1. Adding a sulphonylurea:3,6
With many years of clinical experience, gliclazide and glipizide have good efficacy, especially in leaner patients. There is a risk of hypoglycaemia (but considerably lower than that of the longer acting glibenclamide), especially in the elderly at night and those that skip meals. A sulphonylurea can cause mild weight gain. It may “exhaust” pancreatic ß-cell function earlier than some other drugs, but these are drugs we know well and feel comfortable with, though sometimes falsely so.
This drug is rarely used in primary care, and does have its pros and cons. It seems better suited for use in overweight men as an insulin sensitizer. It may reduce steatohepatitis7 and may have a role in cardiovascular risk reduction, especially after transient ischaemic attacks (TIAs) or stroke.8 Pioglitazone raises high-density lipoprotein (HDL) cholesterol levels. It does not cause hypoglycaemia, when used alone or with metformin, and is a once daily drug. But, pioglitazone usually causes weight gain, and the risk of fluid retention in some patients means it shouldn’t be used in those with a history of heart failure. Pioglitazone also causes osteoporosis and increases absolute fracture risk by around 2%, especially in women.9 It has been rarely associated with macular oedema. The adverse events associated with pioglitazone may mean that patients are less willing to use it, but I still prescribe pioglitazone in some men with truncal obesity that are not achieving HbA1c targets.
Given 2–3 times daily before meals to reduce carbohydrate absorption, acarbose can cause a weak but definite reduction in HbA1c in high carbohydrate consumers. It might be better placed in “pre-diabetes” patients, as it may reduce cardiovascular risk.10 Gastrointestinal side effects, such as flatulence, can be troublesome to patients.
4. And now DPP-4 inhibitors:6,11
Pharmac funded a new oral hypoglycaemic, vildagliptin, in October 2018. This once or twice daily drug is a useful second- or third-line agent for us all to seriously consider. Vildagliptin works by inhibiting an enzyme (DPP-4) that breaks down GLP-1 and glucose-dependent insulinotropic polypeptide (GIP); incretin hormones secreted from the small intestine. Insulin release is increased only when we eat, and glucagon secretion is reduced (Figure 1). Vildagliptin is weight neutral, and has a low risk of causing hypoglycaemia used alone or with metformin. Conveniently for many, vildagliptin also comes as a combined tablet with different strengths of metformin. Vildagliptin can be used alone, but greater reductions in HbA1c are observed as an add-on to metformin. Vildagliptin may also be effective after metformin and a sulphonylurea as a third oral agent. In studies comparing vildagliptin versus placebo as monotherapy, or in dual or triple combination with a sulphonylurea (as an add-on to metformin), it appears comparable and able to reduce HbA1c by a mean of 0.7–1.1%.12 Vildagliptin has been widely used around the world in the last 8–10 years, especially in Europe and Scandinavia, and so we have a lot of information on safety. DPP-4 agents are well-tolerated; there are some reports of nasopharyngitis, headache and dizziness, and very rare reports of pancreatitis.