Gastrointestinal adverse events of metformin treatment in patients with type 2 diabetes mellitus: a systematic review and meta-analysis with meta-regression of observational studies.

INTRODUCTION: Metformin is the most prescribed medication for type 2 diabetes mellitus (T2DM); there is a well-established link with the elevated incidence of gastrointestinal (GI) adverse events (AE) limiting its administration or intensification. OBJECTIVES: The objective of this systematic review and meta-analysis of observational studies was to evaluate the pooled incidence of GI AE related to metformin use in patients with T2DM. MATERIALS AND METHODS: PUB MED/CINAHL/Web of Science/Scopus were searched from database inception until 29.07.2024 for observational studies in English describing the frequency of GI AE in patients with T2DM treated with metformin. Random-effects meta-analyses were used to derive effect sizes: event rates. RESULTS: From 7019 publications, we identified 211 potentially eligible full-text articles. Ultimately, 21 observational studies were included in the meta-analysis. The prevalence of GI AE was as follows: diarrhea 6.9% (95% CI: 0.038-0.123), bloating 6,2% (95% CI: 0.020-0.177), abdominal pain 5,3% (95% CI: 0.003-0.529), vomiting 2.4% (95%: CI 0.007-0.075), constipation 1.1% (95%: CI 0.001-0.100). The incidence of bloating (coefficient -4.46; p < 0.001), diarrhea (coefficient -1.17; p = 0.0951) abdominal pain (coefficient -2.80; p = 0.001), constipation (coefficient -5.78; p = 0.0014) and vomiting (coefficient -2.47; p < 0.001) were lower for extended release (XR) metformin than metformin immediate release (IR) formulation. CONCLUSIONS: This study highlights the prevalence of GI AE in patients receiving metformin, with a diarrhea predominance, followed by bloating, diarrhea, abdominal pain, constipation, and vomiting. The incidence is lower in patients administered with XR metformin. TRIAL REGISTRATION: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021289975 , identifier CRD42021289975.

Metformin use and preeclampsia risk in women with diabetes: a two-country cohort analysis.

BACKGROUND: Metformin is a hypoglycaemic medication that has been proposed to treat or prevent preeclampsia. Combining national birth data from Scotland and Sweden, we investigated whether metformin used during pregnancy was associated with an altered risk of developing a hypertensive disorder of pregnancy. METHODS: We utilised data from two population-based cohorts: Scotland (2012-2018) and Sweden (2007-2019). Nulliparous women with gestational diabetes or type 2 diabetes who had birth outcome data linked with medications prescribed during pregnancy were included. The association between metformin prescription and hypertensive disorders of pregnancy was characterised using inverse probability weighted regression analysis, adjusting for variables that predict metformin use and potential confounders. Adverse neonatal outcomes were included as secondary outcomes. Results from both countries were then combined in a meta-analysis using a random effects model. RESULTS: The Scottish cohort included 3859 women with gestational diabetes or type 2 diabetes. Of these women, 30.8% (n = 1187) received at least one metformin prescription during pregnancy. For Sweden, 7771 women with gestational diabetes were included where 19.3% (1498) used metformin during pregnancy. Metformin prescription was not associated with an altered risk of any hypertensive disorder of pregnancy (Scotland adjusted relative risk (aRR) 0.88 [95% confidence interval (CI) 0.66-1.19]; Sweden aRR 1.08 [95% CI 0.86-1.37]) or preeclampsia (Scotland aRR 1.02 [95% CI 0.66-1.60]; Sweden aRR 1.00 [95% CI 0.72-1.39]). Combining adjusted results in a meta-analysis produced similar findings, with a pooled RR of 0.98 (95% CI 0.79-1.18) for any hypertensive disorder and RR 1.01 ([95% CI 0.73-1.28]) for preeclampsia. For neonatal outcomes, metformin was associated with a reduced risk of birthweight > 4500 g in Scotland (aRR 0.39 [95% CI 0.21-0.71]) but not in Sweden. There was no association between metformin and preterm birth or birthweight < 3rd or < 10th percentiles. Pooling results from both countries, metformin was not associated with adverse neonatal outcomes, including preterm birth (RR 1.00 [95% CI 0.89-1.13]), and birthweight < 10th percentile (RR 0.82 [95% CI 0.60-1.13]) or < 3rd percentile (RR 0.78 [95% CI 0.41-1.48]). CONCLUSIONS: In this two-country analysis, metformin use in pregnancy among women with diabetes was not associated with an altered risk of developing any hypertensive disorder of pregnancy. In the combined meta-analysis, metformin was not associated with an altered risk of adverse neonatal outcomes.

Metformin-associated lactic acidosis: a serious complication of a common drug.

Metformin-associated lactic acidosis (MALA) is a rare and potentially life-threatening complication of metformin use. It typically occurs in patients who are diabetic and also have other risk factors for lactic acidosis, including kidney and liver conditions, malignancy, or use of certain medications. We report a case of MALA in a man in his 70s with diabetes who presented with gradually worsening gastrointestinal symptoms, including severe abdominal pain and nausea. He reported these symptoms in the setting of metformin use with an acute kidney injury (AKI), likely brought on by poor oral intake and excessive antibiotic use for a urinary tract infection. He was promptly started on intravenous fluids with a bicarbonate drip to concurrently treat his prerenal AKI and lactic acidosis, which resulted in rapid resolution of his symptoms. Renal function normalised within 12 days of admission. Since diabetic patients commonly use metformin and are also at higher risk of renal dysfunction, this case highlights the vulnerability of this group of patients and the need for increased knowledge and awareness of MALA.

Causal association between antidiabetic drugs and erectile dysfunction: evidence from Mendelian randomization.

Background: Antidiabetic drugs are widely used in clinical practice as essential drugs for the treatment of diabetes. The effect of hypoglycemic drugs on erectile dysfunction has not been fully proven due to the presence of multiple confounding factors. Methods: Two-sample Mendelian randomization (TSMR) was used to examine the causal effect of antidiabetic drugs (including metformin, insulin and gliclazide) on erectile dysfunction. We used five robust analytic methods, of which the inverse variance weighting (IVW) method was the primary method, and also assessed factors such as sensitivity, pleiotropy, and heterogeneity. Effect statistics for exposures and outcomes were downloaded from publicly available data sets, including open Genome-Wide Association Studies (GWAS) and the UK Biobank (UKB). Results: In some of the hypoglycemic drug use, there was a significant causal relationship between metformin use and erectile dysfunction [Beta: 4.9386; OR:1.396E+02 (95% CI:9.13-2135); p-value: 0.0004), suggesting that metformin increased the risk of erectile dysfunction development. Also, we saw that gliclazide use also increased the risk of erectile dysfunction [Beta: 11.7187; OR:0.0125 (95% CI:12.44-1.21E+09); P value: 0.0125). There was no significant causal relationship between insulin use and erectile dysfunction [Beta: 3.0730; OR:21.6071 (95% CI:0.24-1942.38); p-value: 0.1806).Leave-one-out, MR-Egger, and MR-PRESSO analyses produced consistent results. Conclusion: The use of metformin and gliclazide have the potential to increase the risk of erectile dysfunction. There is no causal relationship between the use of insulin and erectile dysfunction.

Movement disorders related to antidiabetic medications: a real-world pharmacovigilance study.

BACKGROUND: Diabetic Mellitus (DM) has progressively emerged as a worldwide health problem, leading to the widespread deployment of antidiabetic drugs as the primary therapy in the global population. The incidence of diabetes medications-related movement disorders (drMD) is noteworthy but underestimated by clinical practitioners. RESEARCH DESIGN AND METHODS: In order to address the incidence of drMD in DM patients and realize the serious outcomes associated with drMD, we conducted a real-world pharmacovigilance study of 612,043 DM patients using the FDA Adverse Event Reporting System (FAERS) database from January 2004 to September 2023. Reporting Odd Ratio (ROR) was calculated to reflect the risk of drMD. A multivariable logistic regression analysis was employed to adjust crude ROR with the mixed factors including age, sex and various antidiabetic treatments. Afterward, a Mendelian Randomization (MR) study was performed to elucidate the underlying genetic correlation between the genetically proxied targets of antidiabetic drugs and motor disorders. RESULTS: Among 11,729 cases of motor adverse events in DM patients, six categories of drMD were significantly associated with DM medications. Noticeably, metformin was revealed to drastically increase the incidence of parkinsonism (adjusted ROR:3.97; 95 %CI (3.03, 5.19), p = 5.68e-24), bradykinesia (adjusted ROR:1.69; 95 %CI (1.07,2.59), p = 0.02) and irregular hyperkinesia, including chorea, choreoathetosis and athetosis. Insulin/insulin analogues and GLP-1 analogues presented notably higher odds of tremor: the adjusted ROR (aROR) of insulin and GLP-1 analogue is respectively 1.24 (95 %CI (1.15,1.34), p = 2.51e-08) and 1.78 (95 %CI (1.65,1.91), p = 5.64e-54). The combined therapeutic effects of multiple genetic variants of metformin, especially AMP-activated protein kinase (AMPK) were markedly linked to a greater likelihood of developing secondary parkinsonism (OR:10.816, p = 0.049) according to MR analyses. CONCLUSION: The use of antidiabetic medications was significantly related to an increased incidence of movement disorders in DM patients. Moreover, MR analyses provided further genetic evidence for the pharmacovigilance study. This comprehensive investigation might help physicians recognize neurological adverse events associated with antidiabetic treatments and administer effective interventions.

The optimal dose of metformin to control conversion to diabetes in patients with prediabetes: A meta-analysis.

AIM: This study aims to investigate the optimal dose of metformin for controlling the transition to diabetes in patients diagnosed with prediabetes. METHODS: We systematically searched randomized controlled trials (RCTs) in CNKI, Wanfang, VIP, SinoMed, Scopus, PubMed, Embase, Cochrane Library, Web of Science, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) from inception to February 2024. Meta-analysis was conducted using RevMan 5.4 software. RESULTS: We included 25 randomized controlled trials comprising 2437 patients. The results of the meta-analysis revealed that compared to dose groups of 500 mg/d, 850 mg/d, 1000 mg/d, 1500 mg/d, 1700 mg/d, and 2000 mg/d, a dosage of 750 mg/d of metformin significantly reduced the incidence of diabetes in patients (risk ratio [RR] = 0.21, 95 % confidence interval [CI]: 0.11, 0.41; p < 0.00001), lowered Postprandial Blood Glucose (PBG) (mean difference[MD] = -2.60, 95 % CI: -4.34, -0.86; p = 0.003), and promoted the normalization of blood glucose levels (RR = 2.13, 95 % CI: 1.68, 2.71; p < 0.00001). Regarding safety evaluation, no significant differences were identified among the various dose groups. In contrast, the cohort receiving a daily dosage of 750 mg demonstrated the most pronounced decrease in the incidence of adverse reactions. CONCLUSION: Based on the efficacy and safety evaluation results, our findings suggest that a daily dosage of 750 mg of metformin may represent the optimal dose for controlling the progression from pre-diabetes to diabetes. REGISTRATION: PROSPERO registration ID: CRD42024538322.

[Fatalities associated with failure to adjust drug dose in patients with renal insufficiency: A retrospective study at the Institute of Forensic Medicine in Munich (2019-2023)]. / Medikamenteninduzierte Todesfälle bei Niereninsuffizienz.

Comorbidities in the elderly not only make them more susceptible to kidney disease, but also increase the risk of drug interactions due to polypharmacy. Such patients require regular kidney function tests when treated with renally excreted drugs. We conducted a retrospective study of post-mortem cases over a five- year period. Of 3040 toxicologically investigated cases, 3.8% had a history of renal failure. Thirteen deaths were directly attributable to inadequate drug dosing, 46% of which were related to lactic acidosis due to metformin accumulation. Appropriate dose adjustment could prevent fatal drug toxicity in patients with renal insufficiency.

Perinatal Outcomes Associated With Metformin Use During Pregnancy in Women With Pregestational Type 2 Diabetes Mellitus.

OBJECTIVE: We emulated a modified randomized trial (Metformin in Women With Type 2 Diabetes in Pregnancy [MiTy]) to compare the perinatal outcomes in women continuing versus discontinuing metformin during pregnancy among those with type 2 diabetes treated with metformin plus insulin before pregnancy. RESEARCH DESIGN AND METHODS: This study used two health care claims databases (U.S., 2000-2020). Pregnant women age 18-45 years with type 2 diabetes who were treated with metformin plus insulin at conception were eligible. The primary outcome was a composite of preterm birth, birth injury, neonatal respiratory distress, neonatal hypoglycemia, and neonatal intensive care unit admission. Secondary outcomes included the components of the primary composite outcome, gestational hypertension, preeclampsia, maternal hypoglycemia, cesarean delivery, infants large for gestational age, infants small for gestational age (SGA), sepsis, and hyperbilirubinemia. We adjusted for potential baseline confounders, including demographic characteristics, comorbidities, and proxies for diabetes progression. RESULTS: Of 2,983 eligible patients, 72% discontinued use of metformin during pregnancy. The average age at conception was 32 years, and the prevalence of several comorbidities was higher among continuers. The risk of the composite outcome was 46% for continuers and 48% for discontinuers. The adjusted risk ratio was 0.92 (95% CI 0.81, 1.03). Risks were similar between treatments and consistent between databases for most secondary outcomes, except for SGA, which was elevated in continuers only in the commercially insured population. CONCLUSIONS: Our findings were consistent with those reported in the MiTy randomized trial. Continuing metformin during pregnancy was not associated with increased risk of a neonatal composite adverse outcome. However, a possible metformin-associated risk of SGA warrants further consideration.

Efficacy and Safety of Pioglitazone Add-on in Patients with Type 2 Diabetes Mellitus Inadequately Controlled with Metformin and Dapagliflozin: A Multicenter, Randomized, Double-blind, and Placebo-controlled Study.

PURPOSE: The purpose of this study was to determine the efficacy and safety profile of pioglitazone compared with placebo (PBO) in patients with type 2 diabetes (T2D) inadequately controlled with metformin and dapagliflozin. METHODS: In this prospective, multicenter, randomized, double-blind, PBO-controlled trial, 366 patients with T2D who did not meet glycemic targets (7.0% ≤ glycosylated hemoglobin [HbA1c] ≤ 10.5%), despite treatment with metformin ≥1000 mg and dapagliflozin 10 mg, received either a PBO, 15 mg of pioglitazone daily (PIO15), or 30 mg of pioglitazone daily (PIO30). The primary end point was the mean change in HbA1c from baseline at 24 weeks across the groups. FINDINGS: For the 366 participants (PBO, n = 124; PIO15, n = 118; PIO30, n = 124), the mean age was 55.6 years and mean duration of diabetes was 8.7 years, with a baseline HbA1c of 7.9%. After 24 weeks, HbA1c reduced significantly in the PIO15 and PIO30 groups from baseline, with intergroup differences of -0.38% and -0.83%, respectively, compared with the PBO group. The proportion of patients with HbA1c levels <7% was significantly higher in the PIO15 and PIO30 groups than in the PBO group. The adverse event rates did not significantly differ across the groups, indicating favorable safety profiles for triple combination therapy using metformin, dapagliflozin, and pioglitazone. IMPLICATIONS: The addition of pioglitazone as a third oral antidiabetic medication is an appropriate option for patients with T2D inadequately controlled with metformin and dapagliflozin based on the resulting significant efficacy in glycemic control and favorable safety profile. CLINICALTRIALS: gov identifier: NCT04885712.

Effect of Erdafitinib on the Pharmacokinetics of Midazolam and Metformin in Patients With Advanced Solid Tumors Harboring FGFR Gene Alterations.

Erdafitinib, an oral pan-FGFR inhibitor, is used in locally advanced or metastatic urothelial carcinoma for adults with FGFR3 genetic alterations and whose disease progressed following prior systemic therapy. This drug-drug interaction substudy evaluated the effect of erdafitinib on the pharmacokinetics of midazolam (cytochrome P450 3A4 substrate), and metformin (organic cation transporter 2 substrate). Twenty-five patients with advanced solid tumors harboring FGFR gene alterations received pretreatment with single doses of midazolam and metformin, followed by a daily dose of erdafitinib. Drug-drug interaction assessments were performed at erdafitinib steady state following coadministration of single doses of midazolam and metformin, respectively. Geometric mean ratios for maximum plasma concentration and area under the plasma concentration-time curve (AUC) from time 0 to the last measurable concentration, and AUC from time 0 to infinity were estimated using linear mixed-effects models (90% confidence interval within 80%-125% indicated no interaction). The 90% confidence intervals of geometric mean ratios for maximum plasma concentration, AUC from time 0 to the last measurable concentration, and AUC from time 0 to infinity of midazolam (86.3%, 88.5%, and 82.1%), 1-OH midazolam (99.8%, 97.4%, and 101.5%), and metformin (108.7%, 119.0%, and 113.9%) were either contained or slightly outside the 80%-125% interval and not considered clinically meaningful. Adverse events were consistent with the known erdafitinib safety profile; no new safety signals emerged. Thus, repeated dosing of erdafitinib had no clinically meaningful effect on the pharmacokinetics of midazolam or metformin.

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.

Incretin-based therapy and the risk of diabetic foot ulcers and related events.

AIM: To investigate the effect of dipeptidyl peptidase-4 inhibitors (DPP4-Is) and glucagon-like peptide-1 receptor agonists (GLP1-RAs) on diabetic foot ulcer (DFU) and DFU-related outcomes (lower limb amputation [LLA], DFU-related hospitalization and mortality). METHODS: We performed a cohort study with data from the Clinical Practice Research Datalink Aurum database with linkage to hospital data. We included people with type 2 diabetes starting treatment with metformin. Then we propensity score matched new users of DPP4-Is and sulphonylureas (N = 98 770), and new users of GLP1-RAs and insulin (N = 25 422). Cox proportional hazards models estimated the hazard ratios (HRs) for the outcomes. RESULTS: We observed a lower risk of DFU with both DPP4-I use versus sulphonylurea use (HR 0.88, 95% confidence interval [CI]: 0.79-0.97) and GLP1-RA use versus insulin use (HR 0.44, 95% CI: 0.32-0.60) for short-term exposure (≤ 400 days) and HR 0.74 (95% CI: 0.60-0.92) for long-term exposure (>400 days). Furthermore, the risks of hospitalization and mortality were lower with both DPP4-I use and GLP1-RA use. The risk of LLA was lower with GLP1-RA use. The results remained consistent across several sensitivity analyses. CONCLUSIONS: Incretin-based therapy was associated with a lower risk of DFU and DFU-related outcomes. This suggests benefits for the use of this treatment in people at risk of DFU.

Metformin exposure and the incidence of lactic acidosis in critically ill patients with T2DM: A retrospective cohort study.

OBJECTIVE: The objective of this study was to investigate the correlation between metformin exposure and the incidence of lactic acidosis in critically ill patients. METHODS: The patients with type 2 diabetes mellitus (T2DM) were included from Medical Information Mart for Intensive Care IV database (MIMIC-IV). The primary outcome was the incidence of lactic acidosis. The secondary outcomes were lactate level and in-hospital mortality. Propensity score matching (PSM) method was adopted to reduce bias of the confounders. The multivariate logistic regression was used to explore the correlation between metformin exposure and the incidence of lactic acidosis. Subgroup analysis and sensitivity analysis were used to test the stability of the conclusion. RESULTS: We included 4939 patients. There were 2070 patients in the metformin group, and 2869 patients in the nonmetformin group. The frequency of lactic acidosis was 5.7% (118/2070) in the metformin group and it was 4.3% (122/2869) in the nonmetformin group. There was a statistically significant difference between the two groups (P < 0.05). The lactate level in the metformin group was higher than in the nonmetformin group (2.78 ± 2.23 vs. 2.45 ± 2.24, P < 0.001). After PSM, the frequency of lactic acidosis (6.3% vs. 3.7%, P < 0.001) and lactate level (2.85 ± 2.38 vs. 2.40 ± 2.14, P < 0.001) were significantly higher in the metformin group compared with the nonmetformin group. In multivariate logistic models, the frequency of lactic acidosis was obviously increased in metformin group, and the adjusted odds ratio (OR) of metformin exposure was 1.852 (95% confidence interval (CI) = 1.298-2.643, P < 0.001). The results were consistent with subgroup analysis except for respiratory failure subgroup. Metformin exposure increased lactate level but did not affect the frequency of lactic acidosis in patients of respiratory failure with hypercapnia. However, the in-hospital mortality between metformin and nonmetformin group had no obvious difference (P = 0.215). In sensitivity analysis, metformin exposure showed similar effect as the original cohort. CONCLUSIONS: In critically ill patients with T2DM, metformin exposure elevated the incidence of lactic acidosis except for patients of respiratory failure with hypercapnia, but did not affect the in-hospital mortality.

Preadmission metformin use increased the incidence of hyperlactatemia at admission and 30-day in-hospital mortality among T2D patients with heart disease at high risk of hypoxia.

BACKGROUND: Surprisingly, despite the high prevalence of metformin use in type 2 diabetes (T2D) patients with heart disease, limited safety data is available regarding metformin use in patients with acute and critical heart disease. METHODS: In this single-center retrospective study, patients admitted to the cardiology department for heart failure (HF) or acute coronary syndrome (ACS) between December 2013 and December 2021 and who underwent arterial blood gas analysis at admission with an estimated glomerular clearance rate of ≥45 ml/min/1.73 m2 were identified. The incidences of hyperlactatemia, acidosis, and 30-day in-hospital mortality were compared between preadmission metformin users and nonusers. RESULTS: Of 526 admissions, 193/193 metformin users/nonusers were selected in a propensity score-matched model. Metformin users had greater lactate levels (2.55 ± 2.07 mmol/l vs. 2.00 ± 1.80 mmol/l P < 0.01), a greater incidence of hyperlactatemia [odds ratio (OR) = 2.55; 95% confidence interval (CI), 1.63-3.98; P < 0.01] and acidosis (OR = 1.78; 95% CI, 1.00-3.16; P < 0.05) at admission and a greater incidence of in-hospital mortality (OR = 3.83; 95% CI, 1.05-13.94; P < 0.05), especially those with HF/acute myocardial infarction, elderly age, or without preadmission insulin use. CONCLUSIONS: Our results suggest that, compared to metformin nonusers, preadmission use of metformin may be associated with a greater incidence of hyperlactatemia and acidosis at admission and greater 30-day in-hospital mortality among T2D patients with HF or ACS at high risk of hypoxia, particularly those without preadmission insulin use. The safety of metformin in this population needs to be confirmed in prospective controlled trials.

Metformin Use in the First Trimester of Pregnancy and Risk for Nonlive Birth and Congenital Malformations: Emulating a Target Trial Using Real-World Data.

BACKGROUND: Metformin is a first-line pharmacotherapy for type 2 diabetes, but there is limited evidence about its safety in early pregnancy. OBJECTIVE: To evaluate the teratogenicity of metformin use in the first trimester of pregnancy. DESIGN: In an observational cohort of pregnant women with pregestational type 2 diabetes receiving metformin monotherapy before the last menstrual period (LMP), a target trial with 2 treatment strategies was emulated: insulin monotherapy (discontinue metformin treatment and initiate insulin within 90 days of LMP) or insulin plus metformin (continue metformin and initiate insulin within 90 days of LMP). SETTING: U.S. Medicaid health care administration database (2000 to 2018). PARTICIPANTS: 12 489 pregnant women who met the eligibility criteria. MEASUREMENTS: The risk and risk ratio of nonlive births, live births with congenital malformations, and congenital malformations among live births were estimated using standardization to adjust for covariates. RESULTS: A total of 850 women were in the insulin monotherapy group and 1557 in the insulin plus metformin group. The estimated risk for nonlive birth was 32.7% under insulin monotherapy (reference) and 34.3% under insulin plus metformin (risk ratio, 1.02 [95% CI, 1.01 to 1.04]). The estimated risk for live birth with congenital malformations was 8.0% (CI, 5.7% to 10.2%) under insulin monotherapy and 5.7% (CI, 4.5% to 7.3%) under insulin plus metformin (risk ratio, 0.72 [CI, 0.51 to 1.09]). LIMITATION: Possible residual confounding by glycemic control and body mass index. CONCLUSION: Compared with switching to insulin monotherapy, continuing metformin and adding insulin in early pregnancy resulted in little to no increased risk for nonlive birth among women receiving metformin before pregnancy. Under conventional statistical criteria, anything between a 49% decrease and a 9% increase in risk for congenital malformations was highly compatible with our data. PRIMARY FUNDING SOURCE: National Institutes of Health.

Long-Term Impact on Offspring (5 to 11 Years of Age) of Metformin Use in Pregnancy in Mothers With Diabetes: A Systematic Review and Meta-Analysis.

OBJECTIVE: Data are scant on the impact of metformin use in gestational diabetes mellitus/diabetes in pregnancy on long-term outcomes in children and mothers beyond 5 years of childbirth. This systematic review and meta-analysis aimed to evaluate the long-term impact of metformin use in pregnancy on children and their mothers. METHODS: Electronic databases were searched for studies evaluating metformin compared with insulin for managing gestational diabetes mellitus/diabetes in pregnancy. The primary outcome was the change in body mass index (BMI) in children at the ages of 5 to 11 years. The secondary outcomes were alterations in other anthropometric measures, obesity, and changes in the levels of lipids and adipocytokines in children and mothers. RESULTS: Children at the age of 9 years born to mothers who were treated with metformin during pregnancy had similar BMI (mean difference [MD], 1.09 kg/m2 [95% confidence interval {CI}, -0.44 to 2.62]; P = .16; I2 = 16%), waist circumference-to-height ratio (MD, 0.13 [95% CI, -0.05 to 0.30]; P = .16; I2 = 94%), dual-energy X-ray absorptiometry (DXA) total fat mass (MD, 0.68 kg [95% CI, -2.39 to 3.79]; P = .66; I2 = 70%), DXA total fat percent (MD, 0.04% [95% CI, -3.44 to 3.51]; P = .98; I2 = 56%), DXA total fat-free mass (MD, 0.81 kg [95% CI, -0.96 to 2.58]; P = .37; I2 = 55%), magnetic resonance imaging visceral adipose tissue volume (MD, 80.97 cm3 [95% CI, -136.47 to 298.41]; P = .47; I2 = 78%), and magnetic resonance spectroscopy liver fat percentage (MD, 0.27% [95% CI, -1.26 to 1.79]; P = .73; I2 = 0%) to those born to mothers who were treated with insulin. Serum adiponectin, leptin, alanine aminotransferase, and ferritin were comparable among groups. In children between the ages of 9 and 11 years, the occurrence of obesity, diabetes, or challenges in motor and social development were comparable between the 2 groups. After 9 years of childbirth, BMI and the risk of developing diabetes were similar between the 2 groups of women. CONCLUSION: Metformin use in pregnancy did not show any adverse effects compared with insulin on long-term outcomes in children and their mothers.

[Risk minimalisation measures for medications; are they incorporated in Dutch clinical guidelines?] / Risicominimalisatiemaatregelen voor geneesmiddelen.

OBJECTIVE: Risk minimisation measures (RMM) are put in place to ensure safe and effective use of medicines. This study assessed whether RMM for five medicines are implemented in Dutch clinical guidelines. DESIGN: Descriptive study. METHOD: Dutch clinical guidelines where treatment with valproate, fluoroquinolones, methotrexate, metformin or fluorouracil was recommended were identified. In those guidelines that had been updated after publication of the RMM, we determined whether RMM-information was included in the guideline. RESULTS: Out of 50 identified guidelines recommending treatment with one of the five medicines, only 21 (42%) were revised after RMM-implementation. Of these 21 guidelines, 12 (n = 57%) included RMM-related information. CONCLUSION: Uptake of RMM information in Dutch clinical guidelines is limited and RMM-publication does not prompt guideline updates. This suggests that guidelines alone are not an optimal way to inform health care professionals of new safety warnings.