Drugs

, Volume 55, Issue 4, pp 563–584 | Cite as

Glimepiride

A Review of its Use in the Management of Type 2 Diabetes Mellitus
Adis Drug Evaluation

Summary

Synopsis

Glimepiride is a sulphonylurea agent that stimulates insulin release from pancreatic β-cells and may act via extrapancreatic mechanisms. It is administered once daily to patients with type 2 (non-insulin-dependent) diabetes mellitus in whom glycaemia is not controlled by diet and exercise alone, and may be combined with insulin in patients with secondary sulphonylurea failure.

The greatest blood glucose lowering effects of glimepiride occur in the first 4 hours after the dose. Glimepiride has fewer and less severe effects on cardiovascular variables than glibenclamide (glyburide). Pharmacokinetics are mainly unaltered in elderly patients or those with renal or liver disease. Few drug interactions with glimepiride have been documented.

In patients with type 2 diabetes, glimepiride has an effective dosage range of 0.5 to 8 mg/day, although there is little difference in efficacy between dosages of 4 and 8 mg/day. Glimepiride was similar in efficacy to glibenclamide and glipizide in 1-year studies. However, glimepiride appears to reduce blood glucose more rapidly than glipizide over the first few weeks of treatment. Glimepiride and gliclazide were compared in patients with good glycaemic control at baseline in a 14-week study that noted no differences between their effects. Glimepiride plus insulin was as effective as insulin plus placebo in helping patients with secondary sulphonylurea failure to reach a fasting blood glucose target level of ≤ 7.8mmol/L, although lower insulin dosages and more rapid effects on glycaemia were seen with glimepiride.

Although glimepiride monotherapy was generally well tolerated, hypoglycaemia occurred in 10 to 20% of patients treated for ≤ 1 year and ≥ 50% of patients receiving concomitant insulin for 6 months. Pooled clinical trial data suggest that glimepiride may have a lower incidence of hypoglycaemia than glibenclamide, particularly in the first month of treatment. Dosage is usually started at 1 mg/day, titrated to glycaemic control at 1- to 2-week intervals to a usual dosage range of 1 to 4 mg/day (maximum 6 mg/day in the UK or 8 mg/day in the US).

Conclusions. Glimepiride is a conveniently administered alternative to other sulphonylureas in patients with type 2 diabetes mellitus not well controlled by diet alone. Its possible tolerability advantages and use in combination with other oral antidiabetic drugs require further study. Glimepiride is also reported to reduce exogenous insulin requirements in patients with secondary sulphonylurea failure when administered in combination with insulin.

Pharmacodynamic Properties

Glimepiride acts at ATP-sensitive potassium (Katp) channels on pancreatic β-cells to promote insulin release. It binds to 65kD protein on β-cells, which appears to be a part of the same sulphonylurea receptor that binds glibenclamide. Glimepiride decreases gluco-/hexokinase binding to porin proteins and increases expression of glucokinase mRNA and the glucose transporter GLUT2 in pancreatic cells in vitro.

The maximum effects of glimepiride (relative to placebo) on blood glucose and insulin levels in patients with type 2 (non-insulin-dependent) diabetes mellitus appear during the first 4 hours after the dose. Over this 4-hour period, greater reductions in blood glucose occurred on the 4th day of treatment with glimepiride 2 mg/day than glibenclamide 10.5 mg/day (6.0 vs 5.1 mmol/L, p < 0.05). A weak relationship between blood glucose response and dosage was seen in patients with type 2 diabetes receiving glimepiride 1 to 8 mg/day. Glimepiride increased or did not change glucose utilisation rates in patients with type 2 diabetes in euglycaemic hyperinsulinaemic clamp studies. Glimepiride was also associated with greater reductions in insulinaemia than glibenclamide during exercise, despite similar reductions in blood glucose. Glimepiride may be given before or with breakfast, with equivalent effect.

Effects of glimepiride on extrapancreatic mechanisms appear to be similar to those of other sulphonylureas. The drug appears to act within peripheral cells at a point after insulin receptor interaction, increasing glucose transport and glucose transporter expression (GLUT1 and GLUT4), lipogenesis and glycogenesis. Glimepiride also appeared to reduce insulin resistance and increase hepatic glucose disposal in animal models, but did not alter glucose utilisation in patients with type 1 diabetes; these observations require further confirmation.

Unlike glibenclamide, glimepiride has few effects on cardiovascular variables, with no effects on diazoxide-induced Katpchannel opening in human volunteers. It also has more modest effects on vasculature and heart function (ST segment changes and blood pressure) in in vitro and animal studies than glibenclamide.

Pharmacokinetic Properties and Drug Interactions

After oral administration, glimepiride is completely absorbed, reaching peak plasma concentrations (Cmax) of 103.2 and 550.8 μg/L and areas under the plasma concentration-time curve (AUC) of 326 and 2634 μg/L · h after 1 and 8mg doses, respectively. The time to Cmax (tmax) was 2.4 to 3.75 hours in patients with type 2 diabetes. Plasma protein binding was 99.4% and the volume of distribution was 8.8L. Accumulation does not occur after multiple doses. The drug is metabolised mostly in the liver by CYP2C9 to the active M1 (hydroxy) metabolite, with further dehydrogenation to the inactive M2 (carboxy) metabolite. M1 has a tmax of 1.5 to 4.5 hours. 37 to 52% of a glimepiride dose is found in the urine as M1 or M2 within 48 hours. Clearance (CL) was 2.7 to 3.4 L/h for the parent drug and 8.6 to 10.2 L/h for M1. Over 1 to 8mg doses, the terminal elimination half-life (t1/2β) of the parent drug increased from 3.2 to 8.8 hours, but the all-phase half-life was 1.2 to 1.5 hours. Pharmacokinetics are similar in elderly and younger patients. Although CL tended to increase in patients with renal impairment as creatinine clearance decreased from 3 to 0.6 L/h, the t1/2β was unaffected. The urinary excretion of M1 may be reduced, but no other pharmacokinetic changes are known to occur during liver disease.

Glimepiride does not appear to have clinically significant interactions with warfarin, cimetidine, ranitidine or propranolol. Although not specifically studied, interactions may theoretically exist between glimepiride and other highly protein bound drugs, β-blockers, calcium channel blockers, estrogen, fibrates, statins, nonsteroidal anti-inflammatory drugs, thyroid hormone or sulphonamides, warranting caution during concomitant use. as]Clinical Efficacy

In dose-finding and placebo-controlled studies, the minimum effective dosage of glimepiride (0.5 mg/day) had significantly greater effects than placebo on fasting plasma glucose (FPG, −2.5 vs −1.0 mmol/L) and postprandial glucose (PPG, −4.9 vs − 1.7 mmol/L) in patients with type 2 diabetes mellitus treated for 2 weeks. Clear dose-response differences in FPG, PPG and glycosylated haemoglobin (HbA1c) were seen between glimepiride 1 mg/day and 4 to 8 mg/day in a 14-week study, but the differences were more modest between the latter 2 dosages. However, in a 14-week study, glimepiride 16 mg/day was no more effective in reducing FPG from baseline than 8 mg/day. Once-daily administration was as effective as twice-daily use at dosages of 6 and 8 mg/day.

Glimepiride 1 to 8 mg/day was as effective after 1 year as glibenclamide 1.25 to 20 mg/day in reducing FPG, HbA1c or PPG. In 3 trials, differences in FPG and HbA1c levels between glimepiride and glibenclamide were minor and inconsistent, and efficacy of these 2 agents was equivalent; however, lower fasting insulin and C-peptide levels occurred with glimepiride. Long term extension of 2 of these trials for up to 2.8 years showed no clinically significant differences in efficacy between glimepiride and glibenclamide. Glimepiride 1 to 4 mg/day and gliclazide 80 to 320 mg/day had similar efficacy in patients with good glycaemic control at baseline (FPG ≈6.3 mmol/L, HbA1c ≈5%); glimepiride 1mg was generally equivalent to gliclazide 80mg. However, the mild disease and short (14-week) duration of study made differences between treatments more difficult to find; further comparisons between glimepiride and gliclazide are needed. Glimepiride and glipizide were equivalent in efficacy, decreasing FPG and HbA1c after 1 year’s treatment; however, glimepiride reduced FPG more rapidly during the first 10 weeks of study.

Insulin added to maximal dosages of glimepiride was compared with insulin plus placebo in a 24-week study in obese patients with secondary sulphonylurea failure. Patients in both groups achieved similar FPG and HbA1c levels at end-point (7.6 mmol/L and ≈7.6%). However, patients in the glimepiride plus insulin group required lower insulin dosages (49 vs 78 U/day) and achieved more rapid lowering of FPG after 2 and 4 weeks of treatment than the insulin/placebo group.

Tolerability

The most common treatment-emergent adverse events with glimepiride are dizziness, headache, asthenia and nausea; the drug is generally well tolerated. In comparative trials, common adverse events appeared more often during treatment with glimepiride than with placebo, occurred in similar proportions of glimepiride and glipizide patients, and were less likely to occur with glimepiride than glibenclamide, although these differences were not confirmed by statistical analysis. Serious adverse events also followed this pattern, occurring in 8, 2, 8.8 and 12.4% of glimepiride, placebo, glipizide and glibenclamide recipients, respectively. Serious adverse events were usually not thought to be glimepiride related. In the US comparative trials, hypoglycaemia symptoms occurred in more patients receiving glimepiride than placebo (13.9 vs 2%), in similar percentages of glimepiride and gliclazide recipients (21.2 vs 20.6%) and in fewer glimepiride than glibenclamide patients (10 vs 16.3%). The incidence of hypoglycaemia was 1.7% with glimepiride and 5.6% with glibenclamide during the first month of therapy. Mild hypoglycaemia was more common during glimepiride plus insulin treatment (51%) than with placebo plus insulin (37%) in a 6-month study, but moderate hypoglycaemia was not (11 vs 15%).

Dosage and Administration

Glimepiride is started at a dose of 1 to 2mg once daily with breakfast. Regular blood glucose and HbA1c level monitoring is used to guide therapy. Dosages are titrated every 1 to 2 weeks until glycaemic control or maximum dosages (8 mg/day in the US, 6 mg/day in the UK) are reached. Usual maintenance dosages are 1 to 4 mg/day. In the US, glimepiride 8 mg/day may be combined with insulin in patients with secondary sulphonylurea failure. Patients receiving other sulphonylureas may be switched to glimepiride without a transition period. Glimepiride may be used cautiously in elderly, malnourished or debilitated patients and those with renal or hepatic insufficiency, but is not recommended for use in children or in pregnant or breastfeeding women.

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© Adis International Limited 1998

Authors and Affiliations

  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand

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