Glp

Glucagon-like peptide-1 has the potential to improve glucose metabolism through a variety of different actions as shown in Figure 19.1. Perhaps the most exciting is the suggested potential to improve beta cell insulin biosynthesis. They also inhibit secretion of glucagon, a somewhat neglected hormone in diabetes thus far. Figure 19.2 shows the impairment of the normal incretin response in patients with type 2 diabetes. The incretin Exenatide is currently available in many countries and a long-acting preparation is also in development. It is started at a dose of 5 mg twice daily by subcutaneous injection as the initiation of therapies is often associated with nausea. The dose is then increased to 10 mg twice daily. Use of GLP-1 agonists do not preclude patients from driving. This is therefore particularly useful in patients whose occupation depends on driving public service vehicles. These patients would otherwise lose their livelihood if they start insulin. However, if adequate glycaemic control is not achieved with a GLP-1 agonist then it is important to advise the patient that insulin is necessary. When GLP-1 agonists are added to other oral agents a further 1% (11 mmol/mol) reduction or so in HbA1c can be expected, although some patients may achieve more or less than this. A useful additional effect is weight loss, which is particularly useful in overweight or obese type 2 patients. Excess risk of pancreatitis has been observed in post-marketing studies although the absolute number of events is very small. It is, however, wise to avoid it in patients who may be otherwise at risk of pancreatitis. It is currently not advisable to use this along with insulin, as combination therapy has been shown to result in much higher rates of hypoglycaemia. If prescribed with sulphonylureas it is important that should hypoglycaemia occur, the dose of sulphonylurea is reduced. Liraglutide is a more recently introduced GLP-1 analogue that is given as a single daily dose.

DDP4 Inhibitors

As oral agents these are a useful addition to metformin or sulpho-nylureas as they appear to be relatively well tolerated with no major side effects that have come to light so far. Sitagliptin was the first to become available in the UK and is initially prescribed at a dose of 100 mg daily. Vildagliptin is available at a dose of 50 mg daily. They generally produce reductions of HbA1c between 0.7 and 1% (7.7-11 mmol/mol), do not produce hypoglycaemia on their own and are weight-neutral. These drugs are useful additional therapy as they may produce further reduction in hyperglycaemia. As with GLP-1 agonist therapy, no long-term outcome data are available with this class of drugs.

Obesity

Life-style modification is difficult once patients have type 2 diabetes. The disease itself and the drugs often used by patients with diabetes mean that progressive weight gain often occurs. Reduction in weight using drug therapy brings with it benefits in terms of

Increased insulin secretion from beta-cells in response to GLP-1 secretion triggered by ingested carbohydrate

Increased insulin secretion from beta-cells in response to GLP-1 secretion triggered by ingested carbohydrate

Direct central effect on improving satiety

Figure 19.1 Multiple effects of the incretin GLP-1 on glucose regulation

Direct central effect on improving satiety

Delays gastric emptying

Reduces glucagon secretion following meals

Reduced release of glucose to plasma from hepatic glycogen stores

GLP-1 secreted from the small bowel in response to carbohydrate ingestion

Figure 19.1 Multiple effects of the incretin GLP-1 on glucose regulation

The Incretin Effect: Response to Oral vs IV Glucose

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