Fortunately, evidence showed that metformin was not only effective in preventing hyperglycaemia and countering insulin resistance but that the risk of lactic acidosis was considerably smaller than that of its counterparts, which led to renewed interestin its use as a treatment for diabetes.²

Metformin was officially launched on the market in 1959 in France, Great Britain, Sweden, South Africa, and Malaysia. By 1968, metformin was being used in about 40 countries worldwide with the exception of Eastern European countries and the North American continent. Metformin was only approved by the United States Food and Drug Administrationfor the treatment of T2DM in 1994.^1,2

One of the most influential studies that showed the efficacy and safety of long-term metformin use was the United Kingdom Prospective Diabetes Study, published in TheLancet in 1998. The study found that early use of metformin in obese patients with T2DM led to a reduction in stroke, all-cause mortality, and total diabetes endpoints compared to insulin and sulfonylurea.²

Metformin reduces BG levels by decreasing glucose production in the liver, decreasing intestinal absorption, and increasing insulin sensitivity. Metformin decreases both basal and postprandial BG levels.³

Furthermore, metformin is associated with long-term benefits, including reduced risk of cardiovascular disease and neoplasms.⁴

Why the need for extended-release metformin?

It is well-known that non-adherence results in sub-optimal outcomes in patients with chronic disease. Non-adherence is a major challenge in the effective management of T2DM and a key factor why many patients do not achieve their treatment goals. Non-adherence is associated with poor glycaemic control, increased incidence of hospital admissions, long-term complications, increased mortality rates, and increased healthcare costs.⁵ 

One of the most common reasons why some patients do not adhere to treatment with conventional metformin immediate release (IR) formulations, is gastrointestinal (GI) intolerance. GI intolerance, including diarrhoea, nausea, and vomiting, has been reported in up to 30% of patients treated with metformin.^4,5

Metformin has a complex relationship with the GI tract. It is predominantly absorbed from the small intestine, with a bioavailability of ~60%. However, it also exerts many effects on the intestine. Multiple hypotheses for the mechanism of GI intolerance to metformin have been proposed, including abnormal uptake, increased lactate production, and accumulation of serotonin, histamine or bile acids.⁶

Although GI side-effects tend to resolve with continued use of metformin, it has been reported that chronic diarrhoea led to discontinuation of metformin IR in 75% of patients, resulting in discontinuation and non-adherence rates as high as 46%.⁷

Based on the positive results of studies investigating extended-release (ER) formulations in other diseases, it was postulated that an ER metformin formulation has the potential to improve patient adherence. Metformin ER as associated with a simpler dosing (once daily) regimen and increased GI tolerability.⁸

GI tolerability is improved because maximum plasma metformin concentrations are reached more slowly with the ER formulation compared with conventional IR metformin, although both provide similar exposure at a given total daily dose.⁸

What about glycaemic control?

Derosa et al (2017) compared the GI tolerability and glycaemic control effects of metformin IR and ER formulations in patients with T2DM not well controlled on diet alone (n=253).⁹

Patients were randomised to metformin IR or ER for a period of six months at the maximum tolerated dose. The average dose of metformin IR used was 2000±1000mg/day, while that of metformin ER was 1000±500mg/day.⁹

The team evaluated body weight, HbA1c, fasting and post-prandial glucose, fasting plasma insulin (FPI), homeostasis model assessment insulin resistance (HOMA-IR), lipid profile, and levels of some adipocytokines, including tumour necrosis factor-α (TNF-α), high-sensitivity C-reactive protein (hs-CRP), visfatin (a protein that is preferentially produced in visceral adipose tissue), as well as vaspin (a visceral adipose tissue-derived serpin [family of protease inhibitors], with insulin-sensitising activity, mainly secreted by the visceral adipose tissue).At baseline and after six months, patients were asked to assess treatment satisfaction.⁹

After six months, both formulations gave a similar reduction in body weight and body mass index, however, metformin ER gave a greater improvement in glycaemic control, FPI, and HOMA-IR, compared with both baseline and metformin IR.⁹

A reduction in total cholesterol and low-density lipoprotein cholesterol was observed with metformin ER compared with the IR formulation. Levels of TNF-α, hs-CRP, and vaspin were reduced by metformin ER but not by the IR formulation. Metformin ER also raised the levels of visfatin.⁹

Adverse events (nausea, vomiting, meteorism [the accumulation of gas in the GI tract], and malaise) were more common with metformin IR, both after three months and after six months.9

According to the authors, the superiority of metformin ER could be due to improvements inBG levels (the IR formulation exhibited intermittent BG control), while better or improved lipid and other levels may be the consequence of these BG improvements. In terms of patient satisfaction, metformin ER outperformed the IR formulation.⁹

Patient selection

In South Africa, metformin ER is approved for adult patients with T2DM, especially in those who are overweight when diet and exercise alone do not result in adequate glycaemic control. Metformin ER may be used as initial monotherapy or in combination with other oral antidiabetic agents or insulin.¹⁰

Although both metformin IR and ER formulations are widely used in clinical practice, the  rationale for choosing one formulation over the other has not been widely examined, found Tan et al.⁴

Guidance on which formulations to use is largely absent in clinical practice guidelines, with the exception of the National Institute for Health and Care Excellence guideline, which recommends the use of metformin ER in patients intolerant (defined as GI side-effects such as nausea, abdominal pain, bloating or diarrhoea) to metformin IR.^4,6 

McCreight et al state that intolerance may be overcome by the gradual up-titration of the dose after initiation of treatment, or the use of an ER formulation. In some instances, the use of an ER formulation can resolve intolerance symptoms. However, in 5% of patients,  symptoms are so severe that they opt to discontinue treatment.⁶

Another strategy is to switch to other antidiabetic agents. However, Nabrdalik et al caution that alternative oral antidiabetic agents are either expensive (eg newly marketed agents) or may cause hypoglycaemia (eg sulfonylurea), which is especially dangerous in elderly people. Additionally, there are not enough high-quality data regarding differences in clinical outcomes (especially with long-term use) or cost-effectiveness of alternatives to metformin to be able to unequivocally support any of them.¹¹

Both the American Diabetes Association and the European Association for the Study of Diabetes recommend lowering the metformin dose when GI symptoms occur. Symptoms will resolve over time.¹¹

Tan et al recommend that clinicians consider patient preference when deciding on the type of formulation to prescribe and should consider metformin ER for patients who prefer once-daily dosing.⁴

The selection of metformin preparation thus represents a good example of patient-centred care, where shared decision-making can be beneficial. Clinicians should also consider which patients will benefit most from once-daily administration. For example, adults in full-time employment may benefit from less frequent dosing, while it may not be necessary to prescribe metformin ER to patients with polypharmacy.⁴

Conclusion

Metformin (in the absence of contraindications) can be initiated, concurrent with lifestyle intervention, at the time of diagnosis. Studies show that metformin ER improves patient adherence, resulting in greater glycaemic control, and in turn, improves outcomes and lowers healthcare usage and costs. GI intolerance tends to improve over time.

Metformin ER formulation seems to be more effective than metformin IR in improving glucose control, lipid profile, and levels of some adipocytokines in patients with T2DM.

References