Metformin efficacy and tolerance in obese non-insulin dependent diabetics: a comparison of two dosage schedules

Summary

A comparative open study of metformin unit doses of 500?mg and 850?mg was carried out in 64 obese, non-insulin dependent diabetics on 1.5 to 3?g metformin daily. Glycaemic response, blood lactate, plasma metformin concentrations and tolerance for metformin were assessed. On changing from a 500?mg unit dose to an equivalent total dose of metformin using the 850?mg preparation, there were no significant changes in the random blood glucose, glycated haemoglobin, or blood lactate concentrations. Metformin plasma concentrations remained unchanged except for patients transferred from 1.5 to 2.0?g daily to 850?mg twice daily; in these patients plasma concentrations increased from 1.83±0.87 to 2.50±0.89 μg/l (p < 0.01). Seven patients (3 asymptomatic and 4 with background symptoms) became intolerant of the 850?mg regimen and required to return to the 500?mg dose regimen. After exclusion of patients intolerant of the 850?mg dose regimen (11%), the remaining patients noted no significant change in symptoms and 28% of all patients transferred to the 850?mg dose unit indicated an overall preference for this regimen.     

The effect of metformin treatment on gastric acid secretion and gastrointestinal hormone levels in normal subjects

Summary Gastric acid secretion and gastrointestinal hormone levels were measured in healthy non-diabetic subjects after metformin treatment (1.5 g/day). The maximum acid output was increased from 15.7 ±3.9 mmol/h (mean±SEM) to 30.0±7.1 mmol/h (p < 0.05) and the peak acid output was increased from 16.4±4.1 mmol/h to 31.7±7.2 mmol/h (p < 0.05) after two weeks treatment. Serum insulin, gastric inhibitory polypeptide and secretin levels were normal. After treatment for one week, however, there was a significant increase in fasting vasoactive intestinal peptide (VIP) from 83±6 ng/l to 102±9 ng/l (p < 0.02) and in stimulated VIP from 58±5 ng/l to 79±5 ng/l (p < 0.05). Stimulated glucagon-like immunoreactivity (GLI) was also increased from 82±10 ng/l to 174±24 ng/l (p < 0.01) after one week's treatment. It is suggested that metformin acts as a eak histamine agonist.     

The effects of oral anti-hyperglycaemic medications on serum lipid profiles in patients with type 2 diabetes

Aim:  Patients with type 2 diabetes often have dyslipidaemia, putting them at risk of cardiovascular disease, and are frequently treated with oral anti-hyperglycaemic medications (OAMs). This review compares the effects of OAMs on serum lipids [total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs) and free fatty acids (FFAs)] in patients with type 2 diabetes.
Methods:  medline was searched for entries indexed from January 1966 to November 2002; search terms included the names of OAMs and serum lipids, limited to English language and human subjects. We selected clinical studies in type 2 diabetes of OAM monotherapy that included serum lipid data, treated all patients in a treatment group with the same drug, used therapeutic OAM doses not higher than the maximum recommended in the USA, compared therapy with baseline or placebo and specified statistical tests used. One unblinded investigator selected studies for inclusion. Data reported include number of patients, study length, OAM dose, serum lipid data at baseline and endpoint, p-values and statistical tests.
Results:  Data on the serum lipid effects of sulphonylureas, repaglinide, nateglinide and miglitol were inconclusive. Acarbose increased HDL-C and decreased LDL-C and voglibose reduced TC. Metformin at higher doses reduced TC; data on its effects on other lipids were inconclusive. Rosiglitazone increased LDL-C, HDL-C and TC and reduced FFAs but had no effect on TGs. Pioglitazone increased HDL-C and reduced TGs and FFAs but did not affect LDL-C or TC.
Conclusions:  Lipid changes as a result of improved glycaemic control are not uniform findings associated with anti-diabetic therapy. Only metformin, acarbose, voglibose, rosiglitazone and pioglitazone had significant effects on the lipid profile. These effects should be considered when selecting OAMs for patients with type 2 diabetes.     

CARDIOVASCULAR EFFECTS OF ORAL HYPOGLYCAEMIC DRUGS

1. There is increasing evidence that sulfonylurea and biguanide oral hypoglycaemic drugs have cardiovascular effects and influence risk factors for cardiovascular disease in patients with non-insulin-dependent diabetes because of actions that are unrelated to alterations in glycaemic control. 2. While sulfonylureas may have anti-arrhythmic effects following myocardial ischaemia, there is concern that their action on vascular ATP-sensitive potassium channels may contribute to elevated blood pressure and enhanced vascular responsiveness. 3. In contrast to sulfonylureas, metformin (a biguanide) appears to reduce blood pressure and have beneficial effects on plasma lipoproteins by reducing low-density lipoprotein cholesterol and possibly increasing high-density lipoprotein cholesterol levels. 4. The pharmacological basis and clinical significance of these effects of sulfonylureas and biguanides require further investigation.     

Inhibition of bile salt absorption by blood-sugar lowering biguanides

Summary The effect of blood sugar lowering biguanides (phenethyl-, butyl- and dimethylbiguanide) upon jejunal and ileal transport of bile salts (tauro- and glycocholate) was tested in rat small intestine by an in vitro technique. Biguanides inhibited active transport of bile salts in the ileum, but did not affect diffusional absorption of bile salts in the jejunum. The inhibitory effect was time-dependent and not reversible under in vitro incubation conditions, suggesting that biguanides must enter intestinal mucosal cells in order to exert their inhibitory action on active transport of glucose analogues, amino acids, calcium and bile salts. Since biguanides achieve high tissue concentrations in the small intestine even after parenteral administration, inhibition of ileal bile salt reabsorption by biguanides could possibly explain the lipid- and cholesterol-lowering effect of these oral antidiabetic drugs.