Sixty Years of Diabetes Management in Primary Care
In the 1950s, sulphonylureas were the only oral antidiabetic agents available for routine clinical use. They were associated with hypoglycaemia and weight gain and the American University Group Diabetes Program (1970) suggested that sulphonylureas might aggravate cardiovascular complications.
Biguanides entered routine use in the early 1960s and while they did not cause hypoglycaemia or weight gain, the link with lactic acidosis and the withdrawal of phenformin in the late 1970s restricted their use until the revival of metformin in the 1980s and 90s. Metformin is now the first line drug for all patients with type 2 diabetes unless there is a specific contraindication such as severe renal or liver disease.
In the 1990s, the alpha-glucosidase inhibitor acarbose, the meglitinides and the thiazolidinediones were introduced. The use of acarbose was limited by gastrointestinal intolerance. Meglitinides have been viewed as little more than short-acting sulphonylureas, although there are subtle mechanistic differences Thiazolidinediones have come under a cloud following the withdrawal of rosiglitazone in Europe, due to increased cardiovascular complications, and recent information that pioglitazone may be linked with bladder cancer has caused some concern. It is also associated with weight gain and fluid retention and is contraindicated in patients with cardiac failure. However, due to its effect on insulin sensitivity, which leads to insulin sparing, it still remains a useful drug in the armamentarium for patients with diabetes.
The incretin story gathered pace in the late 1990s and in 2005, a GLP1 analogue exenatide was introduced, closely followed by liragutide. These drugs are delivered by injection. They have the advantage of producing a glucose dependent release of insulin, and therefore do not cause hypoglycaemia. They also have the added benefit of weight loss.
Around the same time, drugs which inhibit the breakdown of GLP-1 by the enzyme DPP-4 were introduced, and sitagliptin has become a market leader in the UK. There are now four DPP-4 inhibitors/gliptins available in the UK. They are, in order of launch in the UK, sitagliptin, vildagliptin, saxagliptin and linagliptin and several others are in late stage development.
A systematic review and meta-analyses of current DPP-4 therapies considered 19 studies (9 with sitagliptin, 6 with vildagliptin, 3 with saxagliptin and 1 with linagliptin) in which 7,136 people were randomised to DPP-4 inhibitor therapy and 6,745 to another glucose lowering therapy. The review concludes that DPP4 inhibitors when added to metformin lower HbA1c to a similar degree as sulphonylureas or pioglitazone but with neutral effects on body weight.
Dapagliflozin the first in a new class of oral glucose lowering agent – the SGLT2 inhibitors – has just (November 2012) received marketing authorisation in Europe for the treatment of type 2 diabetes.
These exciting developments have made decisions on medicines management more complex. The NICE guideline on the management of type 2 diabetes has provided a helpful algorithm.
Therapeutic Advances
All Agents
In the 1950s, sulphonylureas were the only oral antidiabetic agents available for routine clinical use. They were associated with hypoglycaemia and weight gain and the American University Group Diabetes Program (1970) suggested that sulphonylureas might aggravate cardiovascular complications.
Biguanides entered routine use in the early 1960s and while they did not cause hypoglycaemia or weight gain, the link with lactic acidosis and the withdrawal of phenformin in the late 1970s restricted their use until the revival of metformin in the 1980s and 90s. Metformin is now the first line drug for all patients with type 2 diabetes unless there is a specific contraindication such as severe renal or liver disease.
In the 1990s, the alpha-glucosidase inhibitor acarbose, the meglitinides and the thiazolidinediones were introduced. The use of acarbose was limited by gastrointestinal intolerance. Meglitinides have been viewed as little more than short-acting sulphonylureas, although there are subtle mechanistic differences Thiazolidinediones have come under a cloud following the withdrawal of rosiglitazone in Europe, due to increased cardiovascular complications, and recent information that pioglitazone may be linked with bladder cancer has caused some concern. It is also associated with weight gain and fluid retention and is contraindicated in patients with cardiac failure. However, due to its effect on insulin sensitivity, which leads to insulin sparing, it still remains a useful drug in the armamentarium for patients with diabetes.
The incretin story gathered pace in the late 1990s and in 2005, a GLP1 analogue exenatide was introduced, closely followed by liragutide. These drugs are delivered by injection. They have the advantage of producing a glucose dependent release of insulin, and therefore do not cause hypoglycaemia. They also have the added benefit of weight loss.
Around the same time, drugs which inhibit the breakdown of GLP-1 by the enzyme DPP-4 were introduced, and sitagliptin has become a market leader in the UK. There are now four DPP-4 inhibitors/gliptins available in the UK. They are, in order of launch in the UK, sitagliptin, vildagliptin, saxagliptin and linagliptin and several others are in late stage development.
A systematic review and meta-analyses of current DPP-4 therapies considered 19 studies (9 with sitagliptin, 6 with vildagliptin, 3 with saxagliptin and 1 with linagliptin) in which 7,136 people were randomised to DPP-4 inhibitor therapy and 6,745 to another glucose lowering therapy. The review concludes that DPP4 inhibitors when added to metformin lower HbA1c to a similar degree as sulphonylureas or pioglitazone but with neutral effects on body weight.
Dapagliflozin the first in a new class of oral glucose lowering agent – the SGLT2 inhibitors – has just (November 2012) received marketing authorisation in Europe for the treatment of type 2 diabetes.
These exciting developments have made decisions on medicines management more complex. The NICE guideline on the management of type 2 diabetes has provided a helpful algorithm.