Pharmacology: Gliclazide reduces blood glucose levels by correcting both defective insulin secretion and peripheral insulin resistance. This occurs by closure of K+ channels in b-cells of pancreas. Subsequently, Ca2+ channel open leading to increase in intracellular calcium and induction of insulin release. Gliclazide also increases the sensitivity of b-cells to glucose. Gliclazide restores peripheral insulin sensitivity such as decreasing hepatic glucose production and increasing glucose clearance. It has anti-platelet adhesive activity and reduces level of free radicles, thereby preventing vascular complications.
Metformin acts as an antihyperglycaemic agent by improving hepatic and peripheral tissue sensitivity to insulin. It also appears to have beneficial effect on serum lipid levels and so on fibrinolytic activity. Metformin therapy is not associated with increase in body weight.
Rationality: Sulfonylureas & biguanides act complementary to each other. Both compounds have an additive antihyperglycaemic effect without increasing the adverse effects of either pharmacological class.
Gliclazide acts via stimulating b cells of pancreas to release insulin & also increases peripheral sensitivity of insulin. Metformin acts via enhanced peripheral glucose uptake & utilization. It also reduces hepatic glucose production, thereby metformin diminishes insulin resistance.
There are reports in which combination treatment of sulfonylurea with metformin has been reported to achieve satisfactory glycaemic control for several years. Such combination has been reported to be quite useful in comparative studies where secondary sulfonylurea failure had occurred. The combination may therefore provide additional glycaemic control (blood glucose lowering effect by 20%) & thus obviate the need for insulin in some patients.
Since metformin is reported to have predominant peripheral mechanism of action, therefore it lacks the anabolic effects of sulfonylureas and does not cause weight gain.
Gliclazide appears to be useful in both macro-vascular & micro-vascular complications. Metformin is associated with a decrease in fasting & postprandial blood sugar & triglyceride levels, increase in HDL-cholesterol, increase of tissue plasminogen activator, decrease in platelet aggregation. Pharmacokinetically the two drugs appear to be compatible, as metformin is not plasma protein bound & does not get metabolized in liver. So interaction with gliclazide (having 80-90% plasma protein binding & metabolized via liver) does not appear to be possible. Hence the combination of Gliclazide & metformin would help in treatment of Type II diabetes mellitus and probably prevention of its associated macrovascular and microvascular complications.
Pharmacokinetics: Single oral dose of gliclazide, 40 to 120 mg. results in a Cmax of 2.2 to 8 mg./l within 2 to 8 hours. Steady state concentrations are achieved after 2 days of administration of 40-120 mg of gliclazide. Administration of gliclazide with food reduces Cmax and delays Tmax. The volume of distribution is low due to extensive protein binding (85-97%). The half life of gliclazide varies from 8.1-20.5 hours after single dose administration. Gliclazide is extensively metabolized to 7 metabolites predominantly excreted in the urine, the most abundant being the carboxylic acid derivative; 60-70% of the dose is excreted in the urine and 10-20% in the faeces. Metformin has absolute oral bioavailability of 50-60%. GIT absorption is complete within 6 hrs of ingestion metformin is rapidly distributed in body after absorption. The renal elimination of metformin is biphasic. 95% of the absorbed metformin is eliminated during primary elimination phase having half-life of 6 hours. Rest of the 5% is eliminated during slow terminal elimination phase with mean half-life of 20 hours. Metformin is not bound to plasma proteins, 40-60% of the dose is recovered as unchanged drug in urine with a further 30% recovered as unchanged drug in faces.