Good glycaemic control reduces hospitalisation in patients with diabetes. Traditional oral hypoglycaemic agents, thiazolidinediones, incretin mimetics and DPP-4 inhibitors all have roles to play
Principal Pharmacist for Diabetes
University Hospitals Leicester
Member of the UKCPA diabetes committee
Diabetes is a chronic condition, characterised by hyperglycaemia due to impaired insulin secretion with or without insulin resistance. The prevalence of diabetes is increasing worldwide. The latest estimates, from October 2009, indicate there were over 145,000 new cases of diabetes diagnosed in the UK during the past year, bringing the total number of those diagnosed to 2.6 million.
Defining ‘good glycaemic control’
‘Good glycaemic control’ is a term that has still not been officially agreed. Clinical trials continue to provide information in helping to understand what is optimal glycaemic control. Two of the first landmark clinical trials, the DCCT and the UKPDS demonstrated a clear benefit of tight glycaemic control compared to conventional control in the development and progression of diabetic complications, for type 1 and type 2 diabetes respectively. The DCCT tight glycaemic control group achieved a mean average HbA1c of 7.4%, compared to the conventional control group with a mean average of 9.1%. The UKPDS tight glycaemic control group achieved a mean average of 7.0% compared to 7.9% in the conventional control group. Hence we have known for many years since these trials that the lowering of blood glucose plays an important role in managing the patient with diabetes and potentially keeping him or her out of hospital due to diabetic complications as their disease progresses. But the question still exists as to what is the best HbA1c target.
Current guidance from the National Institute of Clinical Excellence (NICE) suggests an optimal HbA1c target of less than 6.5% for most of those with type 2 diabetes. However it is recommended that targets should be individualised and that for some, a higher target would be more appropriate especially if there is a risk of hypoglycaemia at the lower target. This NICE guidance also warns against aiming for targets lower than 6.5%. For those with type 1 diabetes, the recommended target is less than 7.5%.
To add to the evidence, and to validate the NICE warning that ‘lower is not always better’ the recently published ACCORD, and ADVANCE studies confirm that there is no benefit in cardiovascular outcome by lowering the HbA1c to less than 6.5%. In fact the ACCORD trial was stopped early, as an interim analysis showed that there was an increased mortality rate in the tightly-controlled group that had a target HbA1c value of 6%. (Mean average HbA1c achieved at the time of analysis was 6.4%). The ADVANCE study did show a reduction in nephropathy in the intensive group, however since most patients with type 2 diabetes die from cardiovascular disease, the significance of this finding in the context of other trial results is unclear.
Avoidance of diabetic ketoacidosis
Diabetic ketoacidosis (DKA) is one of the most common reasons for patients with type 1 diabetes to be admitted to hospital. DKA commonly occurs on first presentation with type 1 diabetes, in those who do not adhere to insulin regimens and in those with type 1 diabetes who experience concurrent illness (commonly nausea and vomiting, which renders them unable to eat properly). In the first group there is not a lot that can be done to avoid hospital admission if diabetes has not yet been diagnosed. Likewise if patients wilfully omit insulin doses, then apart from careful explanation as to the importance of insulin, there is not a lot that can be done. However for the latter group, who mistakenly omit insulin, there is a common misconception that when unable to eat insulin is not required. This practice is unsafe, since in many cases those experiencing concurrent illness require more insulin than normal, whether or not they are able to eat. This increase in basal insulin requirement is due to the production of counter-regulatory hormones that frequently occurs in times of stress. All patients on insulin need to be counselled about ‘sick day rules’ in order to avoid admission to hospital, during times of illness.
Generally these patients need to be given contact numbers for help if they become unwell and be advised to increase the frequency of glucose monitoring to 4-hourly or more often and test urine for ketones on a regular basis. Carbohydrate intake should be maintained as much as possible using sugary drinks or fruit juice, soups, jelly or snack foods if they are having difficulty in eating. Fluid intake is important and patients should be advised to have a glass of water every hour, aiming for 3 litres in 24 hours. If the blood glucose level is less than 12mmol/L and ketone result is negative-small, patients should continue their normal insulin dose. If the blood glucose level is between 12–18mmol/L and the ketone result is negative-small, the patient should re-test within 4 hours or at the next meal and add 4 extra units of insulin to doses of up to 20 units and 8 extra units to doses greater than 20 units. If the blood glucose level is more than 18mmol/L and ketone levels are moderate or significant, patients should take 50% extra insulin. If blood glucose is more than 20mmol/L and ketones are moderate or significant the dose of insulin should be doubled. If the patient is vomiting and blood glucose levels are over 16mmol/L then medical help should be sought especially if there is no improvement after the second test or the next insulin injection.
Avoidance of hypoglycaemia
Hypoglycaemia is another reason why people with diabetes may be admitted to hospital. Hypoglycaemia is generally defined as a blood glucose level of less than 3.5mmol/L, although a consensus definition amongst leading diabetes organisations is lacking. Hypoglycaemia is mostly caused by medication used to treat diabetes, especially insulin secretagogues (eg, sulphonlyureas) and exogenous insulin. Most patients on insulin will at some time have experienced a hypoglycaemic episode with 25% of those who have taken insulin for more than five years having experienced severe hypoglycaemia (‘severe hypoglycaemia’ being defined as hypoglycaemia that requires intervention by another person in treating it). Sulphonylureas are less likely to cause hypoglycaemia, however it is estimated that in the UK alone, in one year, more than 5000 patients will experience severe hypoglycaemia caused by a sulphonylurea. The burden to the NHS of hypoglycaemia requiring a hospital admission is quite substantial with the cost of each admission being estimated at approximately £1000.
In the UK doctors in general practice surgeries are given targets (known as Quality and Outcomes Framework [QOF] targets) set by the government, in order to try to improve patient care. General practices are rewarded by financial incentives for meeting these targets. The QOF targets for glycaemic control in patients with diabetes for the year 2009/2010, have been reduced since the previous year’s targets, with the current lowest HbA1c target being set at 7% (compared to 7.5% last year). Since the lowering of the QOF targets, we have noticed that more patients are being admitted to the hospital’s Accident and Emergency Department with severe hypoglycaemia. This is currently being audited, however it is extremely worrying since it is putting patients at risk as hypoglycaemia can cause death if not treated promptly.
Hypoglycaemia, if caught early, can be quickly and easily treated at home, however for patients who have hypoglycaemia unawareness (no longer experience the warning symptoms) or for those who do not know what to do, hypoglycaemia can be very dangerous. All patients on insulin (and their carers) and those on oral insulin secretagogues should be counselled on how to treat hypoglycaemia. Upon experiencing hypoglycaemic symptoms, if home blood glucose monitoring equipment is available, then a blood glucose level should be checked, if not then just treat as hypoglycaemia anyway. If the person is able to swallow safely without the risk of aspiration, then oral glucose is the most effective treatment eg, glucose tablets, glucose powder, glucose drinks (ie, Lucozade). Hot drinks should be avoided in an emergency as there is a risk of burning, likewise drinks containing milk are also not advisable since the fat content slows down the absorption of the sugars. If unable to swallow or if there is a risk that aspiration might occur, parenteral treatment should be given (either intravenous glucose or glucagon). In this case the carer would need to call for emergency help. After treating hypoglycaemia, blood glucose levels should be re-measured about 10–15 minutes later. If below 4.0mmol/L more glucose should be consumed and if above 4.0mmol/L and the next meal is more than one hour away, then long-acting carbohydrate is also required eg, a piece of bread or a couple of biscuits.
Treatment of hyperglycaemia
NICE has recommended a treatment pathway for patients with type 2 diabetes[4,9] in order to lower blood glucose levels. (All those with type 1 diabetes will require insulin). Firstly a safe target HbA1c should be agreed, taking into consideration factors such as the patient’s age, the presence of diabetic complications, whether or not he or she lives alone, whether or not he or she would be able to recognise and treat hypoglycaemia. The treatment pathway begins with lifestyle modifications, such as attention to diet and exercise. If this is not successful in lowering blood glucose levels, then oral medication should be given. Treatment usually begins with metformin or a sulphonylurea (or both if monotherapy is unsuccessful). If glycaemic targets are still not being met, then the addition of a thiazolidinedione, dipeptidyl peptidase-4 (DPP-4) inhibitor, incretin mimetic or insulin may be considered, depending on the degree of insulin resistance, whether or not weight increase would be problematic and the patient’s ability to manage insulin.
People with diabetes have elevated blood glucose levels, which require lowering in order to prevent the development of diabetic complications, which in the long-term often lead to hospital admission and eventual death. Even though the exact definition of ‘good glycaemic control’ has not been universally agreed, it is generally accepted that a target HbA1c of around 6.5–7.5%, will improve the outcome for most patients. However overzealous treatment to levels of less than 6.5% must be avoided as they are probably detrimental to health. Target HbA1c levels should be agreed on an individual basis for patients based on the likelihood of causing hypoglycaemia by setting too tight targets. Achievement of the desired target may require a combination of treatments in accordance with published guidelines. Patient education and counselling especially on DKA avoidance and the recognition and prompt treatment of hypoglycaemia should also be given in order to reduce the need for hospital admission.
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