in the group if a standardized mean difference > 10% was found. To evaluate the association between treatment and study outcomes, both conditional logit and mixed effect logistic regressions were used when the sample size was ≥ 100. RESULTS A total of 2666 patients were found in the SEMI-COVID-19 Registry, 1297 on glucose-lowering drugs in monotherapy and 465 in combination with metformin. After propensity matching, 249 patients on metformin, 105 on dipeptidyl peptidase-4 inhibitors, 129 on insulin, 127 on metformin/dipeptidyl peptidase-4 inhibitors, 34 on metformin/sodium-glucose cotransporter 2 inhibitor, and 67 on metformin/insulin were selected. No at-home glucose-lowering drugs showed a significant association with in-hospital death; the composite outcome of the need of intensive care unit admission, mechanical ventilation, or in-hospital death; in-hospital complications; or long-time hospital stays. CONCLUSIONS In patients with type 2 diabetes mellitus admitted for COVID-19, at-home glucose-lowering drugs showed no significant association with mortality and adverse outcomes. Given the close relationship between diabetes and COVID-19 and the limited evidence on the role of glucose-lowering drugs, prospective studies are needed.
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Observational study of the efficacy of prolonged-release metformin in people with prediabetes.
Hostalek, U, Zilahi, Z
Current medical research and opinion. 2020;(3):397-401
Abstract
Objectives: Prediabetes is characterized by elevation of indices of blood glucose that is insufficient to provoke a diagnosis of type 2 diabetes, but markedly increases the risk of developing type 2 diabetes in the future. Lifestyle interventions are the main therapeutic intervention for the management of prediabetes. Current guidelines also support treatment of prediabetes with metformin for selected subgroups of patients, and metformin has a therapeutic indication for this use in a number of countries.Methods: We performed an observational, non-interventional study of the effects on glycaemia of prolonged-release metformin (Glucophage XR, referred to henceforth as metformin XR) in 686 subjects with prediabetes. Metformin was prescribed according to physicians' usual care practices, and the study duration was 12 weeks.Results: Mean (SD) fasting plasma glucose (FPG) at baseline was 6.2 (0.4) mmol/L [111 (8) mg/dL) and was reduced by -0.55 (0.7) mmol/L [-10 (13) mg/dL] after 12 weeks of metformin XR. FPG was normalized to below the American Diabetes Association cut-off for the diagnosis of prediabetes (<5.7 mmol/L [100 mg/dL]) in 43% of subjects. Increasing age, increasing body mass index, not following a weight-loss diet and alcohol use predicted a lower probability of normalized FPG. Metformin was well tolerated, with most side effects occurring in the gastrointestinal system, as expected.Conclusions: Metformin XR normalized FPG in about two-fifths of subjects with prediabetes. These real-world data add further support a role for metformin in the management of prediabetes, in line with current guidelines in this area.
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Metformin improves blood glucose by increasing incretins independent of changes in gluconeogenesis in youth with type 2 diabetes.
Cravalho, CKL, Meyers, AG, Mabundo, LS, Courville, A, Yang, S, Cai, H, Dai, Y, Walter, M, Walter, PJ, Sharma, S, et al
Diabetologia. 2020;(10):2194-2204
Abstract
AIMS/HYPOTHESIS Metformin is the only approved oral agent for youth with type 2 diabetes but its mechanism of action remains controversial. Recent data in adults suggest a primary role for the enteroinsular pathway, but there are no data in youth, in whom metformin efficacy is only ~50%. Our objectives were to compare incretin concentrations and rates of glucose production and gluconeogenesis in youth with type 2 diabetes before and after short-term metformin therapy compared with peers with normal glucose tolerance (NGT). METHODS This is a case-control observational study in youth with type 2 diabetes who were not on metformin (n = 18) compared with youth with NGT (n = 10) who were evaluated with a 2 day protocol. A 75 g OGTT was administered to measure intact glucagon-like 1 peptide (iGLP-1), gastric inhibitory polypeptide (GIP) and peptide YY (PYY). Insulinogenic index (IGI) and whole-body insulin sensitivity were calculated using glucose and insulin levels from the OGTT. Basal rates of gluconeogenesis (2H2O), glucose production ([6,6-2H2]glucose) and whole-body lipolysis ([2H5]glycerol) were measured after an overnight fast on study day 2. Youth with type 2 diabetes (n = 9) were subsequently evaluated with an identical 2 day protocol after 3 months on the metformin study. RESULTS Compared with individuals with NGT, those with type 2 diabetes had higher fasting (7.8 ± 2.5 vs 5.1 ± 0.3 mmol/l, mean ± SD p = 0.002) and 2 h glucose concentrations (13.8 ± 4.5 vs 5.9 ± 0.9 mmol/l, p = 0.001), higher rates of absolute gluconeogenesis (10.0 ± 1.7 vs 7.2 ± 1.1 μmol [kg fat-free mass (FFM)]-1 min-1, p < 0.001) and whole-body lipolysis (5.2 ± 0.9 vs 4.0 ± 1.4 μmol kgFFM-1 min-1, p < 0.01), but lower fasting iGLP-1 concentrations (0.5 ± 0.5 vs 1.3 ± 0.7 pmol/l, p < 0.01). Metformin decreased 2 h glucose (pre metformin 11.4 ± 2.8 vs post metformin 9.9 ± 1.9 mmol/l, p = 0.04) and was associated with ~20-50% increase in IGI (median [25th-75th percentile] pre 1.39 [0.89-1.47] vs post 1.43 [0.88-2.70], p = 0.04), fasting iGLP-1 (pre 0.3 ± 0.2 vs post 1.0 ± 0.7 pmol/l, p = 0.02), 2 h iGLP (pre 0.4 ± 0.2 vs post 1.2 ± 0.9 pmol/l, p = 0.06), fasting PYY (pre 6.3 ± 2.2 vs post 10.5 ± 4.3 pmol/l, p < 0.01) and 2 h PYY (pre 6.6 ± 2.9 vs post 9.0 ± 4.0 pmol/l, p < 0.01). There was no change in BMI, insulin sensitivity or GIP concentrations pre vs post metformin. There were no differences pre vs post metformin in rates of glucose production (15.0 ± 3.9 vs 14.9 ± 2.2 μmol kgFFM-1 min-1, p = 0.84), absolute gluconeogenesis (9.9 ± 1.8 vs 9.7 ± 1.7 μmol kgFFM-1 min-1, p = 0.76) or whole-body lipolysis (5.0 ± 0.7 vs 5.3 ± 1.3 μmol kgFFM-1 min-1, p = 0.20). Post metformin iGLP-1 and PYY concentrations in youth with type 2 diabetes were comparable to levels in youth with NGT. CONCLUSIONS/INTERPRETATION Overall, the improved postprandial blood glucose levels and increase in incretins observed in the absence of changes in insulin sensitivity and gluconeogenesis, support an enteroinsular mechanistic pathway in youth with type 2 diabetes treated with short-term metformin.
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Metformin Usage Index and assessment of vitamin B12 deficiency among metformin and non-metformin users with type 2 diabetes mellitus.
Shivaprasad, C, Gautham, K, Ramdas, B, Gopaldatta, KS, Nishchitha, K
Acta diabetologica. 2020;(9):1073-1080
Abstract
AIM: The present study aimed to evaluate the combined effect of both dose and duration of metformin therapy on vitamin B12 levels in patients with type 2 diabetes mellitus (T2D). METHODS We recruited 2887 patients with T2D between January 2018 and November 2019 and categorized them into two groups (metformin and non-metformin users) matched for age, mean duration of diabetes, and BMI. We calculated the "Metformin Usage Index" (MUI) which was defined as the product of the dose of metformin (mg) used and its duration divided by 1000. Vitamin B12 levels were compared between the two groups, and its association with MUI was assessed using correlation and multistep logistic regression analyses. RESULTS Vitamin B12 levels < 200 pg/ml and between 200 and 300 pg/ml were noted among 24.5% and 34.5% metformin users, respectively; this was significantly higher than among non-metformin users (17.3% and 22.6%, respectively) [P < 0.001]. Overall, a vitamin B12 level < 300 pg/ml was found in 52.2% of the subjects. There was a significant association between an MUI > 5 and a high risk of vitamin B12 deficiency [P < 0.01]. The highest risk was observed among patients with an MUI > 15 [odds ratio (OR) 6.74, 95% CI 4.39-10.4] followed by patients with an MUI > 10 (OR 5.12, 95% CI 3.12-8.38). CONCLUSIONS The MUI can be employed as a risk assessment tool for evaluation of vitamin B12 deficiency in patients with T2D. Further prospective studies are required to determine the MUI thresholds in populations with good nutritional statuses and low prevalence of vitamin B12 deficiency.
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Real-world experience of metformin use in pregnancy: Observational data from the Northern Territory Diabetes in Pregnancy Clinical Register.
Maple-Brown, LJ, Lindenmayer, G, Barzi, F, Whitbread, C, Connors, C, Moore, E, Boyle, J, Kirkwood, M, Lee, IL, Longmore, D, et al
Journal of diabetes. 2019;(9):761-770
Abstract
BACKGROUND In Australia's Northern Territory, Indigenous mothers account for 33% of births and have high rates of hyperglycemia in pregnancy. The prevalence of type 2 diabetes (T2D) in pregnancy is up to 10-fold higher in Indigenous than non-Indigenous Australian mothers, and the use of metformin is common. We assessed birth outcomes in relation to metformin use during pregnancy from a clinical register. METHODS The study included women with gestational diabetes (GDM), newly diagnosed diabetes in pregnancy (DIP), or pre-existing T2D from 2012 to 2016. Data were analyzed for metformin use in the third trimester. Regression models were adjusted for maternal age, body mass index, parity, and insulin use. RESULTS Of 1649 pregnancies, 814 (49.4%) were to Indigenous women, of whom 234 (28.7%) had T2D (vs 4.6% non-Indigenous women; P < 0.001). Metformin use was high in Indigenous women (84%-90% T2D, 42%-48% GDM/DIP) and increased over time in non-Indigenous women (43%-100% T2D, 14%-35% GDM/DIP). Among Indigenous women with GDM/DIP, there were no significant differences between groups with and without metformin in cesarean section (51% vs 39%; adjusted odds ratio [aOR] 1.25, 95% confidence interval [CI] 0.87-1.81), large for gestational age (24% vs 13%; aOR 1.5, 95% CI 0.9-2.5), or serious neonatal adverse events (9.4% vs 5.9%; aOR 1.32, 95% CI 0.68-2.57). Metformin use was independently associated with earlier gestational age (37.7 vs 38.5 weeks), but the risk did not remain independently higher after exclusion of women managed with medical nutrition therapy alone, and the increase in births <37 weeks was not significant on multivariate analysis. CONCLUSIONS We found no clear evidence of any adverse outcomes related to the use of metformin for the treatment of hyperglycemia in pregnancy.
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An observational study of vitamin b12 levels and peripheral neuropathy profile in patients of diabetes mellitus on metformin therapy.
Gupta, K, Jain, A, Rohatgi, A
Diabetes & metabolic syndrome. 2018;(1):51-58
Abstract
METHODS A descriptive, observational study was completed in a tertiary care hospital between November 2014 and March 2016. Fifty consecutive patients of Type 2-Diabetes Mellitus who had been on metformin therapy for at least three months were included in our study. Several Parameters were compared with vitamin B12 levels and severity of peripheral neuropathy (using Toronto Clinical Scoring System (TCSS) and Nerve Conduction Velocity). These included the duration of diabetes, duration of metformin usage, dietary history, and HbA1c levels. Definite B12 deficiency was defined as B12<150pg/ml and possible B12 deficiency as <220pg/ml. RESULTS In our study, we found a negative correlation between duration of metformin use and Vitamin B12 levels(r=-0.40). The mean Vitamin B12 levels seen in our study was 212.3pg/mL. There is a positive correlation between the duration of metformin therapy and peripheral neuropathy (r=0.40). The mean TCSS score was 6.8. The percentage of patients with mild neuropathy was 28%, with moderate neuropathy was 20% and severe neuropathy in 12% of the patients. The average duration of metformin use in patients without peripheral neuropathy was 5.5yrs whereas the average length of metformin use in patients with peripheral neuropathy was 10.4 yrs. CONCLUSION Patients on long-term metformin therapy are at a high risk for Vitamin B12 deficiency and peripheral neuropathy. Interval Screening for peripheral neuropathy is recommended for patients on metformin even if Vitamin B12 levels appear to be normal.
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Renal function markers and metformin eligibility.
Tavares Bello, C, Castro Fonseca, R, Sousa Santos, F, Sequeira Duarte, J, Azinheira, J, Vasconcelos, C
Minerva endocrinologica. 2018;(3):246-252
Abstract
BACKGROUND Metformin is the cornerstone of the pharmacological therapy for type 2 diabetes mellitus (T2DM). It belongs to the biguanide class of drugs and it improves hepatic insulin resistance and enhances GLP-1 and peptide YY secretion. Despite being considered safe regarding hypoglycemic risk, renal dysfunction remains the main obstacle to its use due to the underlying risk of lactic acidosis. In the recent past many authors used creatinine values as the decisive marker when it came to choose between pharmacological agents in DM. Serum creatinine values equal or above 1.4 and 1.5 mg/dL were considered contraindications for metformin use in women and men respectively. Nowadays, creatinine is not the only surrogate of renal dysfunction and formulas such as the MDRD and CKD-EPI, that besides serum creatinine also include variables such as gender, age and race, have replaced serum creatinine as the standard for renal function assessment. Furthermore, since the associations between metformin and lactic acidosis in renal disease are not straightforward, its use has been considered safe down to creatinine clearances of 30 mL/min/1.73 m2. The authors describe a population with T2DM being treated with metformin and evaluate the impact of the solo evaluation of serum creatinine or CKD-EPI on biguanide prescription. METHODS Retrospective, observational, single-center study. All type 2 diabetic patients with regular follow up in a Central University Hospital Endocrinology-Diabetology Outpatient Clinic who were being treated with metformin and had at least 2 creatinine and estimated glomerular filtration rate (eGFR) measurements in the last decade were included. Patients were stratified according to renal function-based metformin contraindication criteria: creatinine group included patients with serum creatinine levels above 1.4 and 1.5 mg/dL in women and men respectively, and eGFR group included patients with eGFR below 30 mL/min/1.73 m2. The entire population and both groups are described and compared regarding comorbidities, demographic and laboratory data. The authors report the impact of each renal function marker (serum creatinine or eGFR) when used solo regarding metformin prescription eligibility. RESULTS A total of 2218 patients (61.3% females) with a mean age of 70±12 years is studied. Mean diabetes duration was 11.8±8.8 years. No cases with an eGFR below 30 mL/min/1.73 m2 were identified. On the other hand, in patients with GFR greater than 30 mL/min/1.73 m2, creatinine alone would contraindicate therapy in 274 patients (12.4% of the study population). Comparing Stage 3 chronic kidney disease patients without creatinine contraindication criteria with those with creatinine based contraindication, the data reveals that a higher prevalence of males, with longer diabetes duration, higher target organ damage (cerebrovascular disease, peripheral artery disease, heart failure, neuropathy and retinopathy) and with worse glycemic control were prevalent more in the elevated creatinine group. The use of serum creatinine as the single marker for renal function would significantly reduce metformin eligibility (OR=0.88, 95% CI: 0.8-0.95, P=0.002). CONCLUSIONS Metformin is the first line pharmacological agent in type 2 diabetes mellitus patients, being associated with significant HbA1c reductions and improvements in both micro and macrovascular outcomes. Avoiding its use due to imprecise renal function markers would potentially render the patient deprived of optimal pharmacological therapy for T2DM. Creatinine contraindication criteria alone are associated with unnecessary under prescription of metformin.