This site is intended for health professionals only

Newer therapies in type 2 diabetes

Jill Hill
Diabetes Nurse Consultant
NHS Birmingham East and North

Type 2 diabetes causes a number of disabling complications and is getting more common and newer therapies can improve glycaemic control without weight gain and less risk of hypoglycaemia

Type 2 diabetes is a common condition leading to costly micro-vascular (retinopathy, nephropathy, neuropathy) and macro-vascular complications. Improved glycaemic control reduces micro-vascular complications and this, together with the rapidly increasing numbers of people developing the condition, means the increasing arsenal of antidiabetes drugs available is to be welcomed.1 This article gives an overview of traditional agents, discusses the new drugs and describes NICE recommendations for their use.

Traditional treatments
Until relatively recently, there were just two classes of oral anti-diabetes treatments for lowering blood glucose in people with type 2 diabetes. In the author's early experience as a diabetes nurse, metformin was prescribed if the person was overweight, and a sulphonylurea if lean. When monotherapy became ineffective, the other drug was added in and then both were stopped and insulin commenced as glycaemic control deteriorated further.

The control of blood glucose in someone without diabetes is complex, and is not just related to the amount of glucose passing into the blood stream from food digested in the gut (specifically carbohydrates) and the amount of insulin produced in response by pancreatic beta cells. The liver is important as an organ of glucose storage (as glycogen) and producer of glucose (via glycogenolysis or breakdown of glycogen, and gluconeogenesis, or producing glucose from fatty and amino acids).

More recently, there has been increasing interest in the role of gut hormones (the incretin system) in slowing down gastric emptying and promoting a feeling of satiety, reducing glucagon production after meals (therefore reducing liver glucose production), and glucose-dependent stimulation of beta cells related to the quantity of carbohydrate passing through the gut.2

[[Tab 1 newer therapies]]

Type 2 diabetes is a complex condition, associated with insulin resistance and increasing beta cell failure. It is progressive which means therapy needs to be tailored to the individual and stage of diabetes, initially aimed at improving sensitivity to endogenous insulin, then to stimulating more insulin production from failing beta cells, and finally gradual insulin supplementation by injections.3,4

The glitazones (thiazolidinediones) were introduced about 20 years ago: rosiglitazone followed by pioglitazone. They were promoted as insulin sensitizers, tackling the main problem associated with many overweight people with type 2 diabetes (ie. insulin resistance). The main side-effect was fluid retention so they are contraindicated in people with heart failure. Recently, there were concerns about the occurrence of small bone fractures, particularly in women. In 2010, rosiglitazone was removed by the manufacturers because of mounting concerns about increased risk of adverse cardiac events compared to other antidiabetes drugs, first identified by Nissan and Wolski.5

Problems with traditional treatments
Weight gain is a common side-effect of pioglitazone, sulphonylureas and insulin.6 This is unfortunate as most people with type 2 diabetes are overweight. There can be a vicious cycle of increasing medication to control blood glucose, but weight gain increases insulin resistance, as well as exacerbating other co-morbidities, such as sleep apnoea and arthritis, and affecting self-esteem. Despite more organised diabetes care, glycaemic control has not improved significantly while obesity levels have increased in the type 2 population.7

Another common side-effect of sulphonylureas and insulin
therapy is the risk of hypoglycaemia. Until recently, the frequency and impact on people with type 2 diabetes were not recognised. In an audit in 2008 by the East of England Ambulance Service, hypoglycaemia accounted for 30% of all diabetes-related call-outs.8 There were similar rates of hypoglycaemia episodes in type 2 diabetes treated with sulphonylureas as with insulin. Over the year-long study period, 39% of sulphonylurea users reported having mild hypo (51% people using insulin) and 7% had a severe hypoglycaemic episode (same as 7% of people using insulin).

Severe hypoglycaemia is associated with seizures, transient ischaemic attacks and coma, particularly in older people.9 About 40 road traffic accidents each month are estimated to result from hypoglycaemia, resulting in approximately five deaths annually.10

Risk of hypoglycaemia is a particular concern in the elderly, those living alone, drivers and those with declining renal function. Hypoglycaemia and fear of hypoglycaemia have a big impact on quality of life, and anxiety about hypoglycaemia may be a significant barrier to patients aiming for target HbA1c.11

Newer therapies
The most recently available anti-diabetes drugs are associated with the incretin hormone system. These hormones are naturally produced in the small intestines and have various effects related to blood glucose control as described above. Incretin hormone levels are reduced in people with type 2 diabetes.12 There are two classes of drugs related to one specific incretin hormone: glucagon-like peptide-1 or GLP-1:
The GLP-1 (glucagon-like peptide-1) receptor agonist is a subcutaneous injection, which mimics the action of GLP-1. There are two agents available: exenatide (Byetta) and liraglutide (Victosa).

DPP-4 (Dipeptidyl peptidase-4) inhibitors (also known as gliptins) are once- or twice-daily oral agents that inhibit naturally-occurring DPP-4 (an enzyme that deactivates the incretin hormone GLP-1). The mode of action for DPP4- inhibitors is to prolong the action of endogenous incretin GLP-1 hormone and therefore increase its effectiveness. There are three preparations available: sitagliptin (Januvia), vildagliptin (Galvus) and saxagliptin (Onglyza) with more on the way.

Both these classes of drugs increase the amount of insulin produced by the beta cells when blood glucose is elevated, and reduce the amount of glucagon released from the pancreatic alpha cells after a meal (therefore reducing the amount of glucose produced by the liver). As the efficacy of the DPP4-inhibitors is limited by the amount of endogenous GLP-1 hormone produced in the gut, the GLP-1 agonists generally have a more pronounced effect on insulin release and reduction of glucagon release and therefore have a more significant impact on reducing glycated haemoglobin (HbA1c).

Unlike most traditional anti-diabetes drugs, these new therapies do not cause weight gain, and in fact GLP-1 agonists can be associated with considerable weight loss. They also have a low risk of causing hypoglycaemia (although they may potentiate the effect of sulphonylureas and insulin). Although the DPP4- inhibitors as a class seem to be well-tolerated, the GLP-1 receptor agonists are significantly associated with nausea and vomiting and there were some early concerns when exenatide was first launched that there was an increased risk of pancreatitis. Patients should be warned to stop the therapy and seek medical attention should they develop acute abdominal pain when using this therapy.

Both GLP-1 agonists are licensed for combination with metformin or a sulphonylurea in patients with insufficiently controlled blood glucose with monotherapy, and in combination with metformin and a sulphonylurea, or metformin and pioglitazone in patients with insufficiently controlled blood glucose on dual therapy. However, NICE has restricted the use of exenatide to triple therapy (in combination with metformin and sulphonylurea, or metformin and glitazone) as an alternative to insulin if HbA1c is 7.5% (59 mmol/mol) or greater and the patient has a body mass index (BMI) of 35 kg/m2 or greater (with appropriate adjustment for other ethnic groups) and specific psychological or medical problems associated with body weight, or has a BMI less than 35 kg/m2 but use of insulin therapy would have significant occupational implications.13

Liraglutide was the second GLP-1 receptor agonist to become available and is covered by NICE TA203, which includes use as dual therapy.14 As this is a technology appraisal, mandatory funding arrangements must be in place to provide it, whereas exenatide is covered by a clinical guideline which does not have this requirement. NICE recommends discontinuing the treatment unless at least a 1% drop in HbA1c and 3% reduction in weight are achieved after six months.

Treatment pathway from NICE
NICE guidelines for the management of type 2 diabetes were revised in clinical guideline 66 and further revised (CG 87) in 2009 to include new agents.13,15 The HbA1c target for most people should be 6.5% (48 mmol/mol) or less for the first two steps. This is based on the “legacy effect” from the UK Prospective Diabetes Study follow-up, which demonstrated long-term benefits from tight control at time of diagnosis and the early stages of the condition.16 The target changes to 7.5% (59 mmol/mol) at Step 3 as diabetes progresses, as the benefits of tight glycaemic control is less clear and may in fact be harmful (see Tables 2 and 3).17

[[Tab 2 newer therapies]]
[[Tab 3 newer therapies]]

References

  1. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-53.
  2. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006;368(9548):1696-705.
  3. UK Prospective Diabetes Study (UKPDS) Group. UK Prospective Diabetes Study 16. Overview of 6 years' therapy of type II diabetes: a progressive disease. Diabetes 1995;44:1249-58.
  4. Bailey CJ, Day C. Antidiabetic drugs. British Journal of Cardiology 2003;10:128-36.
  5. Nissan SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular cause. N Engl J Med 2007;356:2457-71.
  6. Barnett A, Allsworth J, Jameson K, Mann R. A review of the effects of antiglycaemic agents on body weight: the potential of incretin targeted therapies. Curr Med Res Opin 2007;23:1493-507.
  7. Lusignan S, Sismanidis C, Carey IM, DeWilde S, Richards N, Cook DG. Trends in the prevalence and management of diagnosed type 2 diabetes 1994-2001 in England and Wales. BMC Fam Pract 2005;6:13.
  8. Maillardet V. Diabetes patient service report. London: East of England Ambulance Service NHS Trust; 2008.
  9. UK Hypoglycaemia Study Group. Risk of hypoglycaemia in type 1 and 2 diabetes: effect of treatment modalities and their duration. Diabetologia 2007;50:1140-7.
  10.  Hitchen L. Doctors are failing to tell diabetic people about UK driving rules. BMJ 2006;332:812.
  11. Amiel SA, Dixon T, Mann R, Jameson K. Hypoglycaemia in type 2 diabetes. Diabet Med 2008;25:245-54.
  12.  Nauck M, Stockman F, Ebert R. Reduced incretin effect in type 2 (non-insulin dependent) diabetes Diabetologia 1986;29:46-52.
  13.  National Institute of Health and Clinical Excellence (NICE). Type 2 diabetes: The management of type 2 diabetes. Clinical Guideline 87. London: NICE; 2009.
  14.  National Institute of Health and Clinical Excellence (NICE). Liraglutide for the treatment of type 2 diabetes mellitus. Technology Appraisal Guidance 203. London: NICE; 2010.
  15.  National Institute of Health and Clinical Excellence (NICE). Type 2 diabetes. Management of type 2 diabetes. Clinical Guideline 66. London: NICE; 2008.
  16.  Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008;359:1577-89.
  17.  Currie CJ, Peters JR, Tiernan A (2010) Survival as a function of HbA1c in people with type 2 diabetes: a retrospective study. Lancet 2010;375:481-9.
  18.  Driving and Vehicle Licensing Agency. For Medical Practitioners. At a glance Guide to the current Medical Standards of Fitness to Drive. Drivers Medical Group, Swansea; 2009.