Sulfonylureas will decrease blood glucose on average by 30 to 60mg/dL (1.5-3 mmol/L) and lower HbA1c by about 1.0% to 2.5%. The glucose-lowering potency of sulfonylureas is directly related to the initial glucose concentration at the onset of treatment, and is greater the higher the initial glucose concentration (2,6). In the UKPDS, the starting HbAlc concentration was around 9% and was lowered to about 7% by diet during the run-in period. The HbA1c was lowered on average by 0.9% using chlorpropamide or glibenclamide (identical to glyburide in the United States) compared with the diet group, and this difference persisted during the 10 years of the study in patients controlled by sulfonylureas (1). Over this time, the mean HbA1c of all treatment groups increased by about 2%, reflecting the overall loss of beta-cell function. However, this increase in HbA1c was seen in all treatment groups and was not a consequence of sulfonylurea treatment, but rather was a consequence of the disease itself. Clearly, increased efforts are required to achieve good glucose control over time in patients with type 2 diabetes.

About 25% of the patients treated with sulfonylureas after diagnosis of type 2 diabetes will achieve a fasting plasma glucose < 140 mg/dL, which is still above the recommended ideal range of 80 to 120 mg/dL of fasting glucose (2,6). A good response is predicted by a moderately elevated fasting blood glucose of 140 to 220 mg/dL before onset of treatment, and a high-fasting plasma C-peptide and absence of markers of type 1 diabetes (GAD65 and/or IA2 antibodies). About 50% to 75% of newly diagnosed patients will require a second agent apart from lifestyle changes to achieve a blood glucose control of < 140 mg/dL or 7.8 mmol/L, and thus are regarded as partial responders.

Patients with no or a poor response often have antibodies to GAD65 and belong to the group with latent autoimmune diabetes of adults' (LADA), which is a type 1 diabetes and represents about 10% of patients. Their age at onset of LADA is above 50 years and the BMI was around 23 to 25 kg/m2 in several studies, thus was lower than in type 2 diabetes where BMI of 27 to 30 kg/m2 are frequently reported. C-peptide in these patients is usually < 1 ng/ mL1, while this is elevated in type 2 diabetes.

Patients with a good initial response to sulfonylureas usually show a declining response over time, resulting in a failure rate of about 5% per year. Within 10 years of treatment the majority of patients with type 2 diabetes appear to develop an insufficient response to sulfonylureas, termed "secondary failure." Clinical causes may be an increased need of insulin due to weight gain, chronic inflammation, immobilization or dietary factors. However, a decline in beta cell function has been observed in long-term studies, independent of the agents used for treatment, and represents a presently unmodifiable aspect of type 2 diabetes. The pathophysiology of this process is unknown. Early studies suggested that sulfonylureas may stress beta cells by increased demand, possibly causing secondary beta cell failure.

The UKPDS followed patients over about 9 years and documented that beta cell failure occurs independently of the type of treatment and was observed with metformin and with insulin to a similar degree as with sulfonylureas (10). Beta cell failure must apparently be regarded as an inherent aspect of the pathogenic process of type 2 diabetes. A recent trial compared monotherapy with glibenclamide, metformin, and rosiglitazone in 4360 newly diagnosed type 2 diabetes patients. Monotherapy treatment failure at 5 years, defined as a fasting plasma glucose above 180 mg/dcl, occurred at a rate of 34% with glibenclamide, 21% with metformin, and 15% with rosiglitazone. This is the first study suggesting different rates of beta cell failure related to the type of antidiabetic agent used (11).

A possible cofactor causing a decline of beta cell function may be seen in the chronic challenge of beta cells by supranormal levels of glucose, termed glucose toxicity, which permanently activates the secretory signaling pathways, thereby leading to their desensitiza-tion. This includes the signaling pathway activated by KATP-channel inhibitors. The disturbances in lipid metabolism typical of type 2 diabetes with elevated free fatty acids provide another putatively toxic component, termed by analogy "lipotoxicity," which should be improved with thiazolidinediones.

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