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Drug Review - Metformin

Drug Review - Metformin

Introduction

Mechanism of action

Glycaemic efficacy

Hypoglycaemia

Weight

Microvascular and macrovascular outcome studies

Non-glycaemic benefits

Adverse effects and special precautions

Dosing and prescribing

Metformin extended-release

 

INTRODUCTION

Metformin, a biguanide, was isolated from Galega officinalis (goats rue), which was used to treat symptoms characteristic of diabetes mellitus in medieval times. French diabetologist  Jean Sterne was the first to publish studies about its glucose lowering effect in humans in 1957, when he dubbed the drug “gluco-phage” (glucose-eater).1

The common occurrence of lactic acidosis with other biguanides has led to their withdrawal, and metformin is currently the only commercially available biguanide. It has been registered in the United Kingdom since 1958, in the United States since 1994 and in South Africa since August 1974. Metformin is the most commonly used oral therapy for the treatment of type 2 diabetes worldwide and forms the backbone of treatment in most published guidelines.

Mechanism of action

(Optional reading)
The exact mechanisms of action of metformin have been debated. The predominant anti-hyperglycaemic effect was thought to be through the reduction in hepatic glucose production and increased insulin-mediated glucose uptake by skeletal muscle. However, the importance of its gut based mechanism of action is gaining significance.2,3

Reduced hepatic glucose output is thought to be mediated through inhibition of liver mitochondrial electron transport, leading to activation of the enzyme AMP-activated protein kinase. Increased cellular AMP leads to blockade of glucagon- dependent hepatic glucose production as well as direct  inhibition of gluconeogenesis through inhibition of a key  enzyme, fructose-1,6-bisphosphatase.

At the level of skeletal muscle, increase in glucagon receptor– stimulated adenylate cyclase has been shown to increase glucose transporter activity (GLUT-4) and glucose uptake.

Gut effects include the stimulation of jejunal enteroendocrine L-cells to produce glucagon-like peptide-1 (GLP-1) and peptide YY, alteration of bile acid metabolism and the gut microbiome, as well as delayed and reduced glucose absorption.2,3,4 The increase in GLP-1 levels with metformin are similar to those seen with DPP- 4 inhibitors.5 Recent observations that smaller doses of delayed- release metformin (Met-DR), which increases drug delivery to the ileum, is as effective as higher doses of immediate release metformin (Met-I) and extended-release metformin (Met-XR), suggests that gut may be the major target for metformin action. Suppression of hepatic glucose output may in fact be neuro- humorally mediated via the gut.3,6

Peripheral effects include the stimulation of fatty acid oxidation and an increase in systemic measures of insulin sensitivity (as is common with many glucose lowering therapies). However, the role of metformin in insulin-mediated glucose uptake is not proven, and therefore, contrary to popular belief, cannot be classified as an insulin sensitiser.7,8

Glycaemic efficacy9,10,11

Systematic reviews and meta-analyses of randomised controlled trials show that:

  • Metformin monotherapy lowers HbA1c by a mean of -1.1% to -1.3% compared to placebo or diet alone (range from -0.5% to -1.8% for daily metformin doses ranging from 500 mg to 3000 mg)
  • Metformin added to other oral therapies lowers HbA1c by a mean of 0.9% compared to placebo
  • Metformin added to insulin therapy lowers HbA1c by a mean of 0.8% compared to insulin alone

Hypoglycaemia

Hypoglycaemia does not occur in patients (with or without diabetes) receiving metformin alone under usual circumstances of use, but could occur when caloric intake  is  deficient,  when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose- lowering agents (such as sulphonylureas and insulin) or ethanol.4 UKPDS 34 reported no cases of severe hypoglycaemia in patients taking metformin alone.12

Weight

In the UKPDS, metformin monotherapy was not associated with weight gain compared to diet alone, in a group over 10.7 years of follow-up.12 Meta-analyses confirm that metformin is weight neutral and may result in modest weight loss (mean -1.2 kg) in some patients.

Although uncommon, metformin can occasionally result in anorexia and marked weight loss (cachexia), particularly in older non-obese patients. Unexplained severe weight loss warrants further investigation to exclude other causes.13 Cessation of metformin therapy leads to weight regain in the absence of other causes.

Microvascular and macrovascular outcome studies

The UKPDS demonstrated significant reductions in diabetes- related deaths, all cause mortality and myocardial infarction in the 342 newly diagnosed obese type 2 diabetes patients randomised to metformin, compared to the 411 obese patients randomised to conventional therapy. Despite a trend, there was no significant reduction in microvascular endpoints.12

In a secondary analysis comparing metformin treatment with sulphonylureas, (chlorpropamide and glibenclamide) and insulin treated obese patients, metformin significantly reduced all cause mortality and strokes, but not myocardial infarction or diabetes- related deaths.12

In a supplementary UKPDS trial, 537 obese and non-obese patients   inadequately controlled with maximal doses of sulphonylureas were randomly assigned to continue sulphonylureas alone or to add metformin therapy.12 The addition of metformin resulted in an unexpected 96% increase in diabetes related deaths. The investigators suggested that this was due to an unexpectedly low mortality in the sulphonylurea-only cohort, and added that an epidemiological assessment in 4416 patients did not show an increased risk in diabetes-related death in patients treated with a combination of sulphonylurea and metformin.12 Nevertheless, these results have raised concerns about the sulphonylurea-metformin combination. Subsequent studies addressing this issue have yielded conflicting results, with some confirming the higher cardiovascular risk with the sulphonylurea-metformin combination.
Subsequent  systematic  reviews, observational, population and prospective studies to clarify the monotherapy benefit of metformin, or its potential cardiovascular risk with sulphonylurea therapy have unfortunately yielded conflicting results, with some reporting lower and others reporting higher risks.11,14,15,16,17,18,19,20,21 The balance of evidence from these, and prospective randomised trials favours cardiovascular safety and probable benefit with metformin monotherapy compared to placebo. The controversy over metformin-sulphonylurea combinations is addressed in the section on sulphonylureas.

Non-glycaemic benefits

Lipids: Metformin has a favourable effect on lipid profile when compared to placebo, sulphonylureas and insulin. It significantly reduces total cholesterol, LDL-cholesterol and triglycerides and increases HDL-cholesterol.11,22,23,24

Cancer: Population studies have shown that metformin is associated with a significant reduction of cancers (breast and prostate, in particular) .23,25 The exact mechanism of tumour suppression is not known.

Heart Failure: Despite the package insert listing heart failure (HF) as a contraindication, metformin several retrospective studies have reported a lower risk of all-cause death and hospitalisations in diabetes patients with HF.26,27,28

Other: Laboratory studies have shown that metformin may have beneficial anti-inflammatory, anti-coagulant and anti-oxidative effects, and may improve endothelial dysfunction and tumour suppression.23,24

Adverse Effects and Special Precautions

Gastrointestinal (GI) side effects: GI disturbances are the commonest side effects of metformin, occurring in 20-30% of users, and is not dose dependent.24,29 These include abdominal pain, nausea, vomiting, diarrhoea, bloating, taste disturbances and appetite loss. GI tolerability is improved when the metformin dose is up-titrated gradually but about 7% of patients using metformin will discontinue therapy due to GI disturbances.29  The extended-release formulation, apart from offering improved compliance with once daily dosing, may also improve GI tolerability in some patients.30 We can find no evidence that film- coated (FC) tablets have any advantage for GI disturbances.

Vitamin B12 (cobalamin or B12) deficiency: The  prevalence  of low serum B12 levels among metformin treated patients (10- 30%) is higher compared to non-diabetic individuals and those not taking metformin, especially  in  those  receiving  higher doses for more than four years.31,32,33,34,35,36 Several researchers have recommended routine screening for B12 deficiency in metformin treated patients, but there are no formal guidelines on the subject.36 The mechanism of B12 deficiency with metformin is unknown. Postulated mechanisms have included bacterial overgrowth, changes in small bowel motility, changes in  bacterial flora, competitive inhibition or inactivation of B12 absorption, or an effect of calcium on cell membranes.37,38  

Recent advances in assessing true B12 deficiency (measuring methylmalonic acid (MMA) and homocysteine), has called into question our assessment of B12 insufficiency and deficiency with metformin. True B12 deficiency should be associated elevated levels of plasma MMA and homocysteine.39 However, in some studies where these were measured, this has not been the case, implying that the potential mechanism for low serum levels of B12 might be an increased uptake and intracellular accumulation of B12.40 This may well explain why previous reports of low levels of serum B12 have usually not been associated with the typical haematological or clinical features of B12 deficiency.23,31,41,42 In controlled clinical trials, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease is very rarely associated with anaemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation.4

The clinical relevance of low serum B12 levels in metformin treated patients warrants further research. Until there is further clarity, routine screening or prophylaxis for B12 deficiency is not recommended; however it should be measured in patients with other risk factors for B12 deficiency, and in those with anaemia or neuropathy. Patients suspected of having clinical B12 deficiency should be evaluated with measurement of serum B12 and at least one marker of intracellular B12 status. If the latter measurement is not available, one should correct the serum deficiency of this inexpensive vitamin using high dose intramuscular injections, as the amount available in general multivitamins (6 μg) may not be enough to correct the biochemical deficiency.43

Lactic acidosis: Biguanides have gained notoriety for lactic acidosis but this appears to have little justification for metformin. Large database analyses have shown that the incidence of lactic acidosis is about 4 cases per 100 000 person years for metformin users versus 5 cases per 100 000 person years for non-metformin users.44,45,46 Metformin therapy has not been associated with higher
rates of lactic acidosis, and may actually improve outcomes, in patients with acute myocardial infarction, heart failure, mild- moderate renal failure and liver disease.28,45,47,48 However, the drug should not be prescribed in patients with the most severe forms of these diseases.

The suggested blanket precaution of withholding metformin therapy prior to and after the administration of iodinated contrast media or general anaesthesia is historical. The reassessment of the risks of lactic acidosis has led the U.S Food and Drug Administration (FDA) to revise these recommendation for iodinated contrast media.49 SEMDSA makes similar recommendations for patients undergoing general anaesthesia as well (see below).

Recommendations for metformin with iodinated contrast media or general anaesthesia

Metformin should be discontinued at the time of or before an iodinated contrast imaging procedure or general anaesthesia in:

  • Patients with an eGFR between < 60 mL/minute/1.73 m2
  • Patients with a history of liver disease, alcoholism, or heart failure
  • Patients who will receive intra-arterial iodinated contrast

Re-evaluate eGFR 48 hours after the procedure; restart metformin if renal function is stable and the patient is eating normally.

Dosing and Prescribing

Head to head comparisons of lower metformin doses (1000 mg per day) versus higher doses (2000 mg per day) demonstrate an additional  significant  reduction  of  HbA1c  by  0.25%.9  There is debate whether doses higher than 2000 mg per day provide additional glucose lowering. However, the cardiovascular disease benefit observed with metformin therapy in the UKPDS study occurred with a mean daily dose of 2550 mg per day, which justifies this as the reasonable maximal therapeutic dose.12 The registered maximum total dose for metformin is 3000 mg/day.

Prescribing in chronic kidney disease

The 2012 SEMDSA Guideline 50 recommended a relaxation of the renal contraindications to metformin therapy based on the evidence available at that time48 (See Table below). The FDA has also relaxed its renal recommendations since 2016.49 Renal function must be monitored at least annually (or more frequently when abnormal) in all patients.

Table: Metformin recommendations in renal disease

Estimated glomerular
filtration rate (eGFR)
 		 Action
 
> 60ml/minute/1.73m2 No renal contraindication to metformin
Monitor renal function annually
45-59 ml/minute/1.73 m2 Continue use but increase monitoring of renal function (every six months)
30-44 ml/minute/1.73 m2 Prescribe metformin with caution
Do not exceed 1 000 mg total daily dose
Closely monitor renal function (every three months)
<30ml/minute/1.73 m2 Stop Metformin

 

Metformin extended-release

The extended-release (XR) formulation of metformin uses a GelShield Diffusion System that allows once daily for doses up to 2000 mg. This reduces the tablet burden and potentially improves adherence and compliance.51 The outer gel layer of the tablet may be excreted intact resulting in patients noticing ghost tablets in the stool. This, by design, is normal.52

When administered once daily it is essential that metformin XR be given with the evening meal as the system relies partly on delayed gastric emptying at night.4,53 Metformin XR offers once daily equivalence for doses ranging from 500 mg to 2000 mg when compared to same daily dose of standard metformin administered two or three times a day.4,54,55 Administering the 2000 mg dose of metformin XR twice a day showed marginally better placebo-corrected HbA1c reductions (-1.2% vs. -0.9%) but this was not statistically significant.55

Although a composite analysis of metformin XR placebo controlled studies show lower rates of diarrhoea, nausea and discontinuations when compared to the composite of standard metformin placebo controlled studies, one cannot draw firm conclusions because they compare different studies.4,56 In two head-to-head studies, adverse events including GI disturbances were similar in patients initiated on standard metformin versus the XR.53,54 However, a number of small studies have shown that when patients with pre-existing GI disturbances with standard metformin are switched to metformin XR, the GI tolerability improves and fewer patients need to discontinue therapy.30,52,57 GI tolerability of metformin XR also appears to be better in Asian patients with low discontinuation rates (2-4%).55,58

Authors: Aslam Amod and Fraser J. Pirie
Editors: Zaheer Bayat, Ankia Coetzee, Nazeer A Mohamed, Joel A Dave, Tanya E Kinvig

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Drugs mentioned

NeoHealth® ID 18982 · updated 10/26/2021