Metformin clinical studies

Clinical studies indicate a lipid-lowering effect of biguanides (metformin), particularly in patients with hyperlipoproteinaemia type IV (Gustafson et al., 1971 Descovich et al., 1978). A slight reduction in total serum cholesterol was also noted in non-diabetic hyperlipidaemia by Aro et al. (1985). In a double-blind cross-over study of 9 weeks duration with 1 or 2g metformin, cholesterol was reduced from 328 mg per 100 ml to 313 mg per 100 ml... 

Metformin used as monotherapy reduced plasma glucose levels in normal-weight Type-II diabetics considerably (172 to 103 mg per 100 ml), whereas serum insulin was unchanged over a 3 month period (Jackson et al., 1987). The hypoglycaemic action of metformin became fully effective within 2-3 weeks of treatment. Clinical studies point out that gastrointestinal side effects can be avoided if medication is started slowly and taken postprandially (Fig. 25). 

A reduction in hyperinsulinaemia caused by metformin has been demonstrated in several clinical studies (Schatz et al., 1972 Hausmann and Schubotz, 1975 Ferlito et al., 1983). Sensitivity to insulin was also found to be increased after short-term biguanide treatment with phenformin, buformin and metformin. Biguanides increase both sensitivity to insulin and responsiveness in muscle and to a lesser extent in adipose tissue (Bailey et al., 1984). 

Clinical studies have been reported on the effects of hypogly cemlc biguanides on weight reduct ion.77-79 Recent studies suggest that tolerance develops within 16-32 weeks after Metformin therapy.77... 

Nine Metformin combinations with these drags were used in protracted antidiabetic therapy in mrrlticenter clinical studies with durations of 16 to 26 weeks and 328 to 1250 patients. 

An average increase in the hypoglycemic activity of a combination of two drugs compared with Metformin perpet se, according to clinical study data... 

The role of concomitant medication is not clear due to the lack of good clinical studies [9]. It is recommended to stop nonsteroidal anti-inflammatory drugs, metformin for the risk of lactic acidosis with decreasing renal function, and diuretics. Usually, diuretics used for long-term treatment of hypertension and inhibitors of the renin-angiotensin system should not be discontinued. 

A 1-year randomized double-blind study in 639 type 2 diabetic patients [13] showed clinically equivalent improvements in glycaemic control for the combination therapy of metformin and SU (HbAlc decrease 1.36%) or pioglitazone and SU (HbAlc decrease 1.20%). Pioglitazone addition to SU significantly reduced triglycerides (-16% vs. -9% p = 0.008) and increased HDL-cholesterol (14% vs. 8% p < 0.001) compared with metformin... 

Rosiglitazone has been studied in combination with acarbose, digoxin, metformin, nifedipine, ranitidine, warfarin, and oral contraceptives [67,72] There have been no clinically significant effects on the pharmacokinetics of any of these agents in combination with rosiglitazone. 

In a placebo-controlled study in 12 healthy subjects cefalexin 500 mg increased the AUC and maximum serum levels of a single 5(X)-mg dose of metformin by 24% and 34%, respectively. Cefalexin reduced the renal clearance of metformin by 14% by inhibiting metformin tubular secretion via the organic cation system. The clinical relevance of these small changes is uncertain, but they could be greater with longer-term use. The authors recommend that patients receiving metformin with cefalexin should have metformin levels monitored or an alternative antibacterial to cefalexin should be considered. However, based on the available evidence this seems somewhat overcautious. 

Memantine is predicted to interact with other drugs that use the same renal cationic transport system leading to increased levels of memantine and/or the other drug. The manufacturer lists cimetidine, ranitidine, hydrochlorothiazide, metformin, procainamide, qninidine, qninine and triamterene as possible examples. However, in an interaction study, the concurrent use of memantine and hydrochlorothiazide/triamterene did not result in any change in the steady-state AUC of memantine or triamterene, and the AUC of hydrochlorothiazide showed a modest reduction of about 20%. This degree of change is unlikely to be clinically relevant. Therefore, whether any clinically important interactions occur via this mechanism remains to be established. 

Preiss D, Sattar N, McMurray JJ (2011) A systematic review of event rates in clinical trials in diabetes mellitus the importance of quantifying baseline cardiovascular disease history and proteinuria and implications for clinical trial design. Am Heart J 161 210-219 Phung OJ, Schwartzman E, AUen RW, Engel SS, Rajpathak SN (2013) Sulphonylureas and risk of cardiovascular disease systematic review and meta-antilysis. Diabet Med 30 1160-1171 Roumie CL, Hung AM, Greevy RA et al (2012) Comparative effectiveness of sulfonylurea and metformin monotherapy on cardiovascular events in type 2 diabetes mellitus a cohort study. Ann Intern Med 157 601-610... 

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