Biguanides

Observational studies

In a large American study in 3234 non-diabetic people with a raised fasting blood glucose and a raised blood glucose 2 hours after a glucose load, diabetes occurred in 7.8 cases per 100 participants per year after a mean treatment period of 2.8 years with metformin 850 mg bd; there were 11 cases per 100 participants per year after placebo and 4.8 cases per 100 participants per year after a life-style intervention program [ ]. Gastrointestinal symptoms were most frequent in those who took metformin. In a later study, glucose tolerance tests were performed after a 14-day washout period of metformin and placebo in the patients who had not developed diabetes [ ]. Diabetes was more frequently diagnosed in the metformin group, but when the diabetes conversions during treatment and washout were combined, diabetes was still significantly less common in the metformin group.

Comparative studies

Metformin and troglitazone have been compared in 21 patients with type 2 diabetes unresponsive to glibenclamide 10 mg bd [ ]. Metformin stabilized weight and reduced adipocyte size, leptin concentrations, and glucose transport. GLUT1 and GLUT4 in isolated adipocytes were not changed. Insulin-stimulated whole-body glucose disposal rate increased by 20%. Troglitazone caused increases in body weight, adipocyte size, leptin concentrations, and basal and insulin-stimulated glucose transport. GLUT4 protein expression was increased two-fold and insulin-stimulated whole-body glucose disposal rate increased by 44%.

Placebo-controlled studies

In a placebo-controlled study in 40 patients with impaired glucose tolerance metformin 500 mg bd for 6 months increased insulin-stimulated glucose metabolism by 20% with minimal improvement in glucose tolerance; this effect was maintained after 12 months [ ].

In 82 children aged 10–16 years with type 2 diabetes, metformin lowered HbA _1c and fasting blood glucose compared with placebo [ ]. More patients who took placebo had to drop out because more medication was necessary. Most of the adverse events (abdominal pain, diarrhea, nausea, vomiting) occurred during metformin treatment.

Combinations of hypoglycemic drugs

The different mechanisms of action of the various classes of hypoglycemic drugs makes combined therapy feasible: the sulfonylureas and meglitinides stimulate insulin production by different mechanisms, the biguanides reduce glucose production by the liver and excretion from the liver, acarbose reduces the absorption of glucose from the gut, and the thiazolidinediones reduce insulin resistance in fat. It is not necessary to wait until the maximal dose of one drug has been reached before starting another. However, sulfonylureas and meglitinides should no longer be used when endogenous insulin production is minimal. Combinations of insulin with sulfonylureas or meglitinides should only be used while the patient is changing to insulin, except when long-acting insulin is given at night in order to give the islets a rest and to stimulate daytime insulin secretion.

This subject has been reviewed in relation to combined oral therapy. In a systematic review of 63 studies with a duration of at least 3 months and involving at least 10 patients at the end of the study, and in which HbA _1c was reported, five different classes of oral drugs were almost equally effective in lowering blood glucose concentrations [ ]. HbA _1c was reduced by about 1–2% in all cases. Combination therapy gave additive effects. However, long-term vascular risk reduction was demonstrated only with sulfonylureas and metformin.

In a placebo-controlled study in 116 patients who responded insufficiently to metformin 2.5 g/day, rosiglitazone 2 or 4 mg bd was added for 26 weeks [ ]. HbA _1c and fasting plasma glucose improved and hemoglobin fell. Edema was reported in 5.2% of the patients who took rosiglitazone and two patients withdrew because of headache.

Metformin has been reviewed, with special attention to therapy in combination with other hypoglycemic drugs [ ]. The general conclusions were that it can effectively lower HbA _1c concentrations, Improve lipid profiles, and improve vascular and hemodynamic indices.

Contraindications

Contraindications to treatment with biguanides are:

• 1.

  impaired renal function (serum creatinine may not be a sufficient indicator; creatinine clearance must be estimated);

• 2.

  an increased risk of impaired renal function in intercurrent diseases with fever, congestive heart failure, or infections of the urinary tract, during treatment with diuretics, intravenous pyelography, or severe dieting;

• 3.

  states associated with tissue hypoxia (respiratory insufficiency, heart insufficiency, anemia, and peripheral vascular disease);

• 4.

  hepatitis and hepatic cirrhosis;

• 5.

  excessive use of alcohol;

• 6.

  wasting diseases;

• 7.

  preoperatively and postoperatively.

In general, biguanides should not be used in people aged over 75 years [ ].

Of 308 patients 73% had contraindications, risk factors, or intercurrent illnesses necessitating withdrawal of metformin [ ]: 19% had renal impairment, 25% heart failure, 6.5% respiratory insufficiency, and 1.3% hepatic impairment; 51% had advanced coronary heart disease, 9.8% atrial fibrillation, 3.3% chronic alcohol abuse, 2% advanced peripheral arterial disease, and 0.7% were pregnant.

Four fatal cases in 18 months in a community hospital were reported; three had clear contraindications [ ]: a 45-year-old woman with liver cirrhosis, a 64-year-old man with coronary artery disease, and a 65-year-old man with peripheral arterial disease and asthma; a 74-year-old man had renal insufficiency.

In a retrospective study of 1874 patients with type 2 diabetes taking metformin, 25% had contraindications, including acute myocardial infarction, cardiac failure, renal impairment, and chronic liver disease [ ]. However, contraindications often did not lead to withdrawal of metformin: in 621 episodes, only 10% stopped taking it. Only 25% and 18% stopped taking metformin when they developed renal impairment or myocardial infarction, respectively. One patient developed lactic acidosis, but this may have been a consequence of myocardial infarction.

Contraindications to the use of metformin have been debated [ ], in relation to the reduced number of cardiovascular events seen in the obese patients treated with metformin in the UK Prospective Diabetes Study (UKPDS) [ ]. The authors stated inter alia that lactic acidosis is rare (1–5 cases per 100 000) and that in the absence of renal insufficiency accumulation of metformin is rare. Moreover, the authors of a Cochrane systematic review concluded that treatment with metformin was not associated with an increased risk of lactic acidosis [ ]. Tissue hypoxia is often the trigger for metformin accumulation. Many physicians do not comply with the official British contraindications. The authors suggested the following necessary precautionary measures:

• withdraw the drug during periods of suspected tissue hypoxia (myocardial infarction and sepsis);

• withdraw 3 days after the administration of an iodine-containing contrast medium and 2 days before general anesthesia;

• check renal function in both cases before metformin is restarted;

• serum creatinine over 150 μmol/l is a contraindication.

To this one could add that drugs that compromise renal function should not be combined with metformin.

Others have stated that metformin is contraindicated when serum creatinine concentrations are over 133 μmol/l (1.5 mg/dl) in men or 124 μmol/l (1.4 mg/dl) in women [ ].

However, creatinine is sometimes a poor predictor of renal function. For example, it must be related to muscular mass and the “normal” serum creatinine may be too high in a person of 50 kg and little muscle. It is therefore better to use creatinine clearance below 60 ml/min as a criterion.

For some reactions the usefulness of withdrawing metformin before operations, except in emergency, cardiac, and vascular surgery and in operations requiring deliberate hypotension, has been discussed [ ] and the creatinine threshold value has been discussed [ ].

Reconsideration of contraindications has also been proposed in a prospective study in patients with serum creatinine concentrations of 130–220 μmol/l and coronary heart disease (n = 226), congestive heart failure (n = 94) and chronic obstructive pulmonary disease (n = 91). Half of the patients continued to take metformin and the other half stopped [ ]. Bodyweight and HbA _1c increased over 4 years in those who stopped taking metformin. Lactic acid concentrations were similar in the two groups. Deaths were similar in the two groups (62 and 64 respectively). The incidences of myocardial infarction, all cardiovascular events, and cardiovascular mortality were the same. Changes in additional therapy were only significant for insulin (30% versus 45% respectively) and diet (25% versus 0% respectively).

Cardiovascular

The cardiovascular effects of metformin have been reviewed [ ]. Metformin reduces blood pressure and has a beneficial effect on blood lipid concentrations.

In a retrospective study, cardiovascular deaths in patients using a sulfonylurea only (n = 741) were compared with deaths in patients taking a sulfonylurea + metformin (n = 169) [ ]. In patients taking the combination the adjusted odds ratios (95% CI) were:

• overall mortality 1.63 (1.27, 2.09);

• mortality from ischemic heart disease 1.73 (1.17, 2.55);

• stroke 2.33 (1.17, 4.63).

The patients taking the combination were younger, had had diabetes for longer, were more obese, and had higher blood glucose concentrations.

Nervous system

Two cases of encephalopathy, which improved after metformin was withdrawn, have been reported [ ].

• One week after starting to take metformin 850 mg in divided dose a 74-year-old man became confused and disoriented and had speech abnormalities and bilateral horizontal gaze-evoked nystagmus. Electroencephalography suggested a toxic-metabolic encephalopathy. Metformin was withdrawn, he became alert and oriented, and the electroencephalogram normalized.

• A 67-year-old man took metformin for 4 years after which repaglinide 3 mg/day was added. After 3 weeks he became confused and had general diffuse myoclonic jerks and bilateral asterixis. The electroencephalogram showed a general slowing. He improved after stopping both hypoglycemic drugs and became asymptomatic within 3 days. Metformin was reinstituted, as repaglinide was considered to have caused the changes. However, within 2 days the same clinical picture evolved. After withdrawal of metformin he normalized progressively and he had no confusion over the next year.

Sensory systems

Altered vision has been attributed to metformin [ ].

• A 62-year-old man with diabetes was given metformin 750 mg bd and his blood glucose concentration fell from 22 to 15 mmol/l within 4 days. The dose of metformin was increased to 850 mg bd and the blood glucose concentration fell to 8.7 mmol/l over the next week. Within 2 days of starting therapy his vision became blurred. Slit lamp examination 2 weeks later showed cracked shaped lines on the lens. The cracks resolved spontaneously by 3 months.

Although the timing made metformin a possible candidate in this case, it is much more likely that the problem was caused by rapid changes in blood glucose concentration and the associated fluid shifts.

Metabolism