1.21) and insulin (Table 1.20) are available for pharmacological treatment of type 2 diabetes.
The competitive α-amylase inhibitors (acarbose, miglitol) delay digestion of complex carbohydrates. By this mechanism they reduce the postprandial rise of glucose, serum insulin, and gastric inhibitory polypeptide (GIF) and stimulate release of glucagon-like peptide 1 (GLP-1) [363]. The antidiabetic effect is seen promptly after the first dose. Their efficacy is well documented [364–368].
Major adverse drug effects are flatulence, abdominal discomfort, and bloating, which usually occur during the first 2-3 weeks of treatment, particularly if the dosage is increased too rapidly. These effects are promptly reversible after discontinuation of treatment but may cause noncompliance problems. It is therefore strongly recommended to start with a very low dose (e. g., 50 mg acarbose at breakfast) and titrate the dose very slowly upwards according to how it is tolerated. Other adverse events are very rare. Monotherapy with α-amylase inhibitors does not cause hypoglycemia nor weight gain 1365-368]. There is no risk of tachyphylaxia. These drugs may be combined with sulfonylurea, metformin, or insulin. Their effect is additive. If hypoglycemia occurs during combination therapy, monosaccharides must be given as antidote.
The main metabolic effect of metformin is inhibition of hepatic glucose production, with little effect on peripheral insulin sensitivity [369,370]. The molecular mechanisms of this effect are not known. Fasting and daytime blood glucose are reduced by metformin. It may take a couple of days or even weeks until the full therapeutic effect has developed.
The antidiabetic effect of metformin alone [133,371,372] and in combination [373,374] is well documented.
Metformin monotherapy does not cause hypoglycemia or weight gain. There is no risk of tachyphylaxia. The drug may be combined with insulin, glitazones, glinides, sulfonylurea, and α-amylase inhibitors. In combination with sulfonylurea or insulin it is able to reduce weight gain [133].
However, in the UKPDS, the addition of metformin treatment to poorly controlled patients receiving sulfonylurea significantly increased the risk of diabetes-related and all-cause mortality [133]. A recent retrospective analysis has cast further doubt on the benefit of this combination [375]. This finding of the UKPDS has been criticized on methodological grounds [376] and the relevance of this observation has been questioned. The American Diabetes Association decided not to change the guidelines on the pharmacological treatment of hyperglycemia in NIDDM [377], because the study had not provided assurance about the risk or benefit of the combination of sulfonylurea and metformin.
A rare but possibly fatal adverse event is lactic acidosis. The risk of this complication increases with overdose or reduced elimination of metformin (serum creatinine > 1.2 mg/dl) and in all conditions in which lactate production is increased or lactate utilization decreased, such as shock, sepsis, hypoxia, alcohol abuse, or narcosis. Ketosis may be aggravated by metformin. Frequent but harmless adverse events include reversible gastrointestinal discomfort and diarrhea. The contraindications for metformin must be carefully taken into account.
Sulfonylurea stimulates endogenous insulin secretion, leading to a decrease in postprandial and fasting blood glucose. The effect is mediated by the closing of ATP-dependent potassium channels in the plasma membrane of pancreatic β cells. This mechanism explains why the efficacy of sulfonylurea depends on the existence of an endogenous insulin reserve. Although administration of sulfonylurea makes the β cells more sensitive to glucose stimulation, the impaired first-phase insulin secretion, which is the most important defect in type 2 diabetes, is not restored [378,379].
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
