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Glyset

Clinical Pharmacology
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CLINICAL PHARMACOLOGY

Glyset

Miglitol is a desoxynojirimycin derivative that delays the digestion of ingested carbohydrates, thereby resulting in a smaller rise in blood glucose concentration following meals. As a consequence of plasma glucose reduction, GLYSET Tablets reduce levels of glycosylated hemoglobin in patients with Type II (non-insulin-dependent) diabetes mellitus. Systemic nonenzymatic protein glycosylation, as reflected by levels of glycosylated hemoglobin, is a function of average blood glucose concentration over time.

Mechanism of Action

In contrast to sulfonylureas, GLYSET does not enhance insulin secretion. The antihyperglycemic action of miglitol results from a reversible inhibition of membrane-bound intestinal α-glucoside hydrolase enzymes. Membrane-bound intestinal α-glucosidases hydrolyze oligosaccharides and disaccharides to glucose and other monosaccharides in the brush border of the small intestine. In diabetic patients, this enzyme inhibition results in delayed glucose absorption and lowering of postprandial hyperglycemia.

Because its mechanism of action is different, the effect of GLYSET to enhance glycemic control is additive to that of sulfonylureas when used in combination. In addition, GLYSET diminishes the insulinotropic and weight-increasing effects of sulfonylureas.

Miglitol has minor inhibitory activity against lactase and consequently, at the recommended doses, would not be expected to induce lactose intolerance.

Pharmacokinetics

Absorption

Absorption of miglitol is saturable at high doses: a dose of 25 mg is completely absorbed, whereas a dose of 100 mg is only 50% - 70% absorbed. For all doses, peak concentrations are reached in 2-3 hours. There is no evidence that systemic absorption of miglitol contributes to its therapeutic effect.

Distribution

The protein binding of miglitol is negligible (<4.0%). Miglitol has a volume of distribution of 0.18 L/kg, consistent with distribution primarily into the extracellular fluid.

Metabolism

Miglitol is not metabolized in man or in any animal species studied. No metabolites have been detected in plasma, urine, or feces, indicating a lack of either systemic or pre-systemic metabolism.

Excretion

Miglitol is eliminated by renal excretion as unchanged drug. Thus, following a 25-mg dose, over 95% of the dose is recovered in the urine within 24 hours. At higher doses, the cumulative recovery of drug from urine is somewhat lower due to the incomplete bioavailability. The elimination half-life of miglitol from plasma is approximately 2 hours.

Special Populations

Renal Impairment

Because miglitol is excreted primarily by the kidneys, accumulation of miglitol is expected in patients with renal impairment. Patients with creatinine clearance <25 mL/min taking 25 mg 3 times daily exhibited a greater than two-fold increase in miglitol plasma levels as compared to subjects with creatinine clearance >60 mL/min. Dosage adjustment to correct the increased plasma concentrations is not feasible because miglitol acts locally. Little information is available on the safety of miglitol in patients with creatinine clearance <25 mL/min.

Table 1: Results of Monotherapy Study with GLYSET

Study Treatment HbA1c (%) 1-hour Postprandial Glucose (mg/dL)
Mean Change from Baseline* Treatment Effect** Mean Change from Baseline Treatment Effect**
1 (U.S.) Placebo +0.71 --- +24 ---
GLYSET 50 mg t.i.d.*** +0.13 -0.58† -39 -63†
2 (U.S.) Placebo +0.47 --- +15 ---
GLYSET 50 mg t.i.d. -0.22 -0.69† -52 -67†
GLYSET 100 mg t.i.d. -0.28 -0.75† -59 -74†
3 (non-U.S.) Placebo +0.18 --- +2 ---
GLYSET 25 mg t.i.d. -0.08 -0.26 -33 -35†
GLYSET 50 mg t.i.d. -0.22 -0.40 -45 -47†
GLYSET 100 mg t.i.d. -0.63 -0.81† -62 -64†
GLYSET 200 mg t.i.d.‡ -0.84 -1.02† -85 -87†
4 (non-U.S.) Placebo +0.01 --- +8 ---
GLYSET 50 mg t.i.d. -0.35 -0.36† -20 -28†
GLYSET 100 mg t.i.d. -0.57 -0.58† -25 -33†
5 (non-U.S.) Placebo +0.32 --- +17 ---
GLYSET 100 mg t.i.d. -0.43 -0.75† -38 -55†
*Mean baseline ranged from 7.54 to 8.72% in these studies.
** The result of subtracting the placebo group average.
*** t.i.d. = 3 times daily
† p ≤ 0.05
‡Although results for the 200 mg 3 times daily are presented for completeness, the maximum recommended dosage of GLYSET is 100 mg 3 times daily.

Table 2: Results of Combination Therapy with GLYSET Plus Sulfonylurea (SFU)

Study Treatment HbA 1c (%) 1-hour Postprandial Glucose (mg/dL)
Mean Change from Baseline* Treatment Effect** Mean Change from Baseline Treatment Effect**
6 (U.S.) Placebo + SFU +0.33 --- -1 ---
GLYSET 50 mg t.i.d.*** + SFU -0.49 -0.82† -69 -68†
GLYSET 100 mg t.i.d. + SFU -0.41 -0.74† -73 -72†
7 (U.S.) Placebo + SFU +1.01 --- 48 ---
GLYSET 25 mg t.i.d. + SFU +0.71 -0.30 -2 -50†
GLYSET 50 mg t.i.d. + SFU +0.39 -0.62† -13 -61†
GLYSET 100 mg t.i.d. + SFU +0.28 -0.73† -33 -81†
8 (non-U.S.) Placebo + SFU +0.16 --- +10 ---
GLYSET 100 mg t.i.d. + SFU -0.50 -0.66† -36 -46†
*Mean baseline ranged from 8.56 to 9.16% in these studies.
** The result of subtracting the placebo group average.
*** t.i.d. = 3 times daily
†p ≤ 0.05

Hepatic impairment
Brand Name: Glyset
Generic Name: Miglitol

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