SummaryThe ancient Egyptians thought that diabetes was due to an ‘imbalance of the four bodily elements’ and that the best treatment to give these patients was a mixture of ground earth, water, wheat and lead. Thankfully, things have improved a little since then! In fact, the most important advance in diabetes management occurred in 1921 when the young surgeon Frederick Banting and the even younger medical student, Charles Best, first isolated insulin.
The ancient Egyptians thought that diabetes was due to an ‘imbalance of the four bodily elements’ and that the best treatment to give these patients was a mixture of ground earth, water, wheat and lead. Thankfully, things have improved a little since then! In fact, the most important advance in diabetes management occurred in 1921 when the young surgeon Frederick Banting and the even younger medical student, Charles Best, first isolated insulin.
Insulin was lifesaving for many thousands of people with diabetes (those with type 1 diabetes) and health preserving for many millions more (those with type 2 diabetes). It is interesting to note that it was not until the 1940s that the hypoglycaemic effect of the sulphonamides was first recorded and the mid-1950s before the first oral agent for the management of type 2 diabetes came on the scene. This was the first sulphonylurea, followed closely by the first biguanide. To date, we have a number of different sulphonylureas at our disposal, but the only biguanide still in use is metformin. It was another 30 years before the next new drug class came on the scene, the á-glucosidase inhibitors (e.g. acarbose). The latter has, unfortunately, relatively limited potency and a high frequency of unpleasant gastrointestinal side-effects.
At last, in this first decade of the new millennium, we suddenly have a wealth of new products coming through. Potentially the most interesting of these is a new class of insulinsensitising agents, called the thiazolidinediones or glitazones.
Why do we need new agents for the management of type 2 diabetes? The United Kingdom Prospective Diabetes Study (UKPDS) showed very clearly that only a small percentage of patients with type 2 diabetes will manage long term on diet alone and that, over time, the great majority will need combination oral treatment and/or insulin to get even close to glycaemic targets. The UKPDS also demonstrated that type 2 diabetes is a progressive disease with an almost inevitable deterioration in glycated haemoglobin (HbA1C) over time, and that none of the current therapies (i.e. the sulphonylureas, metformin or insulin) will slow disease progression. In addition, use of these traditional agents is associated with unwanted consequences such as gastrointestinal disturbances in around 10% of those taking metformin, and a risk of weight gain and hypoglycaemia with the sulphonylureas and insulin. Although these drugs will remain very important agents for the foreseeable future, the above limitations provide a strong rationale for the development of new therapies to add to the armamentarium currently at our disposal. Ideally, new drugs should have better tolerability/side-effect profiles and should directly target the fundamental defects in disease development and progression, thereby preventing what has in the past been an inevitable deterioration in diabetic control.
The glitazones have much potential in that they appear to target the fundamental defects of type 2 diabetes. They act by combining with an intranuclear receptor, which then elicits effects on carbohydrate and lipid metabolism similar to that seen when insulin combines with its receptor. This means that these agents have an insulin-sparing effect thereby improving insulin sensitivity and reducing insulin resistance, one of the two fundamental defects of type 2 diabetes. There is also evidence that they may also improve pancreatic â-cell function, which is the other primary defect of type 2 diabetes.
These agents have been shown in clinical trials not only to have beneficial effects from the point of view of glycaemia, but may also benefit the lipid profile and reduce blood pressure by a small amount. These actions presumably relate to an improvement in insulin resistance. This view is supported by the fact that other recent studies have demonstrated improvement in other cardiovascular risk markers commonly associated with the metabolic syndrome and cardiovascular disease (e.g. C-reactive protein [CRP], plasminogen activator inhibitor-1 [PAI-1] and microalbuminuria). Recent studies have also reported that these agents may slow/halt progression from impaired glucose tolerance to overt type 2 diabetes. This is in the context of a number of relatively small clinical trials, which are now being repeated in much larger studies.
These preliminary findings, therefore, suggest that the glitazones not only improve glycaemic control, but also have the potential to reduce cardiovascular risk and prevent/slow progression from impaired glucose tolerance to type 2 diabetes, and indeed to slow further progression of established type 2 diabetes. A number of large-scale clinical trials are now underway to answer these questions and determine definitively whether or not these agents show significant advantages over the traditional oral agents for the management of type 2 diabetes.
In summary, there are a wealth of reasons why newer drugs for the management of type 2 diabetes are to be welcomed. These include the fact that there are presently only a limited range of therapies available, and these may be associated with side-effects such as gastrointestinal disturbance (metformin and acarbose) and weight gain/hypoglycaemia (the sulphonylureas and insulin). Traditional agents do not affect disease progression whilst combination therapy is commonly required to achieve guideline targets. For these reasons the advent of the glitazones is to be welcomed, particularly as they appear to have the potential to improve cardiovascular outcomes and prevent/slow disease progression with generally very good tolerability profiles. Large-scale clinical trials will determine whether these drugs will have a moderate or highly significant impact on diabetes management in the future.
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This Editorial has been written by the specialist opinion leader, Professor Anthony Barnett, Professor of Medicine and Consultant Physician at the University of Birmingham and Birmingham Heartlands Hospital and published in the latest issue of the serial publication, Drugs in Context.
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