Metformin for pregnancy and beyond: the pros and cons

Newman, C. & Dunne, F. P. | 2021| Metformin for pregnancy and beyond: the pros and cons | Diabetic Medicine | https://doi.org/10.1111/dme.14700

The authors of this review set out to review the benefits and potential pitfalls of metformin use in pregnancy. To this end they conducted a literature search of web-based databases (including PubMed, CENTRAL via the Cochrane Library and EMBASE) using identified search terms. They read the full texts of any relevant texts published in English and searched clinicaltrials.gov for relevant unpublished trials. The team included randomised controlled trials (RCTs), cluster RCTs, pilot and feasibility studies in our review. They excluded conference abstracts, case reports and case series. Observational data which were deemed to be of high quality were also considered. Additionally, the researchers searched bibliographies for all relevant publications to identify other studies.

In this paper they report their findings that metformin has many maternal advantages when taken during and after pregnancy, including reduced maternal GWG, PTD and insulin requirements, a reduction in operative delivery and possible reduction in hypertensive disorders and future type 2 diabetes. Some benefits are even greater for women with a BMI more than or equal to 30 kg/m2 (Source: Newman & Dunne, 2021).

Abstract

Context and Aim

Metformin has been used in pregnancy since the 1970s. It is cheap, widely available and is acceptable to women. Despite its increasing use, controversy remains surrounding its benefits and risks. Metformin effectively reduces hyperglycaemia for the mother during pregnancy and it reduces rates of macrosomia and neonatal hypoglycaemia. However, concern exists surrounding an increase in the rate of SGA births and obesity in childhood. We aim to review the evidence and expert opinion behind metformin in pregnancy through to the post-partum period.

Methods

We performed a literature review of relevant studies from online databases using a combination of keywords. We also searched the references of retrieved articles for pertinent studies.

Results

There is strong evidence that metformin is safe in early pregnancy with no risk of congenital malformations. If used throughout pregnancy, it is likely to lead to reduced maternal weight gain and reduced insulin dose in women with type 2 diabetes. In infants, metformin reduces hypoglycaemia and macrosomia but may increase the rate of infants born SGA. There is some evidence of an increased risk of obesity and altered fat distribution in offspring. Metformin appears well tolerated in pregnancy and is more acceptable to women than insulin therapy.

Conclusion

Due to increasing rates of maternal obesity, GDM and type 2 diabetes, metformin use in pregnancy is increasing. Overall, it appears safe and effective but further research is needed to examine mechanisms linking metformin to obesity reported during childhood in some follow-up studies.

  • Metformin has been used outside of pregnancy for decades and has multiple benefits in pregnancy including reduced weight gain and a potential decrease in pre-eclampsia (PET).
  • However, some clinicians have concerns regarding its use due to increased rates of small for gestational age (SGA) births and adiposity in infants exposed to metformin.
  • With the rising rates of obesity and gestational diabetes (GDM), cheap, acceptable and effective treatments for hyperglycaemia are needed.
  • This study follows the use of metformin from the pre-conception to the post-partum period and examines the evidence for and against its use.

The primary paper is available from the journal Diabetic Medicine

Metformin Should Not Be Used to Treat Prediabetes

Davidson, M.B. (2020)| Metformin Should Not Be Used to Treat Prediabetes | Diabetes Care| DOI: 10.2337/dc19-2221

Abstract

Based on the results of the Diabetes Prevention Program Outcomes Study (DPPOS), in which metformin significantly decreased the development of diabetes in individuals with baseline fasting plasma glucose (FPG) concentrations of 110-125 vs. 100-109 mg/dL (6.1-6.9 vs. 5.6-6.0 mmol/L) and A1C levels 6.0-6.4% (42-46 mmol/mol) vs. less than 6.0% and in women with a history of gestational diabetes mellitus, it has been suggested that metformin should be used to treat people with prediabetes. Since the association between prediabetes and cardiovascular disease is due to the associated nonglycemic risk factors in people with prediabetes, not to the slightly increased glycemia, the only reason to treat with metformin is to delay or prevent the development of diabetes. There are three reasons not to do so. First, approximately two-thirds of people with prediabetes do not develop diabetes, even after many years. Second, approximately one-third of people with prediabetes return to normal glucose regulation. Third, people who meet the glycemic criteria for prediabetes are not at risk for the microvascular complications of diabetes and thus metformin treatment will not affect this important outcome. Why put people who are not at risk for the microvascular complications of diabetes on a drug (possibly for the rest of their lives) that has no immediate advantage except to lower subdiabetes glycemia to even lower levels? Rather, individuals at the highest risk for developing diabetes-i.e., those with FPG concentrations of 110-125 mg/dL (6.1-6.9 mmol/L) or A1C levels of 6.0-6.4% (42-46 mmol/mol) or women with a history of gestational diabetes mellitus-should be followed closely and metformin immediately introduced only when they are diagnosed with diabetes.

Rotherham NHS staff can request a copy of this article from the Library

Are preoperative metformin prescriptions associated with a lower risk of postoperative mortality and readmission among patients with type 2 diabetes who underwent a major surgical intervention?

Reitz, K.M. et al. (2020). Association Between Preoperative Metformin Exposure and Postoperative Outcomes in Adults With Type 2 Diabetes. JAMA Surg. Published online April 08, 2020. doi:10.1001/jamasurg.2020.0416
Are preoperative metformin prescriptions associated with a lower risk of postoperative mortality and readmission among patients with type 2 diabetes who underwent a major surgical intervention? This is the question used to inform research into US patients with diabetes who were had a preoperative prescription and those without preoperative prescription, the research team looked at data from over 5000 patients who had undergone surgery. The researchers identified an association between metformin prescriptions before major surgery and reduced risk-adjusted mortality and readmission following the procedure (Source: Reitz, 2020 et al).

Key Points


Question
  Are preoperative metformin prescriptions associated with a lower risk of postoperative mortality and readmission among patients with type 2 diabetes who underwent a major surgical intervention?

Findings  In this cohort study of 5460 patients with diabetes who had a major surgical procedure, preoperative prescriptions of metformin were associated with a statistically significant decrease in the risk of 90-day mortality as well as 30- and 90-day readmission compared with no such prescriptions.

Meaning  Findings from this study suggest that preoperative metformin prescriptions may be associated with decreased postoperative mortality and readmission compared with no preoperative exposure to this medication, but further research is needed to ascertain if this relationship is causal.

Abstract

Importance  Adults with comorbidity have less physiological reserve and an increased rate of postoperative mortality and readmission after the stress of a major surgical intervention.

Objective  To assess postoperative mortality and readmission among individuals with diabetes with or without preoperative prescriptions for metformin.

Design, Setting, and Participants  This cohort study obtained data from the electronic health record of a multicenter, single health care system in Pennsylvania. Included were adults with diabetes who underwent a major operation with hospital admission from January 1, 2010, to January 1, 2016, at 15 community and academic hospitals within the system. Individuals without a clinical indication for metformin therapy were excluded. Follow-up continued until December 18, 2018.

Exposures  Preoperative metformin exposure was defined as 1 or more prescriptions for metformin in the 180 days before the surgical procedure.

Main Outcomes and Measures  All-cause postoperative mortality, hospital readmission within 90 days of discharge, and preoperative inflammation measured by the neutrophil to leukocyte ratio were compared between those with and without preoperative prescriptions for metformin. The corresponding absolute risk reduction (ARR) and adjusted hazard ratio (HR) with 95% CI were calculated in a propensity score–matched cohort.

Results  Among the 10 088 individuals with diabetes who underwent a major surgical intervention, 5962 (59%) had preoperative metformin prescriptions. A total of 5460 patients were propensity score–matched, among whom the mean (SD) age was 67.7 (12.2) years, and 2866 (53%) were women. In the propensity score–matched cohort, preoperative metformin prescriptions were associated with a reduced hazard for 90-day mortality; ARR, 1.28%  and hazard of readmission, with mortality as a competing risk at both 30 days and 90 days. Preoperative inflammation was reduced in those with metformin prescriptions compared with those without. E-value analysis suggested robustness to unmeasured confounding.

Conclusions and Relevance  This study found an association between metformin prescriptions provided to individuals with type 2 diabetes before a major surgical procedure and reduced risk-adjusted mortality and readmission after the operation. This association warrants further investigation.

 

Related: Diabetes UK Metformin associated with reduced mortality rates after major surgery

JAMA Surgery