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How metformin repositioned itself as first-line treatment for type 2 diabetes

Jenny Bryan looks at how the results of the UK Prospective Diabetes Study propelled metformin back into the medical limelight

by Jenny Bryan

Jenny Bryan looks at how the results of the UK Prospective Diabetes Study propelled metformin back into the medical limelight

 

The antidiabetes drug, metformin, had already been on the market for 20 years when the results of the UK Prospective Diabetes Study (UKPDS), reported in 1998,1 propelled it into the medical limelight and helped to reposition it as first-line treatment for type 2 diabetes.

Also in its favour were the rising levels of obesity, which gave the weight-neutral metformin a significant edge over the weight-increasing sulphonylureas that had been the traditional mainstay of type 2 diabetes treatment.

Tony Barnett, clinical director of diabetes and endocrinology at Birmingham Heartlands Hospital, recalls that metformin was recognised as a good drug when it first appeared in the late 1970s, but the size of the tablets in the early days, the gastrointestinal (GI) side effects and stories of lactic acidosis raised some concerns.

“Sulphonylureas were the mainstay of treatment because they were rapid-acting and very effective in the short term. Weight gain and some loss of efficacy over time were noted but not considered too big an issue when we only had a limited number of drugs from which to choose,” he explains.

Even before UKPDS was published, metformin had been gaining ground from sulphonylureas for treating obese patients, but the trial highlighted other advantages of metformin treatment.

 

UKPDS and glucose control

UKPDS was designed in the 1970s when type 2 diabetes was still widely called non-insulin dependent diabetes mellitus, and glucose targets were twice what they are today.

The study compared the effects of conventional treatment during the 1980s for newly diagnosed type 2 diabetes (diet followed by drugs if a fasting plasma glucose of <15 mmol/l could not be achieved) with intensive treatment (drugs from the outset to get FPG <6 mmol/L).

Intensive blood glucose control with sulphonylureas or insulin in newly diagnosed type 2 diabetes patients resulted in 12 per cent fewer diabetes-related endpoints (p=0.029) and non-significant reductions in diabetes-related deaths, myocardial infarctions (MI) or all-cause mortality, compared with conventional glucose control.2

Most of the reduction in diabetes endpoints was due to a 25 per cent reduction in microvascular endpoints (eg, retinopathy or nephropathy) (p=0.0099). Intensive sulphonylurea or insulin treatment was associated with more hypoglycaemic episodes and a mean 2.9kg greater weight gain during the 10-year follow up than with conventional treatment.

The main test of the benefits of intensive glucose control with metformin came in a separate part of the study — of newly diagnosed type 2 patients who were overweight.1

This showed that intensive treatment with metformin was associated with a 32 per cent reduction in diabetes-related endpoints (p=0.002) compared with conventional treatment, a 42 per cent reduction in diabetes-related deaths (p=0.017) and a 36 per cent reduction in all-cause mortality (p=0.011). The change in body weight for patients intensively treated with metformin was similar to that in patients who had conventional therapy.

When results of intensive treatment with metformin in overweight patients were compared with overweight patients treated with sulphonylureas or insulin, a greater effect was seen for metformin for diabetes-related endpoints (p=0.0034), all cause-mortality (p=0.021) and stroke (p=0.032), and patients had fewer hypoglycaemic episodes.

“UKPDS showed that metformin was cardioprotective, weight neutral and caused fewer ‘hypos’ than sulphonylurea treatment, but the message still took longer to take hold in some eastern European and Asian countries compared with western Europe and the UK,” Professor Barnett points out.

The British were certainly ahead of the Americans, for whom metformin was still a new drug when UKPDS was published, following its belated arrival on the US market in 1994, owing to lingering concerns about its safety.

 

A chequered start for the biguanides

Metformin is one of the biguanide group of antidiabetes drugs, whose origins go back to the guanidine-containing French lilac, or goat’s rue, that was used in the Middle Ages to treat symptoms of diabetes. Metformin was first described in the scientific literature in 1957.3

But the related compounds, phenformin and buformin, reached the market first and it was their lactic acidosis-causing effects that made physicians so cautious with metformin in the early days and delayed the drug’s arrival in the US.

Metformin improves insulin sensitivity and the glucose-lowering effect is attributed mainly to decreased glucose output from the liver, and to enhanced glucose uptake in the tissues.4

Metformin also has small beneficial effects on lipid levels, notably through triglyceride reduction.4

Although much rarer than with phenformin, lactic acidosis can occur with metformin and the drug is contraindicated in patients with significant renal, hepatic and cardiac impairment. Also, it should be used with care in those with renal insufficiency.

 

Formulation improvements

Metformin has a relatively short half life, estimated at 1.5–4.9 hours,4 so initial formulations required multiple daily dosing, with potential adherence problems. A more recently introduced once-daily formulation may cause fewer GI side effects as well as having potential advantages for adherence.

However, in its recent type 2 diabetes guidelines, the National Institute for Health and Clinical Excellence recommended extended release formulations of metformin only where intolerance to an immediate-release preparation has been documented.5

In the UK, metformin is also available in fixed dose combinations with the glitazones, rosiglitazone and pioglitazone, and the dipeptidyl peptidase-4 (DPP4) inhibitor, vildagliptin. Such formulations can reduce the overall dosing burden for type 2 diabetes patients who may well be on multiple other oral agents for lipid and blood pressure control.

 

Life after UKPDS

Since UKPDS, two large observational studies — in Canada6 and Scotland7 — have confirmed the advantages of metformin over sulphonylureas for reduced risk of cardiovascular morbidity and mortality in type 2 diabetes patients.

In its type 2 diabetes guidelines, NICE pointed out that nearly all the positive data concerning metformin have related to overweight people. However, since most people with type 2 disease are overweight, this makes the data more rather than less relevant.

NICE, therefore, recommended metformin as first-line treatment for overweight and obese type 2 diabetes patients, whose glucose is inadequately controlled with lifestyle interventions, and advised physicians to consider metformin as first-line treatment for patients who are not overweight, unless they do not tolerate it or have hyperglycaemic symptoms that require the rapid response to therapy that a sulphonylurea can provide.5

Since the NICE guidelines were produced, a 10-year follow up of UKPDS has been published.8 This showed that, although differences in glycated haemoglobin levels were lost after the first year, beneficial effects of intensive treatment on cardiovascular outcomes had persisted and were especially evident in the metformin-treated patients.

In the sulphonylurea– insulin group, there was a 9 per cent reduction in any diabetes-related end point (p=0.04), a 24 per cent reduction in microvascular disease (p=0.001), a 15 per cent reduction in MI (p=0.01) and a 13 per cent reduction in death from any cause (p=0.007).  

In the metformin group, there was a 21 per cent reduction in any diabetes-related end point (p=0.01), a 33 per cent reduction in MI (p=0.005), and a 27 per cent reduction in all-cause mortality (p=0.002). The authors concluded that there was a sustained legacy effect of intensive glucose control that was longer than previously reported.

Professor Barnett believes the long-term data from UKPDS underline the importance of tight glucose control as soon as possible after type 2 diabetes is diagnosed.

“If we can protect the vasculature in the first five to 10 years after diagnosis, it looks as though we can get lasting cardiovascular benefits, especially with metformin,” he says.

With metformin recommended as first-line treatment in national and international guidelines, Professor Barnett considers it a tough act to follow and he can understand why pharmaceutical companies have chosen to pursue alternative mechanisms for controlling glucose rather than developing metformin “me-toos”:

“Even if they could develop a drug like metformin, they’d have to carry out large outcomes studies to show it had comparable cardiovascular endpoints, and that would take too long and cost too much money. Metformin has long-term data to show it reduces microvascular and macrovascular endpoints, it’s weight neutral, it doesn’t cause ‘hypos’ and it’s cheap. I think it’s pretty unassailable for the foreseeable future.”

 

References

1.    UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854–65.

2.    UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837–53.

3.    Ungar G, Freedman L, Shapiro S.Pharmacological studies of a new oral hypoglycemic drug. Proceedings of the Society for Experimental Biology and Medicine 1957;95:190–2.

4.    Bailey CJ, Turner RC. Metformin. New England Journal of Medicine 1996;334:574–9.

5.    National Collaborating Centre for Chronic Conditions. Type 2 diabetes: national clinical guideline for management in primary and secondary care (update). London: Royal College of Physicians; 2008.

6.    Johnson JA, Simpson SH, Toth EL, Majumdar SR. Reduced cardiovascular morbidity and mortality associated with metformin use in subjects with type 2 diabetes. Diabetic Medicine 2005;22:497–502.

7.    Evans JM, Ogston SA, Emslie-Smith A, Morris AD. Risk of mortality and adverse cardiovascular outcomes in type 2 diabetes: a comparison of patients treated with sulfonylureas and metformin. Diabetologia 2006;49:930–6.

8.    Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow up of intensive glucose control in type 2 diabetes. New England Journal of Medicine 2008;359:1577–89.

Citation: The Pharmaceutical Journal URI: 10964069

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