Glyburide Decreases Insulin Requirement, Increases (β-Cell Response to Mixed Meal, and Does Not Affect Insulin Sensitivity: Effects of Short- and Long-Term Combined Treatment in Secondary Failure to Sulfonylurea

Abstract

In 20 patients with non-insulin-dependent diabetes mellitus (NIDDM) and secondary failure to sulfonylurea, a double-blind randomized study was performed comparing two regimes: insulin plus placebo (IP) and insulin plus glyburide (IG). The protocol included two hospitalization periods (days 1-18 and 78-85) and follow-up at the outpatient clinic for 325 days. The metabolic control was kept as tight as possible. The subjects underwent normoglycemic clamp studies and meal tests with determination of insulin, C-peptide, glucagon, somatostatin, and gastric inhibitory polypeptide in plasma. On IG, they demonstrated marked and long-lasting improvement of metabolic control: HbA1c decreased from 11.1 +/- 0.3% on day 3 to 8.3 +/- 0.4% (P less than .001) on day 78 and 9.1 +/- 0.5% (P less than .001) on day 325. In subjects on IP, the corresponding values were 10.3 +/- 0.5, 8.4 +/- 0.4 (P less than .001), and 8.9 +/- 0.5% (P less than .05). Body weight increased by 6.0 +/- 1.5 kg (P less than .005) on IG and 2.9 +/- 2.1 kg (NS) on IP. The daily insulin requirement decreased on IG from 62.5 +/- 12.9 U/day on day 7 to 33.5 +/- 8.8 U/day on day 83 and 34.6 +/- 8.9 U/day on day 325. On IP the insulin requirement was almost constant: 62.0 +/- 10.7 U/day on day 7, 55.5 +/- 7.7 U/day on day 83, and 54.7 +/- 7.9 U/day on day 325. Insulin sensitivity measured with the hyperinsulinemic clamp (plasma insulin approximately equal to 130 microU/ml) was similar on IP and IG at the initiation of the study and was unchanged on days 18 and 85. A key observation of this study, although the mechanism is unclear, is that isoglycemic-meal-related insulin requirement was diminished by insulin treatment, indicating improvement of meal-related insulin sensitivity. Glyburide increased basal and meal-but not glucagon-stimulated insulin and C-peptide levels, and also augmented the effect of meals on somatostatin release. We conclude that in NIDDM, IG regime promptly and continuously decreased insulin requirement and improved metabolic control. This effect is, at least during the first 3 mo, mainly due to enhanced insulin secretion. IG and IP treatment had no effect on insulin sensitivity during hyperinsulinemic-normoglycemic clamp, whereas meal-related insulin sensitivity was augmented.

Gliclazide and bedtime insulin are more efficient than insulin alone for type 2 diabetic patients with sulfonylurea secondary failure

“…When SU was withdrawn (phase 3), a 50% increase in insulin dose was observed, as also reported in other studies (9,11,(14)(15)(16)(17)21,22). Despite this increment, only three patients among those who responded to combined therapy maintained their FPG below 140 mg/dl in phase 3 (P<0.02).…”

Insulin-like growth factor-I improves glucose and lipid metabolism in type 2 diabetes mellitus.

“…However, these improvements often do not last very long and sulfonylureas or insulin are added. These agents are well known to lower glucose levels, yet with some risk ofhypoglycemia (16). In this study with rhIGF-I treatment, no hypoglycemia occurred although near-normoglycemia was achieved.…”

“…In this study with rhIGF-I treatment, no hypoglycemia occurred although near-normoglycemia was achieved. Furthermore, sulfonylureas and insulin enhance hyperinsulinemia (14), can aggravate insulin resistance directly (5,15) or indirectly by increasing body weight (16,17), and, thereby, increase the atherogenic risk (8,9). Since in this short-term study rhIGF-I lowered not only glucose and triglyceride but also insulin levels, all of which are considered to be cardiovascular risk factors (8,9), rhIGF-I treatment could, in the long run, have beneficial effects on cardiovascular morbidity and mortality.…”

“…However, compliance with reducing diets is often poor and the beneficial effects short lived so that sulfonylureas or insulin are prescribed. Both enhance hyperinsulinemia (14) and can aggravate insulin resistance directly (5,15) or indirectly by increasing body weight (16,17). Therefore, the atherogenic risk rises again (8,9).…”

The effect of glibenclamide on insulin secretion at normal glucose concentrations

“…secretion by pancreatic beta cells without affecting peripheral insulin sensitivity [2][3][4][5]. Perhaps the most important adverse effect of sulfonylurea therapy is the development of hypoglycaemia, though different sulfonylureas may vary in the degree to which they cause this [6][7][8][9].…”