Optimizing metformin therapy in practice: Tailoring therapy in specific patient groups to improve tolerability, efficacy and outcomes.

Metformin is the first-line medication for type 2 diabetes. It is effective and safe, provided some caution is taken in specific populations. In patients with chronic kidney disease, metformin may provide long-term benefits, and it is a first-line therapy for diabetes, but the estimated glomerular filtration rate (eGFR) must be assessed regularly, to minimize the risk for metformin accumulation. When eGFR is 30-60 mL/min/1.73m2, the dose should be reconsidered, and sick-days education provided. Metformin should be discontinued when eGFR falls below 30 mL/min/1.73m2. Metformin accumulation may increase the risk for lactic acidosis if concomitant risk factors for hyperlactataemia (liver or respiratory insufficiency, sepsis, acute heart failure) are present; in these conditions, metformin is contraindicated, even although the available evidence is reassuring. Patients on metformin often complain of gastrointestinal side effects (mainly diarrhoea and nausea) during therapy initiation, but they may sometimes occur after years of stable therapy. These usually resolve if the dose is carefully titrated, or by switching to the extended-release formulation. Patients with obesity may benefit from the significant, although modest, metformin-associated weight loss and appetite reduction. During pregnancy, metformin is associated with a reduction of pregnancy complications, especially in obese women, but some concern remains, because metformin crosses the placenta, and it is associated with a significantly lower mean birth weight than insulin. In the elderly, gastrointestinal tolerability and renal function must be reassessed more often. Vitamin B-12 should be screened regularly in long-time metformin users because metformin may induce clinical vitamin B-12 deficiency.

Glucagon-like peptide-1 receptor agonists and risk of thyroid cancer: A systematic review and meta-analysis of randomized controlled trials.

AIM: To conduct a meta-analysis of randomized clinical trials (RCTs) to investigate whether there is an association between glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment and thyroid cancer. MATERIALS AND METHODS: In this meta-analysis of RCTs, we included studies comparing a GLP-1RA with any comparator, lasting at least 52 weeks, and reporting the incidence of adverse events independently of the principal endpoint and population. All cases of thyroid cancer were collected. RESULTS: We retrieved 64 trials, 26 of which reported at least one incident case of thyroid cancer. GLP-1RA treatment was associated with a significant increase in the risk of overall thyroid cancer (Mantel-Haenzel odds ratio [MH-OR] 1.52 [95% confidence interval {CI} 1.01, 2.29]; P = 0.04, I2 = 0%), with a fragility index of 1, and a 5-year number needed to harm of 1349. The association remained significant when including only trials lasting at least 104 weeks (MH-OR 1.76 [95% CI 1.00, 3.12]; P = 0.05). No significant association was found for papillary thyroid cancer (MH-OR 1.54 [95% CI 0.77, 3.06]; P = 0.22) or medullary thyroid cancer (MH-OR 1.44 [95% CI 0.23, 9.16]; P = 0.55). CONCLUSIONS: Our meta-analysis showed that GLP-1RA treatment could be associated with a moderate increase in relative risk for thyroid cancer in clinical trials, with a small increase in absolute risk. Studies of longer duration are required to assess the clinical implications of this finding.

Fibrosis-4 score for screening of metabolic dysfunction-associated steatotic liver disease (MASLD): Data from a population-based sample in Tuscany.

BACKGROUND AND AIM: To verify the prevalence of positive Fibrosis-4 (FIB-4) score, a screening test for metabolic-associated liver disease, in a large population-based sample in the Tuscany Italian Region, and to identify sub-populations at higher risk which could be targeted by specific screening programs. METHODS AND RESULTS: Population-based survey performed in the Italian region of Tuscany, with Tuscany health informative system's administrative data. We included 594,923 subjects, of which 32% had available data for the FIB-4 calculation. The overall proportion of subjects with an FIB-4 value > 1.3, was 41.6% of those with available exams, and 12,8% of the whole population, whereas 5.4% and 1.7% had FIB-4 >2.67. In those younger than 80 years, FIB >1.3 had a 33.1% and 9.4%. People with diabetes mellitus had higher figures (52.8.% and 28.9% for FIB>1.3). Among subjects aged 70 years or over, 74.9% of those with available data and 38.4% of the general population had a FIB-4>1.3, whereas 32% and 16% had a FIB-4 > 2. CONCLUSIONS: The relevant proportion of FIB-4 positivity in the general population poses a significant burden for further screening with liver elastography. Targeting people with diabetes, excluding people older than 80 years and/or adopting a FIB-4 threshold of 2 in those aged more than 70 years could increase the cost-effectiveness of the screening procedures.

Cardiovascular prevention with glucose-lowering drugs in type 2 diabetes: An evidence-based approach to the categories of primary and secondary prevention.

AIMS: Whether to recommend specifically the glucose-lowering therapies with cardiovascular benefit only in secondary prevention, or also in patients with multiple risk factors (MRF) but without established atherosclerotic cardiovascular disease (ASCVD), is controversial across the guidelines for diabetes. MATERIALS AND METHODS: We performed a meta-analysis of clinical trials with major adverse cardiovascular events (MACE) as an outcome. RESULTS: The definitions of ASCVD and MRF were heterogeneous across trials; nevertheless, the incidence of MACE was 2.8-fold higher in people with ASCVD in trials with sodium-glucose cotransporter 2 inhibitors (SGLT2is), and 3.9-fold in trials with glucagon-like peptide-1 receptor agonists (GLP-1 RA). Both SGLT2i and GLP-1 RA were associated with a significant reduction in the incidence of MACE in people with previous ASCVD [inverse variance-odds ratio 0.91, 95% confidence interval (0.86: 0.97) for SGLT2i, Mantel-Haenszel odds ratio 0.85, 95% confidence interval (0.81: 0.90) for GLP-1 RA], whereas no significant reduction was detected in those without; on the other hand, no significant difference in effect was found between the two groups as well. The sample of patients without ASCVD enrolled in clinical trials is insufficient to draw reliable conclusions in this population; however, even assuming the same benefit detected in people with ASCVD also in those with MRF, the number needed to treat would differ (35 for secondary, 99 for primary prevention of a MACE with a SGLT2i; 21 for secondary, 82 for primary prevention with a GLP-1 RA, respectively), given the difference in absolute cardiovascular risk at baseline. CONCLUSION: The distinction between patients with ASCVD and those without ASCVD and MRF appears therefore justified by available evidence.

Metabolic bariatric surgery as a therapeutic option for patients with type 2 diabetes: A meta-analysis and network meta-analysis of randomized controlled trials.

AIM: To compare different types of metabolic surgery with non-surgical therapy for the treatment of type 2 diabetes (T2D). METHODS: The present network meta-analysis (NMA) includes randomized clinical trials (duration ≥ 52 weeks) comparing different surgery techniques with non-surgical therapy in diabetes patients. The primary endpoints were endpoint HbA1c, body mass index (BMI) and diabetes remission. The secondary endpoints included fasting plasma glucose, lipid profile, blood pressure, arterial hypertension and dyslipidaemia remission, quality of life and surgical adverse events. Indirect comparisons of different types of surgery were performed by NMA. Mean and 95% confidence intervals for continuous variables, and the Mantel-Haenzel odds ratio for categorial variables, were calculated. RESULTS: The types of surgical procedure included laparoscopic adjustable gastric banding, Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), bilio-pancreatic diversion (BPD), greater curvature plication (GCP), one-anastomosis gastric bypass (OAGB) and Duodeno-Jejunal bypass. Thirty-six trials were included. Metabolic bariatric surgery (MBS) was associated with a significantly higher reduction of HbA1c, diabetes remission and BMI compared with medical therapy. In the NMA, a significant reduction of HbA1c was observed with OAGB and SG. Complete diabetes remission significantly increased with all surgical procedures in comparison with non-surgical therapy, except for GCP. In addition, only BPD, RYGB and OAGB were associated with a significant reduction of BMI. CONCLUSIONS: MBS is an effective option for the treatment of T2D in patients with obesity. Further long-term trials of appropriate quality are needed for assessing the risk-benefit ratio in some patient cohorts, such as those with a BMI of less than 35 kg/m2 and aged older than 65 years.

Effectiveness of intermittent fasting for weight loss in individuals with obesity: A meta-analysis of randomized controlled trials.

AIM: To assess whether intermittent fasting (IF) diets are associated with improvement in weight loss, metabolic parameters, and subjective well-being, in people with obesity. DATA SYNTHESIS: We performed a Meta-analysis of Randomized Controlled Trials longer than 2 months, retrieved through an extensive search on MedLine, Cochrane CENTRAL Library, and Embase online databases, comparing weight loss with IF diets and control diets in people with Body Mass index (BMI) > 30 kg/m2. We retrieved 9 trials, enrolling 540 patients. IF was not associated with a significantly greater reduction of body weight or BMI at any time point with respect to controls or in respect to continuous restricted diets, with low-to moderate quality of evidence; no significant difference in efficacy between alternate day fasting and time restricted eating was found. Differences in fasting plasma glucose, total or high-density lipoprotein cholesterol or blood pressure at any time point were not statistically significant, whereas a reduction of low-density lipoprotein cholesterol (MD -8.39 [-15.96, -0.81] mg/dl, P = 0.03; I2 = 0%) was observed at 2-4 months, but not in the longer term. Data on psychological parameters and overall well-being were insufficient to perform a formal meta-analysis, whereas a qualitative synthesis did not show any difference between IF and controls. CONCLUSIONS: IF is not associated with greater or lesser weight loss than non-intermittent fasting diets. Further data on psychological parameters and overall well-being are needed to properly assess the role of IF diets in the management of obesity.

Influenza: Diabetes as a risk factor for severe related-outcomes and the effectiveness of vaccination in diabetic population. A meta-analysis of observational studies.

AIMS: In order to better define the need for influenza vaccination in people with diabetes (DM), we collected all available evidence on the effect of DM as a risk factor for complications of both seasonal and pandemic influenza, and on the specific effectiveness of vaccines in patients with DM. DATA SYNTHESIS: Two distinct systematic searches on MEDLINE, Cochrane, ClinicalTrials.gov and Embase databases were performed, one for each metanalysis, collecting all observational studies and randomized clinical trials performed on humans up to May 31st, 2022. We retrieved 34 observational studies comparing risk for influenza complications in people with or without diabetes, and 13 observational studies assessing vaccine effectiveness on preventing such complications. Mortality for influenza and hospitalization for influenza and pneumonia resulted significantly higher in individuals with versus without DM, both when unadjusted and adjusted data are analyzed. In diabetic individuals vaccinated for influenza overall hospitalization, hospitalization for influenza or pneumonia and overall mortality are significantly lower in comparison with not vaccinated DM subjects, both when unadjusted and adjusted data were analyzed. CONCLUSION: This systematic review and meta-analysis shows that: 1) influenza is associated with more severe complications in diabetic versus not diabetic individuals and 2) influenza vaccination is effective in preventing clinically relevant outcomes in adults with DM with a NNT (number needed to treat) of 60, 319, and 250 for all-cause hospitalization, specific hospitalization, and all-cause mortality, respectively. The identification of diabetic patients as the target of vaccination campaigns for influenza appears to be justified by available clinical evidence.

Effectiveness of low-carbohydrate diets for long-term weight loss in obese individuals: A meta-analysis of randomized controlled trials.

AIM: To assess whether low-carbohydrate (LC) diets are associated with differences in weight loss and well-being in people with obesity, and their cardiovascular and renal safety. MATERIALS AND METHODS: A meta-analysis of randomized controlled trials longer than 3 months, retrieved through an extensive search on MedLine and Embase databases, comparing weight loss with LC and control diets in people with body mass index (BMI) greater than 30 kg/m2 , was conducted. RESULTS: We retrieved 25 trials. Compared with controls, LC diets were associated with significant reduction of body weight at 3-4 (MD -2.59 [-3.93, -1.25] kg) and 6-8 months (MD -2.64 [-4.32, -0.95]), but no difference at 10-14 and 18-30 months, and significantly greater BMI reduction at 3-4 months (-1.66 [-2.70, -0.61] kg/m2 ), but not at other time points. Because only four trials reported data on renal function and psychological variables, renal safety and impact on well-being could not be assessed. Differences in fasting plasma glucose at any time point were not statistically significant. No significant differences in total or LDL cholesterol or blood pressure were found in the long term, whereas a long-term reduction of triglycerides (23.26 [-45.53, -0.98] mg/dl at 18-30 months), and increase of HDL cholesterol (MD 4.94 [0.30, 9.57] mg/dl at 18-30 months), were observed. CONCLUSION: LC diets are associated with greater short-term weight loss than non-carbohydrate-restricted diets and a longer term favourable effect on cardiovascular risk factors. Further evidence on long-term efficacy and renal safety is needed before LC diets can be recommended as the preferred diets in obese people.

Assessment of left ventricular global longitudinal strain in patients with type 2 diabetes: Relationship with microvascular damage and glycemic control.

BACKGROUND AND AIMS: Type 2 Diabetes mellitus (T2DM) is associated with a higher risk of Heart Failure; Left Ventricular (LV) diastolic dysfunction is often considered the first marker of Diabetic cardiomyopathy; however, early preclinical LV systolic dysfunction has also been observed by means of echocardiographic measurement of strain. This study is aimed at assessing determinants of impaired strain and diastolic ventricular dysfunction in patients with T2DM. METHODS AND RESULTS: Cross-sectional study, performed on a consecutive series of patients with T2DM aged 30-80 years, BMI<40 kg/m2, free of cardiovascular disease, assessing metabolic control, microvascular complications, echocardiographic measures. Out of 206 patients, 19.6% had GLS lower than 18. GLS showed a significant inverse correlation with HBA1c, (p = 0.016), BMI (p = 0.002), waist (p < 0.0001), and mean L:H Ratio (p = 0.019). In a multivariate regression for LV GLS including HbA1c, age, sex, BMI and mean RR SDNN index, only HbA1c retained statistical significance: (B = -0.050 [-0.091; -0.009], p = 0.01. Among markers of LV diastolic function, only the E/E' ratio was associated with HbA1c at a univariate analysis, and it retained statistical significance in a multivariate regression including HbA1c, age, sex and disease duration (B = 0.038 [0.03; -0.073], p = 0.032). No significant difference in any parameter of systolic or diastolic function was observed between patients with or without microalbuminuria or diabetic retinopathy. CONCLUSION: In patients with T2DM, a reduced left ventricular global longitudinal strain appears to be independently associated with impaired glucose control and autonomic neuropathy, regardless of microvascular complications.

Sodium-glucose co-transporter-2 inhibitors and all-cause mortality: A meta-analysis of randomized controlled trials.

The present meta-analysis is aimed at assessing the effects of sodium-glucose co-transporter-2 (SGLT2) inhibitors on all-cause mortality and differences across different trials and molecules of the class. We included all randomized clinical trials with a duration of treatment longer than 52 weeks, enrolling at least 100 patients in each arm, and comparing an SGLT2 inhibitor with any comparator or placebo. Out of 139, 235 and 145 items identified, 21 trials were selected, enrolling 39 593 and 30 771 patients in SGLT2 inhibitor and comparator arms, respectively, with a median duration of 104 weeks, and reporting 2474 and 2298 deaths for SGLT2 inhibitors and comparators, respectively. No relevant heterogeneity was found (I2 = 17%). Treatment with SGLT2 inhibitors was associated with a significant reduction in all-cause mortality (MH-OR [95% CI] 0.86 [0.81, 0.91] P < .00001). Meta-regression analyses found a significant direct association of treatment effect only with the proportion of Asian subjects enrolled, and an inverse correlation with the proportion of Caucasian patients. In conclusion, SGLT2 inhibitors reduce all-cause mortality in randomized controlled trials.