The efficacy of sulfonylurea tends to vanish during long-term therapy (late or secondary failure). This may be due to progressive exhaustion of the endogenous insulin reserve. To manage this problem sulfonylurea may be combined with insulin, glitazones, and α-amylase inhibitors. The antidiabetic effect of sulfonylurea treatment alone or in combination is well documented [380,381].
The most frequent adverse event is hypoglycemia, which may begin insidiously and last longer than a day. Sulfonylurea-treated patients usually experience weight gain. Other adverse events are rare. Drug interactions which modulate the efficacy of sulfonylurea are frequent [382].
New oral drugs have recently been developed in order to better mimic physiological insulin secretion and to improve insulin sensitivity.
The glinides (repaglinide and nateglinide) are benzoic acid derivatives which belong to a new class of insulin secretagogues referred to as “prandial glucose regulators.” Compared with glibenclamide these drugs are rapidly absorbed and excreted (tmax of plasma concentration: glibenclamide 300 minutes [383], repaglinide 45 minutes [384], nateglinide 45-60 minutes [385]; t½ of plasma elimination: glibenclamide nine hours [383], repaglinide one hour [384], nateglinide one hour [385]. These drugs bind to specific receptors on the pancreatic β cell, heart, and peripheral muscle cells. In comparison with glibenclamide and gliburide, the binding of nataglinide is much more specific for β cells [386].
The mechanism of action, action profile, and pharmacokinetics of repaglinide and nateglinide are similar but not identical [387]. The binding of repaglinide or nateglinide is rapidly followed by closing of ATP-dependent K+ channels, discontinuous depolarization of the cell membrane, and Ca++ influx, resulting in a rapid insulin release of short duration. In vitro, the insulin-stimulatory effect of repaglinide is enhanced by the presence of physiological concentrations of glucose. Under these conditions repaglinide is several times more potent than glibenclamide [386]. After stimulation with glinides the kinetics of postprandial insulin secretion are more similar to physiological insulin secretion than they are after stimulation with sulfonylurea [388,389].
These drugs cut off postprandial glucose peaks, lower HbAlc, and can be effectively combined with metformin [390–392].
In poorly controlled type 2 diabetic patients formerly treated with metformin, repaglinide monotherapy was as effective as metformin. The combination of repaglinide or nateglinide with metformin seems to be superior to monotherapy [391–393].
Adverse effects of glinides are hypoglycemia, gastrointestinal symptoms, blurred vision, and, rarely, elevated liver enzymes and hypersensitive reactions of the skin. Interactions with drugs metabolized by the cytochrome P450 system may occur. Efficacy is modulated by drug interaction in a similar way as with sulfonylurea.
The thiazolidinediones (glitazones) rosiglitazone and pioglitazone are called “insulin sensitizers.” They lower blood glucose by improving the insulin sensitivity of liver, adipose tissue, and muscle [394,395]. Glitazones develop their metabolic effect through binding to the peroxisome proliferator-activated nuclear receptor-γ (PPAR-γ). This glitazone-activated receptor may become effective as a transcription factor for proteins involved in the regulation of glucose and lipid metabolism. Glitazones improve insulin signaling by increasing the phosphorylation of the insulin receptor, the insulin receptor substrate 1 (IRS-1), and phosphatidylinositol-3 (PI-3) kinase [395]. They also stimulate the expression of glucose transporters GLUT-1 and GLUT-4 [397,398], enhance glucose utilization [399], and suppress hepatic glucose output [400]. Rosiglitazone inhibits the expression of the leptin gene in rat adipocytes [401,402] and stimulates the expression of uncoupling proteins 1 and 3 (UCP1 and UCP3) in preadipocytes [403]. Pioglitazone reduces the expression of TNF-α in muscle and adipose tissue [404]. This effect may be responsible for the favorable influence on the insulin receptor tyrosine kinase and the serine phosphorylation of the insulin receptor [405]. However, a reduced availability of free fatty acids in blood and tissues may also improve insulin sensitivity [406]. The significance of the glitazone effects on proliferation and differentiation of various cell types is unknown. A possible beneficial effect may be inhibition of LDL-induced growth of vascular smooth muscle cells [407].
Adverse effects of glitazones include fluid retention, edema, cardiac failure, anemia, and slight increase in LDL cholesterol and body weight.
Troglitazone, which has been withdrawn from the market, showed severe (fatal) liver toxicity. Rosiglitazone and pioglitazone have been claimed not to be liver toxic, but cases of new liver disease during therapy with rosiglitazone have been reported [408–411], and minor functional disorders may occur. There is at present no proof of a causal relationship, but careful monitoring of liver function is indicated.
Interactions with drugs metabolized by the cytochrome P450 system are possible. Since glitazones have a broad spectrum of effects (there are more than those mentioned in this chapter) and since not all the genes regulated by PPAR-γ seem to be completely known, their safety profile cannot be definitively assessed.
Significant lowering of blood glucose has been reported with glitazones used alone [412]. However, the effect is smaller than with metformin or sulfonylurea [413]. Better effects are seen in combination with metformin [414], sulfonylurea [415], and possibly insulin [416]. At present most clinical information is available only in the