David Levy, MD, FRCP
The pharmacological management of blood glucose in type 2 diabetes remains the most contentious area of diabetes management, and although until relatively recently in the USA the only agents to treat blood glucose were insulin and sulphonylureas, this limited repertoire in no way inhibited the controversy, which started with the University Group Diabetes Project (UGDP) conclusions about the possible hazards of sulphonylureas in the late 1960s . Perhaps scarred by the UGDP experience, and certainly by the disastrous introduction elsewhere of phenformin, metformin was available in many countries for a long time before it was licensed in the USA as recently as 1995. UKPDS, reporting in 1998, used only metformin, sulphonylureas and insulin (with a small acarbose substudy). Multiple classes of agents are now available, and these are likely to increase further, though certainly at a much slower pace than over the past decade….
The furious rate of pharmacological innovation has not been matched by RCTs powered to study significant diabetes outcomes that are important to patients. Until recently regulatory requirements were limited to acute safety and demonstration of glycemic non-inferiority, and very few studies lasted over 6 months, always contentious in a condition that spanned decades, not months. In 2007 the controversy over the cardiovascular safety of rosiglitazone stimulated the Food and Drug Administration in the USA to require demonstration of cardiovascular safety before drug approval, but this is quite different from the widespread practice of claiming potential non-glucose benefits on the basis of small, often mechanistic studies. Other than the tentative UKPDS data relating to the cardiovascular advantage of metformin (and recent epidemiological evidence of its possible cancer-reducing properties), there is even now little evidence for the benefit of specific medication in relation to significant diabetes outcomes. The recent glycemic/macrovascular studies reviewed in Chapter 5 have reinforced this view, and moreover have relegated glycemic control in established type 2 diabetes from the position of primacy it enjoyed for decades to be replaced by a more comprehensive view of the metabolic disorder. Unfortunately, however, because we do not have agents that impact on multiple metabolic problems we necessarily end up considering glycemia in isolation.
Nevertheless, the drugs available to treat blood glucose levels in type 2 diabetes work through independent mechanisms. In a heterogeneous condition such as type 2 diabetes, which can be intercepted along a time continuum of more than 50 years, from pre-diabetes to advanced tissue complications, with different contributions of insulin deficiency and insulin resistance, the availability of these different agents should be regarded as a positive challenge to match where possible patients to medication and not vice versa. The discussion below attempts to discuss pharmacological treatments in this way, rather than using a guidelines-based approach; the controversies here too frequently revolve around the guidelines themselves, rather than the risks and benefits of specific agents.
Metformin (BNF, section 126.96.36.199)
A development of the plant-derived guanidine (occurring in goat’s rue/French lilac, Galega officinalis), metformin was first used clinically in the late 1950s. Established as a first-line treatment for overweight type 2 diabetes patients in the UKPDS, it has been formally trialled and is licensed for use in dual therapy with all other agents, including insulin; with the sulphonylureas, it has become the standard against which all new agents are initially subjected to RCTs.
Mechanism of action and non-glycemic effects
Metformin has peripheral effects only, and does not stimulate insulin secretion, though it requires some insulin for its peripheral actions. It suppresses hepatic glycogenolysis and gluconeogenesis, and stimulates insulin-mediated muscle and adipose tissue glucose disposal. There has been much interest recently in its cellular actions, in particular its effect on AMP-activated protein kinase (AMPK), an important component of an intracellular energy-sensing cascade. The intriguing and consistent epidemiological link between metformin use and decreased risk of developing some cancers, for example breast cancer, may be AMPK-mediated (against a background of generally increased cancer risk in type 2 diabetes patients). Metformin also has minor but beneficial effects on the following:
- Lipids, especially lowering triglycerides, VLDL, and fatty acids (a significant effect only in people with poor glycemic control).
- Blood pressure (not consistent).
- Coagulation factors (e.g. decreased plasminogen activator inhibitor 1).
- Weight: metformin use in UKPDS was associated with weight gain of about 2 kg, compared with about 5 kg in insulin- or sulfonylurea-treated patients. ADOPT (2006) found modest weight loss, about 3 kg over 5 years, most occurring in the first year. Metformin attenuates the weight-increasing effects of sulphonylureas.
It is safe in adult doses in children with type 2 diabetes, and at a dose of 750 mg daily, with or without intensive lifestyle intervention, reduces weight without hypoglycemia in non-diabetic patients with schizophrenia starting on antipsychotic medication . It does not cause hypoglycemia in monotherapy and perhaps this, together with its relatively slow onset of action, certainly in comparison with sulphonylureas, has led to the view that it is a ‘weak’ antihyperglycemic agent; there is, however, no evidence that it is any less potent than other drugs used in type 2 diabetes. Metformin treatment should always be maintained or added to existing insulin therapy: a recent trial over 4 years showed that it:
- prevented weight gain (3.1 kg loss);
- reduced mean HbA1c by 0.4% (4 mmol/mol);
- reduced insulin requirements by 20 units/day;
- reduced macrovascular events by 40%, partly accounted for by the weight loss (though there was no effect on microvascular events, out- comes echoing those of UKPDS) .
Metformin is effective in the dose range 500–2000 mg daily. There is little evidence for increased efficacy at doses over 2 g/day, and although it is frequently prescribed at 3 g/day, side-effects are more likely. This practice also illustrates the general point that once maximum doses of a drug are being approached, serious consideration must be given to choosing the next. Even the immediate-release forms require only twice-daily dosing. Unlike several other agents, metformin has a good dose–response relationship, and even if taken at only 500 mg/day, for example in people who suffer gastrointestinal side-effects at higher doses, it can be expected to reduce HbA1c by about 0.5% (5 mmol/mol). Modified-release preparations (e.g. Glucophage SR in the UK) are designed for once-daily dosing, and clinically markedly reduce gastrointestinal side-effects in patients intolerant of immediate-release metformin. In the UK there are fixed-dose combinations of (immediate-release) metformin with pioglitazone and the DPP-4 inhibitors vildagliptin and sitagliptin. The fixed-dose sulphonylurea/metformin combinations available in the USA are not generally used in the UK.
Metformin should be taken with or immediately before meals, starting at 500 mg once or twice daily, and titrated to maximum effect, using once or twice-weekly fasting home blood glucose monitoring. Gastrointestinal side-effects (dyspepsia, nausea, diarrhoea and flatulence) are common in the first 1–2 weeks of treatment, but fewer than 5% of patients cannot tolerate metformin at any dose, and this proportion may be even lower with the use of modified-released preparations. Delayed side-effects are occasionally seen with immediate-release metformin, even after a period during which it has apparently been well tolerated. Stop treatment for a short time, or replace with modified-release metformin before embarking on gastrointestinal investigations. It has a slow onset of action, with a maximum effect around 4 months, and a sulphonylurea should be used initially with metformin in a newly diagnosed patient with symptomatic hyperglycemia.