Recently inhaled insulin was developed as a noninvasive alternative to subcutaneous insulin administration. From a proof-of-concept study in type 1 diabetic individuals [356] and an observation study in patients with type 2 diabetes [357] it was concluded that inhaled insulin may offer a practical, noninvasive alternative to insulin injections, because it maintains glycemic control without major side effects and may provide greater patient satisfaction than subcutaneously injected insulin. These first clinical studies will stimulate the development of this new form of insulin therapy [358,359].
The insulin analogues glargine, lispro, and aspart have only recently been introduced into clinical practice. Data on their long-term safety and benefit are not yet available and must be awaited before their advantages and disadvantages can be finally assessed. This may not be a theoretical argument, since the binding properties of the analogues to the insulin and IGF-I receptors are not always identical with those of human insulin [360–362]. However, postmarketing surveys of more than a million treatment-years have provided no evidence for any increase in mitogenic risk with lispro (T. Krause. personal communication, 2001).
While the DCCT [127] has clearly shown that intensified insulin therapy is superior to conventional insulin therapy, no long-term studies in type 1 diabetic subjects using combinations of insulin and oral drugs such as metformin or α-amylase inhibitors are available.
Pharmacological Treatment of Type 2 Diabetes
Glucose Metabolism
About 25% of newly diagnosed type 2 diabetic individuals can initially have their condition controlled by nonpharmacological treatment [125]. The others need additional pharmacological therapy. Metabolic control deteriorates continuously from the very start of the disease. For this reason, the number of subjects who need drugs will increase, and those who were initially on monotherapy will eventually need combination drug therapy [125].
Five classes of oral antidiabetic drugs (Table 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].