SU derivatives and Meglinitides

In 1942, a new sulfonamide antibacterial agent developed for the treatment of typhus, was noted to result in hypoglycaemia with seizures and coma. Studies in animals revealed that this effect only occurred when pancreatic tissue was present, leading to the hypothesis that it stimulated the secretion of insulin by the pancreas and that it might be used to treat human diabetes. However, when the first of these so-called sulphonylurea derivatives, carbutamide, was clinically used in 1955, this went not without some dispute, for carbutamide seemed to work only in those with mild diabetes of less than 10 years duration; many argued that a drug which had severe side-effects in 5% of cases was a poor choice for a disease that could also safely be treated by a strict diet. However, soon safer sulfonylurea drugs were developed: tolbutamide (marketed in 1956 and still used today), chlorpropramide (1958) and many more since. While the side-effects of these drugs, notably hypoglycaemia and weight gain, have remained a point of discussion to this day, these drugs are now generally considered the second-line treatment of type 2 diabetes based on their relatively good performance in the UKPDS study and the availability of reassuring long term safety data.

Mechanism of action

The hypothesis that sulfonylurea derivatives stimulate insulin secretion was further corroborated by the fact that their hypoglycaemic action does not occur in persons with long-standing type 1 diabetes or those with pancreatic forms of diabetes (e.g. after total pancreatectomy). Fig 1. Mechanism of action of SUs.  Normally, the rise in ATP/ADP ratio that is the result of the metabolism of an influx of glucose leads to the closure of the ATP-dependent potassium channel, which in turn results in the depolarisation of the beta-cell membrane, the influx of calcium ions and finally the release of insulin from storage granules. SUs close the ATP-dependent potassium channel by a direct action on the SUR subunit, which triggers the same series of events.
Fig 1. Mechanism of action of SUs. Normally, the rise in ATP/ADP ratio that is the result of the metabolism of an influx of glucose leads to the closure of the ATP-dependent potassium channel, which in turn results in the depolarisation of the beta-cell membrane, the influx of calcium ions and finally the release of insulin from storage granules. SUs close the ATP-dependent potassium channel by a direct action on the SUR subunit, which triggers the same series of events.
After a long series of studies, it was demonstrated that sulfonylurea derivatives bind to specific subunit of the ATP-dependent potassium channel of the beta-cell, nowadays called the SUR (SulfonylUrea Receptor). Similar to the the glucose-dependent increase in ATP/ADP ratio, this binding results in closure of the ATP-dependent potassium channel, which leads to depolarisation of the cell membrane followed by calcium-influx and subsequent release of insulin (fig 1). The meglinitides bind to specific sites of the SUR, with the same downstream effects.

Efficacy of Sulfonylurea Derivatives

The sulfonylurea derivatives are potent glucose-lowering drugs as long as the patient has residual insulin secretory capacity. They lower HbA1c levels by about 1.5%. As for many drugs, particularly those developed before the era of evidence based medicine, data on hard enpoints are scarce. The results of the UKPDS indicate an about 30% lower risk of microvascular complications when using SUs to lower HbA1c compared to conventional treatment; while there was no difference in mortality in the UKPDS study, the subsequent observational UKPDS-Follow Up study found a significant 10% relative mortality risk reduction in those previously treated with SU. Some recent observational studies suggest that gliclazide may be associated with more favourable cardiovascular outcomes compared to the other SUs.

Adverse events

The most notable adverse events associated with the use of SUs are hypoglycaemia and weight gain. About 10-30% of patients using SUs for several years will suffer from mild hypoglycaemia, and less than 1% will experience severe hypoglycaemia. The frequency of mild hypoglycaemic episodes is somewhere between 1 and 6 events per year. Individual hypoglycaemia risk is influenced by factors such as age, the duration of diabetes and the type of SU used. Glibenclamide was notorious for a relatively high hypoglycaemia risk; moreover, with the once-daily (longer-acting) SUs such as glibenclamide and glimepiride, a severe hypoglycaemic episode can also persist for a long time necessitating prolonged clinical observation.

In the absence of adaptations in eating pattern or energy expenditure, any drug that will reduce glucosuria will increase calorix exposure and will tend to increase weight. However, notable but not entirely explained differences exist between various classes of drugs. While metformin is weight-neutral or associated with slight weight loss, SUs and insulin tend to increase weight. Some patients report very high weight gains with SUs, but objective data from the UKPDS and other studies show that over the course of several years people using SUs gain about 4 kgs, with controls gaining about 1.5 to 2kgs; thus, SUs are associated with a modest excess weight gain of about 2 to 2.5 kgs (or about 2.5% of initial weight). Apart from these two side-effects that are directly linked to the efficacy of the SUs, over 60 years of use have demonstrated this class of drugs to be generally safe and well-tolerated.

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