Glinides

Meglitinide

Repaglinide (Prandin)

Repaglinide (Prandin), a member of the meglitinide class of compounds, is chemically unrelated to the sulfonylurea (SFUs). It lowers blood glucose by blocking ATP-dependent potassium channels in pancreatic β-cells. This depolarizes the cell and results in the release of insulin in a glucose-dependent manner. Repaglinide monotherapy is indicated as an adjunct to diet and exercise in patients with type 2 diabetes (T2D) whose hyperglycemia cannot be controlled satisfactorily by diet and exercise alone and also for combination therapy use (with metformin (MET) or thiazolidinediones (TZDs)) in patients whose hyperglycemia cannot be controlled by monotherapy with MET, SFUs, repaglinide, or TZDs. Repaglinide causes a rapid rise and fall of insulin secretion when ingested ≤30 minutes prior to a meal and mimics the normal postprandial insulin response that follows ingestion of food. Repaglinide is generally not recommended in combination with SFUs.

Repaglinide was studied in combination with MET in 83 patients with T2D not satisfactorily controlled on exercise, diet and MET alone. Repaglinide dosage was titrated for 4 to 8 weeks, followed by a 3-month maintenance period. Combination therapy with repaglinide and MET resulted in significantly greater improvement in glycemic control compared with repaglinide or MET monotherapy. The greater response in the combination group was achieved at a lower daily repaglinide dosage compared with repaglinide monotherapy. Monotherapy with repaglinide and nateglinide were compared in a 16-week clinical trial in 150 patients with T2D. Doses of both agents were titrated up during the first 3 weeks to a maximum of 16 mg/day for repaglinide and 360 mg/day for nateglinide. At 16 weeks, patients on repaglinide achieved an average reduction in glycosylated hemoglobin (A1C) of 1.67% while those on nateglinide achieved 1.08%; this difference was statistically significant. Furthermore, repaglinide and nateglinide in combination with MET were compared in a 16-week study in 192 patients with T2D (Figure 15-1). All patients began MET therapy in the 4 weeks prior to the trial; 500 mg twice daily for 2 weeks followed by 1,000 mg twice daily for 2 weeks. This was followed by a 2-week titration period and 14 weeks of maintenance therapy. Repaglinide in combination with MET exhibited a statistically significant (P <0.001) greater decrease in A1C (1.28%) than nateglinide with MET (0.67%).

Although not FDA approved, repaglinide works well with carbohydrate-absorption inhibitors, such as acarbose and miglitol, as well as with the TZDs. A potentially useful triple-combination oral antidiabetic regimen includes a TZD in the morning, repaglinide with each meal and MET at bedtime. This triple combination addresses the three major physiologic abnormalities observed in the pathogenesis of hyperglycemia in T2D (insulin resistance, impaired insulin secretion and excessive hepatic glucose production).

Prescribing Repaglinide

Repaglinide can be taken anytime between 30 minutes to immediately before a meal, but is usually taken 15 minutes prior to eating. The starting dose for patients who have not previously received an oral antidiabetic agent or those with an A1C <8% is 0.5 mg/meal. For patients who have previously used oral antidiabetic agents and have an A1C ≥8%, the starting dose is 1 mg/meal or 2 mg/meal. Repaglinide can be titrated up to 4 mg before each meal and a recommended maximum of 16 mg per day. Patients should be instructed that if they miss or add a meal they should omit or add the corresponding repaglinide dose. A maximum recommended daily dose is 16 mg.

Side Effects of Repaglinide

There is a small weight gain (3.3%) when a patient is treated with repaglinide as monotherapy and a low incidence of hypoglycemia. Since repaglinide is also cleared by the liver, it can be used in type 2 diabetic patients when renal impairment is present.

Repaglinide Fixed-Dose Combination

A fixed-dose, single-tablet formulation of repaglinide in combination with MET (PrandiMet) is available. PrandiMet is indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2D who are already treated with a meglitinide and MET or who have inadequate glycemic control on a meglitinide alone or MET alone. PrandiMet is available in tablets containing either 1-mg repaglinide/500-mg MET or 2-mg repaglinide/500-mg MET. The fixed-dose combination tablet of repaglinide and MET has been shown to be bioequivalent to concomitantly administered individual tablets of repaglinide and MET.

Treatment with PrandiMet should be individualized and initiated with 1-mg repaglinide twice daily unless the patient is already taking higher coadministered doses of repaglinide and MET. PrandiMet should be given in divided doses within 15 minutes prior to meals. The total daily dosage should not exceed 10-mg repaglinide/2500-mg MET or 4-mg repaglinide/1000-mg MET per meal.

Enlarge 

d-Phenylalanine Derivative

Nateglinide

Nateglinide (Starlix), a member of the d-phenylalanine class of compounds, is structurally distinct from other available oral antidiabetic agents and, like repaglinide, exerts its glucose-lowering effect by rapid and transient effects on the ATP-sensitive potassium channels of pancreatic β-cells. Binding of nateglinide to SFU receptors leads to membrane depolarization and influx of calcium into the β-cell. The increased intracellular calcium stimulates insulin release from secretory granules. Nateglinide (Starlix) is approved for T2D as initial monotherapy and in combination with MET. Nateglinide, when taken orally up to 30 minutes prior to meals, is rapidly and almost completely absorbed. It stimulates pancreatic insulin secretion within 20 minutes, reaching peak insulin levels within 1 hour and returning to baseline levels within 4 hours of dosing. The extent of insulin secretion is glucose dependent so that more insulin is secreted when needed and its effects are rapidly reversed when glucose levels decrease. Thus insulin is secreted during the early phase after meals, reducing glucose spikes and minimizing prolonged insulin exposure and hypoglycemia.

Early insulin secretion released at the start of a meal suppresses hepatic glucose production and prevents exaggerated postprandial glucose (PPG) levels. Early insulin secretion is impaired in patients with T2D, leading to lack of suppression of hepatic glucose production and a rise in PPG levels. Nateglinide improves early insulin secretion through a fast-on, fast-off effect that mimics normal insulin secretion.

PPG or postmeal glucose excursions are a major component of A1C and are frequently increased yet untreated. When A1C is >7%, 90% of patients have a 2-hour plasma glucose >200 mg/dL. Elevated 2-hour PPG levels are also associated with an increased incidence of CV disease in diabetic individuals. Although there are as yet no outcome studies for targeted PPG levels, the general consensus is that 2-hour postmeal glucose should be <140 mg/dL to 160 mg/dL. These levels are now achievable with the new agents that target PPG control.

Studies have been conducted in both drug-naïve type 2 diabetic patients as well as those previously treated with other antidiabetic agents. In drug-naïve patients, 6 months’ treatment with nateglinide 120 mg 3 times daily before meals achieved comparable reductions in A1C (1%) compared with placebo as 500 mg tid MET with meals (1.1%). In both drug-naïve and previously treated patients combined, A1C was reduced by nateglinide 0.8% and by MET 1.2% compared with placebo. When nateglinide and MET were combined for 6 months, the reduction in A1C (1.9%) compared with placebo was greater than either agent given alone. The preferential effect of nateglinide on PPG levels compared with that of MET was also evident in this study (Figure 15-2). Patients not achieving A1C target levels also benefit from addition of nateglinide. Nateglinide 120 mg 3 times daily before meals added to MET 1,000 mg twice daily reduced A1C an additional 0.6% compared with addition of a placebo.

Prescribing Nateglinide

Nateglinide is indicated as initial therapy, as an adjunct to diet and exercise and in combination with MET. Patients in whom SFUs have failed do not achieve any additional benefit when nateglinide is switched or added. The recommended starting and maintenance dose of nateglinide, as monotherapy or in combination with MET, is 120 mg prior to each main meal. Unlike other antidiabetic agents, dose titration is usually not required. If a meal is skipped, nateglinide should not be given. If a patient is near the A1C goal, a 60-mg dose of nateglinide may be sufficient when initiated as monotherapy or in combination with MET. The dose also does not need to be adjusted in patients with mild to severe renal insufficiency or mild hepatic disease.

Side Effects of Nateglinide

AEs with nateglinide are similar to those with placebo. Small increases in mean uric acid levels (0.20-0.45 mg/dL) have been reported. During clinical trials, hypoglycemia was relatively uncommon (2.4% incidence vs placebo) and resulted in discontinuation of nateglinide in only 0.3% of patients. No severe hypoglycemia occurred requiring assistance of others. Minimal weight gain occurred with nateglinide, <1 kg from baseline values. Nateglinide is safe in elderly diabetic subjects and can be used in those with mild to severe renal insufficiency or mild hepatic insufficiency.

Enlarge 

This article was last updated: October 26, 2022