Pharmacotherapy
If the combination of dietary modifications and healthy lifestyle initiatives fail to achieve adequate control of the diabetes after three months then oral hypoglycaemics are introduced into the treatment plan. There are eight different classes of antidiabetic drug: sulfonylureas, meglitinides, biguanides, thiazolidinediones, DPP-4 inhibitors (the gliptins), GLP-1 receptor agonists, SGLT-2 inhibitors and alpha-glucosidase inhibitors. These eight classes of drugs work in different ways to lower blood glucose levels and a stepwise approach to combination therapy has been suggested.
Sulfonylureas
Sulfonylureas, of which gliclazide is the most commonly prescribed, stimulate the beta cells of the pancreas to release more insulin. This requires some residual beta-cell activity to be present in order to be effective. Examples of second-generation drugs are glipizide and glimepiride (Amaryl). Glibenclamide is long-acting and therefore has a risk of hypoglycaemia making it unsuitable for elderly patients. Gliclazide and tolbutamide are shorter acting. The sulfonylureas are generally taken one to two times a day, before meals. All sulfonylurea drugs have similar effects on blood glucose levels, but they differ in side effects, how often they are taken and interactions with other drugs. The main side effect of sulphonylureas is weight gain which is undesirable for overweight diabetic patients. They can also cause hypoglycaemia; the risk of hypoglycaemia is increased in patients with mild to moderate renal impairment or severe hepatic impairment.
Meglitinides
Meglitinides are drugs that also stimulate the pancreatic beta cells to release insulin. Repaglinide and nateglinide are currently the only two examples of meglitinides. They are taken before each of three meals. Meglitinides stimulate the release of insulin and so have the potential to cause hypoglycaemia, however, because they are shorter acting than the sulfonylureas the risk is lower. The shorter and quicker action of these drugs facilitates flexible dosing and makes them more suitable for patients who have irregular meals e.g. shift workers.
Biguanides
Metformin is the only available biguanide and it lowers blood glucose levels primarily by decreasing the amount of glucose produced by the liver (gluconeogenesis). Metformin also helps to lower blood glucose levels by making muscle tissue more sensitive to insulin increasing peripheral utilisation of glucose and reducing intestinal glucose absorption. It is only effective in the presence of endogenous insulin and so requires some residual functioning of pancreatic islet cells. Metformin does not usually cause hypoglycaemia although it can cause gastrointestinal side effects on initiation of treatment, these can be persistent, particularly with higher doses. Gastro-intestinal side effects can be minimised by initiating treatment at a low dose and increasing the dose gradually to a maximum of 2g daily in divided doses.
The main benefit of metformin is that it leads to weight loss and so is useful for reducing obesity in type 2 diabetics.
Thiazolidinediones (PPAR gamma agonists)
Pioglitazone is now the only available thiazolidinedione since the suspension of the marketing authorisation for rosiglitazone (Avandia) in September 2010 due to fears over cardiac safety. This class of drugs act as agonists of the gamma peroxisome proliferator activated receptor so are also referred to as PPAR gamma agonists. Pioglitazone reduces the peripheral resistance to insulin thereby allowing muscle and fat tissue to take up more glucose and hence reduce blood glucose levels. The CHM advises that the incidence of heart failure is increased when pioglitazone is combined with insulin, especially in those with predisposing factors. Patients should be monitored for any signs of heart failure and the drug should not be used in those with a history of heart failure. In addition the European Medicines Agency has warned about a small increase in the risk of bladder cancer associated with pioglitazone use thereby contra-indicating its use in patients with active or previous bladder cancer. Patients should report any blood in the urine, urinary urgency or other bladder problems immediately. Due to rare reports of liver dysfunction patients should also be monitored closely for symptoms such as nausea, vomiting, abdominal pain, fatigue and particularly jaundice as a precaution.
DPP - 4 Inhibitors (Gliptins)
This class of drugs works by preventing the breakdown of a naturally occurring compound in the body, Glucagon-Like Peptide-1 by inhibiting dipeptidylpeptidase-4. GLP-1 reduces blood glucose levels in the body, but is broken down very quickly so it does not work well when injected as a drug itself. By interfering in the process that breaks down GLP-1, DPP-4 inhibitors allow it to remain active in the body longer, lowering blood glucose levels only when they are elevated. DPP-4 inhibitors do not tend to cause weight gain and tend to have a neutral or positive effect on cholesterol levels. Sitagliptin, saxagliptin, alogliptin, linagliptin and vildagliptin are currently the only DPP-4 inhibitors on the market.
GLP -1 receptor agonists
Exenatide and liraglutide both activate the glucagon-like peptide-1 receptor which has the effect of increasing insulin secretion, suppressing glucagon secretion and slowing gastric emptying. Both drugs are administered via subcutaneous injection and are licensed for combination therapy with metformin alone or in triple therapy with a sulfonylurea or thiazolidinedione. Treatment with these drugs is associated with weight loss which benefits overweight patients.
SGLT-2 inhibitors
Dapagliflozin, canagliflozin and empagliflozin are all inhibitors of sodium-glucose co-transporter 2 (SGLT2). SGLT2 is a transporter protein that filters glucose from the proximal convoluted tubule. Inhibition of this transporter protein reduces reabsorption and increases renal excretion of glucose, lowering blood glucose with a low risk of hypoglycemia. Increased excretion of glucose can have an osmotic effect causing dehydration and hypotension especially in patients taking diuretics. Other side effects of this group of drugs include genital and urinary tract infections, dysuria, polyuria and thirst.
SGLT-2 inhibitors have been linked to an increased risk of diabetic ketoacidosis (DKA) in patients with type 2 diabetes. The European Medicines Agency (EMA) have advised that patients treated with SGLT-2 inhibitors should be tested for raised ketones even where blood glucose levels are normal, and treatment discontinued where DKA is suspected. Patients should be advised to report signs of DKA including nausea and vomiting, excessive thirst, weight loss, unusual fatigue or tiredness and weight loss.
Alpha-glucosidase inhibitors
Acarbose is an alpha-glucosidase inhibitor which helps to lower blood glucose levels by blocking the digestion and absorption of starches in the intestine. It also slows the breakdown of some sugars, such as sucrose. These actions slow the rise in blood glucose levels after a meal. They should be taken with the first bite of a meal. Side effects include flatulence and diarrhoea (possibly requiring withdrawal or a reduced dose).
Combination therapy
The drugs listed above act in different ways to lower blood glucose levels, they may be used together. Current NICE guidance (NG28) advises a stepwise approach to the treatment of type 2 diabetes.8 Metformin is the recommended first line treatment, where this is contra-indicated or not tolerated treatment with a DPP-4 inhibitor, pioglitazone or sulphonylurea should be considered. Dual or triple therapy may be required to adequately control blood glucose levels. Where combinations of the drugs discussed do not effectively control blood glucose levels in patients with type 2 diabetes insulin therapy may be initiated.
Taking more than one drug can be more costly and increase the risk of side effects, but combining medications can improve blood glucose control when taking only a single medication does not have the desired effects. Switching from one single medication to another is not as effective as adding another type of diabetes medicine.
Blood lipids and antiplatelet treatment
NICE guidelines recommend patients with type 2 diabetes who are assessed as having a 10% or greater risk of developing cardiovascular disease are offered atorvastatin 20mg for the prevention of cardiovascular disease.9
NICE also recommends that patients should not be routinely prescribed antiplatelet therapy (aspirin or clopidogrel) for the primary prevention of cardiovascular disease.