Drug treatment for type II diabetes

Drug therapy for diabetes aims to reduce fasting glucose levels and a marker called glycosylated haemoglobin (HbA_1c), which is formed from the oxygen-carrying blood protein with glucose attached. As glucose levels in the blood rise, so does the amount of glycosylated haemoglobin.

Therapy also aims to lower the peak in glucose levels after food, since a rise in glucose levels after eating plays an important role in stimulating insulin resistance and in the development of the complications of diabetes such as retinal damage, neuropathy and kidney damage.

The first line of treatment, usually adopted in less severe cases, is to use the class of antihyperglycemic drugs called sulphonylureas. These include glipizide (Glibenese) and glimepiride (Amaryl). These drugs stimulate the pancreas, a small organ located near to the liver in the centre of the abdomen, to produce more insulin. The drawback of this class of drugs is that they can cause weight gain of up to 5kg. Also, sulphonylureas can cause blood sugar to fall too low, leading to the state called hypoglycaemia.

Glyburide is not recommended for use in people with renal insufficiency (reduced ability of the kidneys to remove waste products), and is also associated with a higher risk of hypoglycaemia. Glipizide and glimepiride are less likely to cause weight gain.

An alternative first-line treatment is metformin (Glucophage), which does not act directly on insulin, but instead reduces production of glucose in the liver. Metformin tends to reduce weight, unlike the sulphonylureas, and has a comparable effect on HbA, as well as reducing insulin levels. It is therefore used commonly in obese patients, but is not suitable for people with antiretroviral-induced fat loss.

Metformin may also reduce triglyceride and LDL cholesterol levels, both of which are often elevated in people with high glucose levels on HAART. Long-term metformin treatment is also associated with a lower risk of heart attack when compared to dietary adjustment or sulphonylurea. One study has shown that a combination of metformin and exercise helps to reduce the risk of heart disease and improves body fat redistribution in HAART-treated HIV-positive patients.¹

The most frequent adverse effects of metformin treatment are abdominal pain, nausea and diarrhoea, which have been reported by up to 50% of patients during the first few weeks of treatment. This side effect profile may make metformin difficult to tolerate for people who are taking protease inhibitor-containing regimens. However, diarrhoea and gastrointestinal problems are less frequent if metformin is taken with food.

Metformin may also increase the risk of lactic acidosis in people taking nucleoside analogue reverse transcriptase inhibitors (NRTIs). It is important that gastrointestinal symptoms of lactic acidosis are not dismissed as known side effects of metformin.

The third class of drugs is the thiazolidinediones, often referred to as glitazones. These drugs increase insulin-stimulated uptake of glucose by muscle cells, but may have other modes of action that are still unclear. This class includes rosiglitazone (Avandia) and pioglitazone (Actos), and has shown equivalent effects to metformin and the sulphonylureas in the control of insulin. In addition, the drugs have also been shown to improve HDL cholesterol levels and reduce triglyceride levels, reduce blood pressure and clotting, but no long-term studies have yet reported on their impact on the risk of cardiovascular disease.

Glitazones are also associated with weight gain, but this effect may not be entirely unwelcome in people with lipodystrophy, because glitazones have been shown to reduce visceral fat deposits and increase levels of subcutaneous fat. However, there is conflicting evidence about this effect on fat distribution in HIV-related lipodystrophy. Two randomised studies in people with varying glucose levels and HAART-associated lipoatrophy showed no improvement in subcutaneous fat levels or weight.^{2 3} However, another randomised study of HIV-positive patients with drug-induced insulin resistance found that subcutaneous fat increased over three months in the patients treated with rosiglitazone compared with negligible change in people on placebo, coupled with improvements in insulin resistance.⁴ The reason for these different findings is not understood. It is possible that subcutaneous fat may not increase if underlying adipose cells have been lost. Alternatively, peripheral fat gain may only be expected when there is an minimum level of insulin and glucose disturbance to correct.

A concern with the use of rosiglitazone in HIV patients is the finding that it boosts blood levels of triglycerides and cholesterol.^{2 4} Elevated lipids are a known risk factor for heart disease and stroke, but the specific long-term consequences of glitazone treatment in the HIV-infected patients who are taking antiretroviral are unknown. There has also been a report of the development of lipomas, small, benign tumours of fat cells, in an HIV-positive man taking the drug.⁵

See Lipodystrophy in Side-effects for further information on use of this class of drugs in the treatment of lipodystrophy.

Therapy may also include the use of insulin in the form of an injection, or a combination of oral agents to achieve control of glucose levels. For example, metformin is available as a co-formulation with glyburide and may be suitable for use in cases where people are unwilling to inject insulin each day. Insulin therapy is usually reserved for severe cases of type II diabetes, although some experts believe that if it could be used earlier, remission of type II diabetes might be achieved more frequently.