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Troglitazone, which has been withdrawn from the market, showed severe (fatal) liver toxicity.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 form of abstracts. The official regulations for the use of glitazones differ between countries.
The efficacy of the new drugs has only been tested using surrogate markers such as blood glucose and HbA1c. Cardiac benefits have been claimed [417], but so far none of these drugs has been tested in large-scale, long-term prospective studies on safety and efficacy such as the UKPDS using ultimate clinical endpoints or other patient-oriented outcomes.
For most clinicians insulin monotherapy is a second choice in type 2 diabetes mellitus, usually in the form of conventional insulin therapy. Since type 2 diabetes is associated with insulin resistance, high doses are usually necessary [418,419].
The insulin dose may be reduced by the addition of oral antidiabetic drugs [381,420,421]. Recently, intensified insulin treatment has been recommended [422]. However, the metabolic control achieved using different insulin regimens was comparable [423,424]. The most important adverse effects of insulin in the treatment of type 2 diabetes are hypoglycemia and weight gain. Weight gain may be reduced by combining insulin with metformin [133,425].
Clinical Aspects
Pharmacological therapy should be evidence-based, achieve the goals of therapy, be safe and causal rather than symptomatic, easy and comfortable for the patient, and inexpensive. Only two landmark studies on pharmacological therapy of type2 diabetes mellitus have used mortality and diabetes-related morbidity as ultimate endpoints. The Kumamoto study [131,426] evaluated the effects of intensive insulin therapy on prevention and progression of retinopathy, nephropathy, and neuropathy, and studied the cost-benefit relationship. The UKPDS [130,133,368] compared standard and intensive treatment with human insulin, chlorpropamide, glibenclamide and other sulfonylurea drugs, metformin, and acarbose. Three aggregate endpoints were used:
