The Effects Of Metformin And Diabinese On Female Sex Hormone Of Type 2 Diabetes Mellitus Patients
[UNIVERSITY OF ILORIN TEACHING HOSPITAL (UITH), ILORIN, KWARA STATE]

2.3.1        METFORMIN USE AS FIRST-LINE THERAPY
As noted, metformin is preferred by most guideline committees as the initial therapy in individuals not able to achieve glycaemic targets despite diet and other lifestyle interventions (Williams, 2014). So widespread is its current use that virtually all diabetes drug development programmes include a series of studies involving the addition of the investigational compound to background metformin therapy. The drug’s efficacy was best illustrated by DeFronzo et al, in a 2005 report. In ‘protocol 1’ of this study, 289 obese participants with uncontrolled diabetes, treated with diet alone, were assigned to receive metformin or placebo (forced titration from 850 mg daily to 850 mg thrice daily if fasting plasma glucose exceeded 7.8 mmol/L and side effects were tolerable).
At 29 weeks, metformin resulted in a lower mean fasting plasma glucose of 10.6 vs 13.7 mmol/l with placebo (p < 0.001); compared with corresponding baseline values, fasting plasma glucose was reduced by 2.9 mmol/l in the metformin group and increased by 0.3 mmol/l in the placebo group. With metformin, mean HbA1c decreased from 8.4% (68.3 mmol/mol) to 7.1% (54.1 mmol/mol), while, with placebo, it increased from 8.2% (66.1 mmol/mol) to 8.6% (70.5 mmol/mol; p < 0.001) The drug’s efficacy is dose-dependent, as demonstrated by Garber and colleagues, who investigated the pharmacodynamic effects with different dosing regimens vs placebo, over 14 weeks in 451 individuals with type 2 diabetes. The minimal efficacious dose of metformin was 500 mg daily and maximal efficacy was achieved at a dose of 2000 mg daily. While some patients may benefit from doses as high as 2500 mg daily, in this study, overall, there were no major differences in fasting plasma glucose and HbA1c when compared with the proximate lower daily dose of 2000 mg.
At 500 mg, metformin decreased fasting plasma glucose by an adjusted mean value of 1.1 mmol/l and HbA1c by 0.9% (9.8 mmol/mol; placebo-subtracted); at 2000 mg, the corresponding reductions were 4.3 mmol/l and 2.0% (21.9 mmol/mol; p ≤ 0.01) (Garber et al., 2007). In both the studies by DeFronzo et al, and Garber et al, the drug was well tolerated with mild gastrointestinal (GI) side effects predominating and no increased risk of hypoglycaemia.
Since these original trials, follow-up and short-term studies (usually 3–6 months) using metformin have demonstrated mean HbA1c reductions on the order of 1% (10.9 mmol/mol) to 1.5% (16.4 mmol/mol), depending, in part, on the baseline value. In head-to-head trials, the drug has been shown to be equipotent to sulfonylureas, thiazolidinediones and glucagon-like peptide-1 (GLP-1) receptor agonists, and, in general, more potent than dipeptidyl peptidase-4 (DPP-4) inhibitors (Bennett et al., 2011; Russell-Jones et al., 2012).
A Diabetes Outcome Progression Trial (ADOPT, 2006) was a long-term randomised, double-blind, controlled clinical trial comparing the durability of glycaemic-control efficacy of a sulfonylurea (glibenclamide, known as glyburide in the USA and Canada), metformin and a thiazolidinedione (rosiglitazone), as initial treatment for recently diagnosed type 2 diabetes. After 5 years, progression to monotherapy ‘glycaemic failure’ (liberally defined as fasting plasma glucose >10.0 mmol/l) was least with rosiglitazone (15% of participants), intermediate with metformin (21%) and greatest with glibenclamide (34%). Similar results were found when using the alternative and perhaps more conventional glycaemic failure definition of plasma glucose >7.8 mmol/l.