The multidirectional assessment of moderate caloric restriction and metformin treatment in obese patients.

Obesity treatment is often burdensome for patients. We used the combination of moderate caloric restriction (CR) with hypoglycemic metformin to assess their multidirectional effect in obese patients. One group was treated only with moderate CR (n=21) the second was treated with moderate CR and 800 mg metformin twice daily (n=23). Serum was drawn before and after treatment. The following parameters were monitored: anthropometric, cardiovascular, inflammatory, metabolic, and markers characteristic for thyroid, liver, pancreas, and kidney functions. Both tested groups did not significantly differ in most tested parameters after the treatment. Two groups reduced anthropometric parameters (body mass, body mass index (BMI), waist circumference) and fat mass but also muscle and fat-free mass, improving systolic blood pressure, insulin and leptin concentration, insulin sensitivity, leptin to adiponectin ratio, and inflammatory markers. Unfortunately, there was little impact on improving dyslipidemia and the thyroid and liver parameters. Free triiodothyronine (fT3) and gamma glutamyl transferase (GGT) activity were decreased in both groups, but triglycerides were reduced only in patients treated with moderate CR. Metformin with CR treatment decreases uric acid and aspartate aminotransferase (AspAT) activity. Metformin treatment with moderate CR in obese patients mainly improved insulin sensitivity, resulting in a reduction of patients with glucose intolerance, improved anthropometric, cardiovascular, and inflammatory mediators, and only slightly enhanced liver and thyroid function. No changes in kidney and pancreas function were observed during the treatment. In conclusion, eight weeks of CR alone and CR with metformin in obese adults improved anthropometric and metabolic markers, reduced muscle mass, fT3, GGT, proinflammatory, and CV parameters, and displayed no changes in kidney and pancreas function. The group treated with metformin after the treatment was still more obese and had higher C-reactive protein (CRP) and homeostasis model assessment-an index of insulin resistance (HOMA-IR), but despite this, considerably reduced the number of patients with glucose intolerance.

Safety vs price in the generic drug market: metformin.

OBJECTIVES: Generic medications represent 90% of prescriptions in the US market and provide a tremendous financial benefit for patients. Recently, multiple generic drugs have been recalled due to the presence of carcinogens, predominantly N-nitrosodimethylamine (NDMA), including an extensive recall of extended-release (ER) metformin products in 2020. STUDY DESIGN: Primary pharmaceutical quality testing and database analysis. METHODS: We tested marketed metformin immediate-release (IR) and ER tablets from a wide sample of generic manufacturers for the presence of carcinogenic impurities NDMA and N,N-dimethylformamide (DMF). We examined the association of level of impurity with drug price and the impact of the 2020 FDA recalls on unit price and prescription fill rate. RESULTS: Postrecall NDMA levels were significantly lower in metformin ER samples (standardized mean difference = -2.0; P = .01); however, we found continued presence of carcinogens above the FDA threshold in 2 of 30 IR samples (6.67%). Overall, the presence of contaminant levels was not significantly associated with price for either IR (NDMA: R2 = 0.142; P = .981; DMF: R2 = 0.382; P = .436) or ER (NDMA: R2 = 0.124; P = .142; DMF: R2 = 0.199; P = .073) samples. Despite recalls, metformin ER prescription fills increased by 8.9% while unit price decreased by 19.61% (P < .05). CONCLUSIONS: Recalls of metformin ER medications were effective in lowering NDMA levels below the FDA threshold; however, some samples of generic metformin still contained carcinogens even after FDA-announced recalls. The absence of any correlation with price indicates that potentially safer products are available on the market for the same price as poorer-quality products.

Cost saving analysis of prediabetes intervention modalities in comparison with inaction using Markov state transition model-A multiregional case study.

BACKGROUND: Prediabetes management is a priority for policymakers globally, to avoid/delay type 2 diabetes (T2D) and reduce severe, costly health consequences. Countries moving from low to middle income are most at risk from the T2D "epidemic" and may find implementing preventative measures challenging; yet prevention has largely been evaluated in developed countries. METHODS: Markov cohort simulations explored costs and benefits of various prediabetes management approaches, expressed as "savings" to the public health care system, for three countries with high prediabetes prevalence and contrasting economic status (Poland, Saudi Arabia, Vietnam). Two scenarios were compared up to 15 y: "inaction" (no prediabetes intervention) and "intervention" with metformin extended release (ER), intensive lifestyle change (ILC), ILC with metformin (ER), or ILC with metformin (ER) "titration." RESULTS: T2D was the highest-cost health state at all time horizons due to resource use, and inaction produced the highest T2D costs, ranging from 9% to 34% of total health care resource costs. All interventions reduced T2D versus inaction, the most effective being ILC + metformin (ER) "titration" (39% reduction at 5 y). Metformin (ER) was the only strategy that produced net saving across the time horizon; however, relative total health care system costs of other interventions vs inaction declined over time up to 15 y. Viet Nam was most sensitive to cost and parameter changes via a one-way sensitivity analysis. CONCLUSIONS: Metformin (ER) and lifestyle interventions for prediabetes offer promise for reducing T2D incidence. Metformin (ER) could reduce T2D patient numbers and health care costs, given concerns regarding adherence in the context of funding/reimbursement challenges for lifestyle interventions.

Adherence to GLP1-RA and SGLT2-I affects clinical outcomes and costs in patients with type 2 diabetes.

AIMS: To evaluate the impact of adherence to glucagon like peptide-1 receptor agonists (GLP1-RA) and sodium-glucose transporter two inhibitors (SGLT2-I) on clinical outcomes and costs in patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: The 121,115 residents of the Lombardy Region (Italy) aged ≥40 years newly treated with metformin during 2007-2015 were followed to identify those who started therapy with GLP1-RA or SGLT2-I. Adherence to drug therapy over the first year was defined as the proportion of days covered >80%. Within each drug class, for each adherent patient, one non-adherent patient was matched for age, sex, duration, adherence to metformin treatment and propensity score. The primary clinical outcome was a composite of insulin initiation, hospitalisation for micro- and macrovascular complications and all-cause mortality after the first year of drug treatment. Costs were evaluated based on reimbursements from the national healthcare system. RESULTS: After matching, 1182 pairs of adherent and non-adherent GLP1-RA users and 1126 pairs of adherent and non-adherent SGLT2-I users were included. In both groups, adherent patients experienced a significantly lower incidence of the primary outcome (HR: 0.85, 95% CI 0.72-0.98 for GLP1-RA and HR: 0.69, 95% CI 0.55-0.87 for SGLT2-I). A significant reduction in hospitalizations was found for adherent patients in the GLP1-RA group but not for the SGLT2-I group. Results were consistent when analyses were stratified by age and sex. While higher drug-related costs in the adherent group were counterbalanced by decreased hospitalisation costs in SGLT2-I treated patients, this was not the case for GLP1-RA. CONCLUSIONS: Higher adherence to drug treatment with GLP1-RA and SGLT2-I during the first year of the drug intake is associated with a lower incidence of adverse clinical outcomes in a real-world setting.

The Association Between Metformin Use and New-Onset ICD Coding of Geographic Atrophy.

Purpose: Metformin has been suggested to protect against the development of age-related macular degeneration (AMD) in multiple observational studies. However, the association between metformin and geographic atrophy (GA), a debilitating subtype of AMD, has not been analyzed. Methods: We conducted a case-control study of patients ages 60 years and older with new-onset International Classification of Diseases (ICD) coding of GA in the Merative MarketScan Commercial and Medicare Databases between 2017 and 2021. Cases were matched with propensity scores estimated by age, region, hypertension, and Charlson Comorbidity Index to a control without GA of the same year. Exposure to metformin was assessed for cases and controls in the year prior to their index visit. Conditional multivariable logistic regression, adjusting for AMD risk factors, was used to calculate odd ratios and 95% confidence intervals (CIs). This study design and analysis were repeated in a sample of patients without diabetes. Results: In the full sample, we identified 10,505 cases with GA and 10,502 matched controls without GA. In total, 1149 (10.9%) cases and 1277 (12.2%) controls were exposed to metformin, and in multivariable regression, metformin decreased the odds of new-onset ICD coding of GA by 12% (95% CI, 0.79-0.99). In the sample of patients without diabetes, we identified 7611 cases with GA and 7608 matched controls without GA. Twenty-nine (0.4%) cases and 63 (0.8%) controls were exposed to metformin, and in multivariable regression, metformin decreased the odds of new-onset ICD coding of GA by 47% (95% CI, 0.33-0.83). Conclusions: Metformin may hold promise as a noninvasive, alternative agent to prevent the development of GA. This finding is notable due to shortcomings in recently approved therapeutics for GA and metformin's overall ease of use and few adverse effects. Additional studies are required to explore our findings further and motivate a clinical trial.

Factors associated with longer survival among older medicare patients after diagnosis of supratentorial primary brain malignancies: a retrospective cohort study.

OBJECTIVES: Despite recent advances, the prognosis for primary malignant brain tumors (PMBTs) remains poor. Some commonly prescribed medications may exhibit anti-tumor properties in various cancers, and neurodegenerative diseases may activate pathways that counteract gliomagenesis. Our study is focused on determining if there is a correlation between the use of metformin, beta-blockers, angiotensin converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs), or the presence of Parkinson's disease (PD), and the survival rates following a diagnosis of a PMBT. METHODS: This analysis of the 100% Texas Medicare Database identified patients aged 66+ years diagnosed with a supratentorial PMBT from 2014-2017. Cox proportional hazards regression was employed to analyze survival following diagnosis and associations of survival with surgical intervention, radiation, PD diagnosis, and prescription of metformin, beta-blockers, ACEIs, or ARBs. RESULTS: There were 1,943 patients who met study criteria, and the median age was 74 years. When medication utilization was stratified by none, pre-diagnosis only, post-diagnosis only, or both pre- and post-diagnosis (continuous), continuous utilization of metformin, beta-blockers, ACEIs, or ARBs was associated with prolonged survival compared to no utilization (hazard ratio [HR]:0.45, 95% CI:0.33-0.62; HR:0.71. 95% CI:0.59-0.86; HR:0.59, 95% CI:0.48-0.72; and HR:0.45, 95% CI:0.35-0.58 respectively). PD was also associated with longer survival (HR:0.59-0.63 across the four models). DISCUSSION: Our study suggests that metformin, beta-blockers, ACEIs, ARBs, and comorbid PD are associated with a survival benefit among geriatric Medicare patients with supratentorial PMBTs.

Use of sodium-glucose cotransporter-2 inhibitors in France: Analysis of French nationwide health insurance database.

AIM: Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) have been commercialized in France for type 2 diabetes since April 2020 and later for heart and renal diseases. Given the recent developments in treating diabetes and the widening of SGLT-2i indications, we aimed to study changes in the use of glucose-lowering drugs in France and to characterize SGLT-2i new users. METHODS: We performed a nationwide utilization study using the French health insurance database. Trends in incidence and prevalence of glucose-lowering drug use were assessed by a repeated cross-sectional study in 2019 and 2021. A cohort study of incident SGLT-2i users was then conducted to describe patient characteristics and the strategy for treating diabetes. RESULTS: The prevalence of SGLT-2i use gradually reached 0.1% in the third quarter of 2021 and increased more significantly to 0.2% thereafter. SGLT-2i became the second most prescribed glucose-lowering drug class after metformin at the end of 2021 (0.1%). Among the cohort of 125 387 SGLT-2i new users (mean age 65.0 years; 60.1% of men), 87.6% presented a diabetic comorbidity. The patient profile changed over the study period with an increasing proportion of patients with cardiovascular (28.7% in 2020 vs. 40.2% in 2021) or renal (7.7% in 2020 vs. 11.8% in 2021) comorbidities at initiation. The main combinations used at SGLT-2i initiation were metformin (12.5%) and metformin plus dipeptidyl peptidase-4 inhibitors (8.1%). One-year probability of SGLT-2i persistence was estimated to be 55%. CONCLUSION: The expansion of indications for SGLT-2i and the broadening of the target population make it essential to assess the reasons for discontinuation and review their safety profile.

The cost-effectiveness of metformin in the US diabetes prevention program trial: Simple interpretations need not apply.

Based on previously published US Diabetes Prevention Program (DPP) cost-effectiveness analyses (CEAs) metformin continues to be promoted as "cost-effective." We review the DPP within-trial CEA to assess this claim. Treatment alternatives included placebo (plus standard lifestyle advice), branded metformin and individual lifestyle modification. We added generic metformin as an alternative. Original published CEA data were taken as given and re-analyzed according to accepted principles for calculating incremental cost-effectiveness ratios (ICERs) in the economic evaluation field. With more than two treatments as in the DPP, these require attention to the rankings of interventions according to cost or effect prior to stipulating appropriate ICERs to calculate. With proper ICERs neither branded nor generic metformin was cost-effective, regardless of the value assumed for the willingness to pay for the quality-adjusted life year outcome assessed. Metformin alternatives were technically inefficient compared to placebo or the lifestyle modification alternative. Net loss calculations indicated substantial costs/health losses to using metformin instead of the optimal lifestyle alternative in response to metformin having been inaccurately labelled "cost-effective" in the original CEA. That CEA and subsequent analyses and citations of such analyses continue to claim that both metformin and lifestyle modification are cost-effective in diabetes prevention based on DPP data. Using metformin implies substantial costs and health losses compared to the cost-effective lifestyle modification. It may be that metformin has a role in cost-effective diabetes prevention, but this has yet to be shown based on DPP data.

INTERACTIONS OF METFORMIN AND OTHER MEDICATIONS IN REDUCING THE ODDS OF AGE-RELATED MACULAR DEGENERATION IN A COHORT OF PATIENTS WITH DIABETES.

PURPOSE: A previous study from our group demonstrated protective effects of the use of metformin in the odds of developing age-related macular degeneration (AMD). This is a subgroup analysis in a cohort of patients with diabetes to assess the interaction of metformin and other medications in protecting diabetic patients against developing AMD. METHODS: This is a case-control analysis using data from the Merative MarketScan Commercial and Medicare databases. Patients were 55 years and older with newly diagnosed AMD and matched to controls. We performed multivariable conditional logistic regressions, which adjusted for known risk factors of AMD and tested multiple interaction effects between metformin and 1) insulin, 2) sulfonylureas, 3) glitazones, 4) meglitinides, and 5) statins. RESULTS: The authors identified 81,262 diabetic cases and 79,497 diabetic controls. Metformin, insulin, and sulfonylureas demonstrated independent protective effects against AMD development. Sulfonylureas in combination with metformin demonstrated further decreased odds of AMD development compared with metformin alone. The other medication group (exenatide, sitagliptin, and pramlintide) slightly increased the odds of developing AMD when taken alone, but the combination with metformin alleviated this effect. CONCLUSION: The authors believe that their results bring them one step closer to finding an optimal effective hypoglycemic regimen that also protects against AMD development in diabetic patients.

Medical Therapy Before, During and After Hospitalization in Medicare Beneficiaries With Heart Failure and Diabetes: Get With The Guidelines - Heart Failure Registry.

BACKGROUND: Patients hospitalized with heart failure (HF) and diabetes mellitus (DM) are at risk for worsening clinical status. Little is known about the frequency of therapeutic changes during hospitalization. We characterized the use of medical therapies before, during and after hospitalization in patients with HF and DM. METHODS: We identified Medicare beneficiaries in Get With The Guidelines-Heart Failure (GWTG-HF) hospitalized between July 2014 and September 2019 with Part D prescription coverage. We evaluated trends in the use of 7 classes of antihyperglycemic therapies (metformin, sulfonylureas, GLP-1RA, SGLT2-inhibitors, DPP-4 inhibitors, thiazolidinediones, and insulins) and 4 classes of HF therapies (evidence-based ß-blockers, ACEi or ARB, MRA, and ARNI). Medication fills were assessed at 6 and 3 months before hospitalization, at hospital discharge and at 3 months post-discharge. RESULTS: Among 35,165 Medicare beneficiaries, the median age was 77 years, 54% were women, and 76% were white; 11,660 (33%) had HFrEF (LVEF ≤ 40%), 3700 (11%) had HFmrEF (LVEF 41%-49%), and 19,805 (56%) had HFpEF (LVEF ≥ 50%). Overall, insulin was the most commonly prescribed antihyperglycemic after HF hospitalization (n = 12,919, 37%), followed by metformin (n = 7460, 21%) and sulfonylureas (n = 7030, 20%). GLP-1RA (n = 700, 2.0%) and SGLT2i (n = 287, 1.0%) use was low and did not improve over time. In patients with HFrEF, evidence-based beta-blocker, RASi, MRA, and ARNI fills during the 6 months preceding HF hospitalization were 63%, 62%, 19%, and 4%, respectively. Fills initially declined prior to hospitalization, but then rose from 3 months before hospitalization to discharge (beta-blocker: 56%-82%; RASi: 51%-57%, MRA: 15%-28%, ARNI: 3%-6%, triple therapy: 8%-20%; P < 0.01 for all). Prescription rates 3 months after hospitalization were similar to those at hospital discharge. CONCLUSIONS: In-hospital optimization of medical therapy in patients with HF and DM is common in participating hospitals of a large US quality improvement registry.

Metformin Use and Age-Related Macular Degeneration in Patients Without Diabetes.

Importance: Metformin use may protect against the development of age-related macular degeneration (AMD) based on results from observational studies. However, its potential effectiveness among patients without diabetes remains unclear. Objective: To assess the association between metformin use and the development of AMD in patients without diabetes. Design, Setting, and Participants: This case-control study used data from 2006 to 2017 in the Merative MarketScan Research Database, a nationwide insurance claims database that includes between 27 and 57 million patients in the US with primary or Medicare supplemental health insurance. Cases with AMD and controls without AMD aged 55 years or older were matched 1:1 by year, age, anemia, hypertension, region, and Charlson Comorbidity Index score. Then, cases and matched controls without a diagnosis of diabetes were selected. In subgroup analyses, cases with dry AMD and their matched controls were identified to explore the association between metformin use and AMD staging in patients without diabetes. Data were analyzed between March and September 2023. Exposures: Exposure to metformin in the 2 years prior to the index date (ie, date of AMD diagnosis in cases and date of a randomly selected eye examination for controls) was assessed from the claims database and categorized into quartiles based on cumulative dose (1-270, 271-600, 601-1080, and >1080 g/2 y). Exposure to other antidiabetic medications was also noted. Main Outcomes and Measures: Odds of new-onset AMD development as assessed by multivariable conditional logistic regression after adjusting for known risk factors for AMD, including female sex, hyperlipidemia, smoking, and exposures to other antidiabetic medications. Asymptotic Cochran-Armitage tests for trend were also performed. Results: We identified 231 142 patients with any AMD (mean [SD] age, 75.1 [10.4] years; 140 172 females [60.6%]) and 232 879 matched controls without AMD (mean [SD] age, 74.9 [10.5] years; 133 670 females [57.4%]), none of whom had a diagnosis of diabetes. The sample included 144 147 cases with dry AMD that were matched to 144 530 controls. In all, 2268 (1.0%) cases and 3087 controls (1.3%) were exposed to metformin in the 2 years before their index visit. After data adjustment, exposure to any metformin was associated with reduced odds of any AMD development (adjusted odds ratio [AOR], 0.83; 95% CI, 0.74-0.87), specifically in the dosing quartiles of 1 to 270, 271 to 600, and 601 to 1080 g/2 y. Any metformin use was also associated with a reduced odds of developing dry AMD (AOR, 0.85; 95% CI, 0.79-0.92), specifically in the dosing quartiles of 1 to 270 and 271 to 600 g/2 y. Adjusted odds ratios for any AMD and dry AMD development did not differ across the dosing quartiles. Asymptotic Cochran-Armitage tests for trend revealed 2-sided P = .51 and P = .66 for the any and dry AMD samples, respectively. Conclusions and Relevance: In this case-control study of a population without a diagnosis of diabetes, metformin use was associated with reduced odds of developing AMD. This association does not appear to be dose dependent. These findings provide further impetus to study metformin's usefulness in protecting against AMD in prospective clinical trials.

Assessment of vitamin B12 levels and cardiovascular risk factors in metformin- and non-metformin-treated type 2 diabetic patients.

Oxidative stress enhances cardiovascular risk. Metformin decreases intestinal absorption of vitamin B12. Our objective was the evaluation of type 2 diabetics focusing on differences due to their treatment. A prospective study on 224 type 2 diabetics was realized between 2015-2018 in Targu Mures, Romania, divided into 2 subgroups (metformin vs. other therapy - 2nd/3rd generation sulfonylureas, insulin, dietary regimen -, followed for at least one year) and non-diabetic controls (n=25) for oxidative stress level comparison. Serum homocysteine (HC), vitamin B12 were determined by chemiluminescence (Immulite One). Lipid peroxidation was assessed by serum malondialdehyde (MDA) measurement (HPLC). Biochemical tests, minerals, cystatin C, high-sensitivity C reactive protein (hs-CRP) were measured on Konelab20Xti, glycated hemoglobin on Nycocard Reader. GraphPad InStat-3 was used for statistics. Negative correlation occured between serum vitamin B12 and HC, this vitamin's level was significantly lower and serum zinc was significantly higher in patients on metformin. Hyperhomocysteinemia was present in 87% of the subjects, 46% had zinc deficiency and 41% elevated hs-CRP. Serum cystatin C showed positive correlation with creatinine. Serum MDA was significantly higher in diabetics compared to control patients. Elevated hs-CRP and homocysteine represent raised cardiovascular risk. Intense oxidative stress, vitamin, mineral deficiencies are frequent in diabetic subjects.

Early use of oral semaglutide in the UK: A cost-effectiveness analysis versus continuing metformin and SGLT-2 inhibitor therapy.

OBJECTIVES: Many people with type 2 diabetes experience clinical inertia, remaining in poor glycaemic control on oral glucose-lowering medications rather than intensifying treatment with a glucagon-like peptide-1 receptor agonist, despite an efficacious, orally administered option, oral semaglutide, being available. The present study evaluated the long-term cost-effectiveness of initiating oral semaglutide versus continuing metformin plus sodium-glucose cotransporter-2 (SGLT-2) inhibitor therapy in the UK. DESIGN: Outcomes were projected over patients' lifetimes using the IQVIA Core Diabetes Model (V.9.0). Clinical data were taken from the oral semaglutide and placebo arms of the patient subgroup receiving metformin plus an SGLT-2 inhibitor in PIONEER 4. Costs, expressed in 2021 Pounds sterling (GBP), were accounted from a healthcare payer perspective. INTERVENTIONS: Modelled patients received oral semaglutide immediately (in the first year of the analysis) or after a 2-year delay, after which all physiological parameters were brought to values observed in the immediate therapy arm. During the simulation, patients intensified with the addition of basal insulin and, subsequently, by switching to basal-bolus insulin. RESULTS: Immediate oral semaglutide therapy was associated with improvements in life expectancy of 0.17 (95% CIs 0.16 to 0.19) years, and quality-adjusted life expectancy of 0.15 (0.14 to 0.16) quality-adjusted life years (QALYs), versus a 2-year delay. Benefits were due to a reduced incidence of diabetes-related complications. Direct costs were estimated to be GBP 1423 (1349 to 1496) higher with immediate oral semaglutide therapy versus a 2-year delay, with higher treatment costs partially offset by cost savings from avoidance of diabetes-related complications. Immediate oral semaglutide therapy was therefore associated with an incremental cost-effectiveness ratio of GBP 9404 (8380 to 10 538) per QALY gained versus a 2-year delay. CONCLUSIONS: Immediate oral semaglutide is likely to represent a cost-effective treatment in people with type 2 diabetes with inadequate glycaemic control on metformin plus an SGLT-2 inhibitor in the UK. TRIAL REGISTRATION NUMBER: NCT02863419.

Cost-Effectiveness of Newer Antidiabetic Drugs as Second-Line Treatment for Type 2 Diabetes: A Systematic Review.

INTRODUCTION: Evidence from cardiovascular outcome trials (CVOTs) for newer antidiabetic drugs is increasingly influencing revised recommendations for second-line therapy in type 2 diabetes (T2D). This systematic review aimed to compare the cost-effectiveness of newer antidiabetic drugs specified as sodium-glucose cotransporter 2 inhibitor (SGLT2i), glucagon-like peptide 1 receptor agonist (GLP-1RA), and dipeptidyl peptidase 4 inhibitor (DPP-4i) for T2D in a second-line setting. METHODS: A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews (PRISMA) guidelines, and all relevant published studies were searched comprehensively in electronic databases, including PubMed, Embase, Web of Science, and International Health Technology Assessment database published from April 2023. The quality of the included studies was evaluated using Consolidated Health Economic Evaluation Reporting Standards (CHEERS) 2022 reporting checklists. RESULTS: We included 28 studies that met the inclusion criteria. Overall reporting of the identified studies largely met CHEERS 2022 recommendations. The CORE and Cardiff models were the most frequently utilized for pharmacoeconomic evaluation in T2D. Four studies consistently discovered that SGLT2i was more cost-effective than GLP-1RA in T2D who were not adequately controlled by metformin monotherapy. Four studies compared GLP-1RA with DPP-4i, sufonylurea (SU), or insulin. Except for one that demonstrated SU was cost-effective, all were GLP-1RA. Five studies revealed that SGLT2i was more cost-effective than DPP-4i or SU. Eleven studies indicated that DPP-4i was more cost-effective than traditional antidiabetic drugs. Four additional studies explored the cost-effectiveness of various antidiabetic drugs as second-line options, indicating that SU, SGLT2i, or meglitinides were more economically advantageous. The most common driven factors were the cost of new antidiabetic drugs. CONCLUSION: Newer antidiabetic drugs as second line are the cost-effective option for T2D from the cost-effectiveness perspective, especially SGLT2i.

Assessment of cognitive impairment and depressive signs in patients with type 2 diabetes treated with metformin from Southeast Mexico: A cross-sectional study.

Multiple factors associate diabetes with cognitive impairment and depression. Antidiabetic drugs have reported antidepressant and pro-cognitive effects in diabetic and non-diabetic subjects. Antidepressant and pro-cognitive effects of metformin are reported in various studies; however, these effects are not consistent among researches. We designed a cross-sectional study. We recruited patients with T2D diagnosis from the Diabetes Clinic of the Regional Hospital of High Specialty "Dr. Gustavo A. Rovirosa Pérez" from January 2019 to May 2022. We included 431 subjects with T2D, 374 patients with metformin treatment and 57 subjects without metformin. These patients were on intensive therapies and had not a previous diagnosis of cognitive impairment or depression. We applied Mini-Mental State Examination (MMSE) to evaluate cognitive impairment, and Hamilton Depression Rating Scale (HAM-D) to assess depressive signs. Our sample had a mean age of 53.77 ± 13.43 years. Metformin users were 374 individuals, and 57 subjects didn't use metformin. MMSE found cognitive impairment in 8.3% (n = 31) of metformin users, and 14.8% (n = 8) of patients without metformin. HAM-D scale showed that 39.5% (n = 147) of patients with metformin had depression signs, subjects without metformin and depressive signs were 44.6% (n = 25). We found no differences between groups for cognitive impairment and depression grades. We did not find associations between metformin treatment, cognitive impairment measures and depression sign measures. However, chronic metformin treatment, insulin use, glycemic control and age could influence our results.

Metformin ameliorates calcium oxalate crystallization and stone formation by activating the Nrf2/HO-1 signaling pathway: Two birds with one stone.

Deposition of calcium oxalate (CaOx) crystals and oxidative stress-induced injury of renal tubular epithelial cell are the primary pathogenic factors of nephrolithiasis. In this study we investigated the beneficial effects of metformin hydrochloride (MH) against nephrolithiasis and explored the underlying molecular mechanism. Our results demonstrated that MH inhibited the formation of CaOx crystals and promoted the transformation of thermodynamically stable CaOx monohydrate (COM) to more unstable CaOx dihydrate (COD). MH treatment effectively ameliorated oxalate-induced oxidative injury and mitochondrial damage in renal tubular cells and reduced CaOx crystal deposition in rat kidneys. MH also attenuated oxidative stress by lowering MDA level and enhancing SOD activity in HK-2 and NRK-52E cells and in a rat model of nephrolithiasis. In both HK-2 and NRK-52E cells, COM exposure significantlylowered the expressions of HO-1 and Nrf2, which was rescued by MH treatment even in the presence of Nrf2 and HO-1 inhibitors. In rats with nephrolithiasis, MH treatment significantly rescued the down-regulation of the mRNA and protein expression of Nrf2 and HO-1 in the kidneys. These results demonstrate that MH can alleviate CaOx crystal deposition and kidney tissue injury in rats with nephrolithiasis by suppressing oxidative stress and activating the Nrf2/HO-1 signaling pathway, suggesting the potential value of MH in the treatment of nephrolithiasis.

Characterization of hepatic fatty acids using magnetic resonance spectroscopy for the assessment of treatment response to metformin in an eNOS-/- mouse model of metabolic nonalcoholic fatty liver disease/nonalcoholic steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease worldwide. Liver biopsy remains the gold standard for diagnosis and staging of disease. There is a clinical need for noninvasive diagnostic tools for risk stratification, follow-up, and monitoring treatment response that are currently lacking, as well as preclinical models that recapitulate the etiology of the human condition. We have characterized the progression of NAFLD in eNOS-/- mice fed a high fat diet (HFD) using noninvasive Dixon-based magnetic resonance imaging and single voxel STEAM spectroscopy-based protocols to measure liver fat fraction at 3 T. After 8 weeks of diet intervention, eNOS-/- mice exhibited significant accumulation of intra-abdominal and liver fat compared with control mice. Liver fat fraction measured by 1 H-MRS in vivo showed a good correlation with the NAFLD activity score measured by histology. Treatment of HFD-fed NOS3-/- mice with metformin showed significantly reduced liver fat fraction and altered hepatic lipidomic profile compared with untreated mice. Our results show the potential of in vivo liver MRI and 1 H-MRS to noninvasively diagnose and stage the progression of NAFLD and to monitor treatment response in an eNOS-/- murine model that represents the classic NAFLD phenotype associated with metabolic syndrome.

The homeostasis model assessment of insulin resistance is a judgment criterion for metformin pre-treatment before IVF/ICSI and embryo transfer cycles in patients with polycystic ovarian syndrome.

Purpose: The aim of this study was to explore the value of the homeostasis model assessment of IR (HOMA-IR) as a judgment criterion for metformin pre-treatment before in vitro fertilization/intracellular sperm injection (IVF/ICSI) and embryo transfer (ET) for polycystic ovarian syndrome (PCOS) patients. Materials and methods: The clinical and laboratory information of PCOS patients who received IVF/ICSI-ET from January 2017 to September 2021 was retrospectively analyzed. We compared the clinical pregnancy rate (primary outcome) and controlled ovarian stimulation (COS)-related parameters (secondary outcomes) between patients with and without metformin pre-treatment for all PCOS patients not grouped by HOMA-IR, PCOS patients with HOMA-IR < 2.71, and PCOS patients with HOMA-IR ≥ 2.71. Results: A total of 969 PCOS patients who received the GnRH-antagonist protocol were included in this study. For all PCOS patients, the metformin group showed comparable clinical pregnancy rates in fresh ET cycles and frozen ET cycles compared with the control group (55.9% vs. 57.1%, p = 0.821 and 63.8% vs. 60.9%, p = 0.497). For PCOS patients with HOMA-IR < 2.71, the clinical pregnancy rates in both fresh ET cycles and frozen ET cycles were statistically similar between the two groups (61.5% vs. 57.6%, p = 0.658 and 70.6% vs. 66.7%, p = 0.535). For PCOS patients with HOMA-IR ≥ 2.71, the clinical pregnancy rate in fresh ET cycles was comparable between the two groups (51.5% vs. 56.3, p = 0.590), but it was statistically higher in the metformin group than in the control group in frozen ET cycles (57.1% vs. 40.0%, p = 0.023). The metformin group had less oocytes retrieved, a lower cleaved oocyte rate, a lower available D3 embryo rate, a lower blastocyst formation rate, and a lower available blastocyst rate than the control group. Conclusion: HOMA-IR is a judgment criterion for metformin pre-treatment before IVF/ICSI-ET in patients with PCOS. Metformin pre-treatment could be added for PCOS patients with HOMA-IR ≥ 2.71 during frozen IVF/ICSI-ET cycles to improve the clinical pregnancy rate.

The National Clinical Care Commission Report to Congress: Leveraging Federal Policies and Programs to Prevent Diabetes in People With Prediabetes.

Individuals with an elevated fasting glucose level, elevated glucose level after glucose challenge, or elevated hemoglobin A1c level below the diagnostic threshold for diabetes (collectively termed prediabetes) are at increased risk for type 2 diabetes. More than one-third of U.S. adults have prediabetes but fewer than one in five are aware of the diagnosis. Rigorous scientific research has demonstrated the efficacy of both intensive lifestyle interventions and metformin in delaying or preventing progression from prediabetes to type 2 diabetes. The National Clinical Care Commission (NCCC) was a federal advisory committee charged with evaluating and making recommendations to improve federal programs related to the prevention of diabetes and its complications. In this article, we describe the recommendations of an NCCC subcommittee that focused primarily on prevention of type 2 diabetes in people with prediabetes. These recommendations aim to improve current federal diabetes prevention activities by 1) increasing awareness of and diagnosis of prediabetes on a population basis; 2) increasing the availability of, referral to, and insurance coverage for the National Diabetes Prevention Program and the Medicare Diabetes Prevention Program; 3) facilitating Food and Drug Administration review and approval of metformin for diabetes prevention; and 4) supporting research to enhance the effectiveness of diabetes prevention. Cognizant of the burden of type 1 diabetes, the recommendations also highlight the importance of research to advance our understanding of the etiology of and opportunities for prevention of type 1 diabetes.

Comparative effectiveness of metformin versus sulfonylureas on kidney function decline or death among patients with reduced kidney function: a retrospective cohort study.

BACKGROUND: Diabetes often causes kidney disease. In this study, we sought to evaluate if metformin use was associated with death or kidney events in patients with diabetes and concurrent reduced kidney function. METHODS: We used data from the Veterans Health Administration, Medicare and National Death Index databases to assemble a national retrospective cohort of veterans who were using metformin or sulfonylureas from 2001 through 2016 and who began follow-up at an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 m2. The primary composite outcome was a kidney event (i.e., 40% decline in eGFR or end-stage renal disease) or death. The secondary outcome was a kidney event (eGFR decline or end-stage renal disease). We weighted the cohort using propensity scores and used Cox proportional models to estimate the cause-specific hazard of outcomes and of treatment nonpersistence as a competing risk. We stratified follow-up into 2 periods, namely the first 360 days from the start of follow-up, and 361 days and beyond. RESULTS: In the first 360 days, the propensity score-weighted cohort included 24 883 patients who used metformin and 24 998 who used sulfonylureas. There were 33.5 (95% confidence interval [CI] 30.9-36.3) and 43.0 (95% CI 40.1-46.0) deaths or kidney events per 1000 person-years for patients who used metformin or sulfonylureas, respectively (hazard ratio [HR] 0.78, 95% CI 0.71-0.85). For the secondary outcome of kidney events, the HR was 0.94 (95% CI 0.67-1.33). In the second period from 361 days onward, the primary outcome event rate was 26.5 (95% CI 24.7-28.5) per 1000 person-years for those who used metformin, compared with 36.3 (95% CI 34.2-38.6) per 1000 person-years for those who used sulfonylureas (HR 0.73, 95% CI 0.67-0.79). Results were consistent for kidney events alone (HR 0.73, 95% CI 0.59-0.91). INTERPRETATION: Metformin use for 361 days or longer after reaching an eGFR of less than 60 mL/min/1.73 m2 was associated with decreased likelihood of kidney events or death in patients with diabetes, compared with use of sulfonylureas. Metformin provided end-organ protection, in addition to glucose control.