Pharmacological management of Type 1 diabetes

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The Diabetes Control and Complications Trial (DCCT 1993) demonstrated that intensive control of blood glucose reduced both microvascular (60% reduction) and macrovascular (44% reduction) complications in patients with type 1 diabetes (1). This study included 1,441 patients with type 1 diabetes, with a mean age 27 years, who were randomised to one of two groups. The active group participated in intensive therapy comprising insulin administered 3-4 times daily with four or more blood tests daily and this was supported by monthly clinics. The control group received twice daily insulin and standard monitoring. The active group had a mean HbA1c of 7% compared to 9% for the control group. This study was fundamental in establishing the need for good glucose control. The only negative finding was that episodes of severe hypoglycaemia increased threefold in the active group compared to conventional therapy in the control group. Some patients had multiple episodes of severe hypoglycaemia. All type 1 diabetic patients require treatment with insulin. Insulin is a large polypeptide hormone, which is inactivated when given orally and must therefore be given by injection. The subcutaneous route is usually preferred although the intravenous route may be used to deliver soluble insulin in emergencies. The BNF states there are three main types of insulin preparations. These include: Short acting preparations which have a relatively rapid onset of action such as soluble insulin, insulin lispro, insulin glulisine and insulin aspart. Soluble insulin activity usually starts about 30 mins - 1 hr after injecting. Peak activity is usually between 2 - 4 hours and the insulin has duration of action of up to 8 hours. Insulin lispro, glulisine and aspart are human insulin analogues and have a faster onset of action and shorter duration than soluble insulin. Therefore they can be used for patients who wish to inject shortly before or after a meal. Intermediate acting preparations such as isophane insulin and insulin zinc suspension. Insulin activity usually starts about 2 hrs after injecting. Peak activity is usually between 4 - 12 hours and the insulin often has duration of action of up to 24 hours. Insulin glargine and detemir are human analogue insulins with a prolonged duration of action. Glargine is given once daily and detemir once or twice daily and may reduce the incidence of nocturnal hypoglycaemia in patients experiencing this whilst on isophane insulin. Long acting preparations such as crystalline insulin zinc suspension. Activity starts about 2 - 4 hrs after injecting. 'Peak' activity is usually between 6 - 20 hours and the insulin may have duration of action of up to 36 hours. These are now rarely used.

The duration of action of a particular type of insulin varies considerably from one patient to another, and needs to be assessed individually.
The BNF provides details of the various insulin preparations and their use. Make notes of these with examples of recommended insulin regimens

Julie is a 22 year old diabetic presents at accident and emergency department with a 2-day history of vomiting and abdominal pain. She is drowsy and her breathing is deep and rapid. There is a distinctive smell from her breath. A diagnosis of diabetic ketoacidosis was made and her biochemistry results after admission were as follows (the figures in brackets refer to normal range):
Na+ K+ HCO-3 Urea Glucose PaCO2 PaO2 136 mmol/L 5.3 mmol/l 8mmol/L 7.0 mmol/L 32 mmol/L 3 kPa 11.3 kPa (135-145) (3.5-5.0) (24-32) (3.0-8.8) (3.5-5.5) fasting (4.5-6) (12-14)

Treatment is commenced with 0.9% saline running in at 1 litre per hour, soluble insulin 6 units per hour, and potassium chloride 20mmol per hour. What is the metabolic imbalance? List the main features. Explain how this metabolic imbalance has arisen and the rationale for treatment. Metabolic imbalance Lack of insulin prevents the uptake of glucose into cells leading to hyperglycaemia and increased lipolysis, which results in an increase in free fatty acids in blood. This rate of production of ketones is in excess of tissue requirement and the ability of the body to excrete them through the kidneys. The ketones therefore build up in blood leading to metabolic acidosis, which is partially compensated by increasing the respiratory rate. Patients with this condition usually have depleted intracellular potassium even though plasma potassium is normal or high. Several factors may have caused this: The patient is dehydrated and retains sodium and water in the kidney at the expense of potassium. Hyperglycaemia leads to an osmotic diuresis leading to further loss of potassium. In this case the patient has been vomiting which may have caused further potassium loss from the gut. Rationale for treatment This is always a medical emergency. The patient requires insulin to counter the hyperglycaemia and isotonic saline to treat the dehydration. Insulin increases the cellular uptake of potassium therefore this should be administered with the insulin. Electrocadiograph (ECG) monitoring is essential. The patient should be monitored frequently and treatment altered rapidly in response to changes in biochemical and haemodynamic indices. It is important to identify the suspected cause of the condition and treat if appropriate. Possible causes may include infection or trauma.

The United Kingdom Prospective Diabetic Study (UKPDS), involving 5,102 patients over 20 years, demonstrated that intensive control of blood glucose and blood pressure can reduce the risk of diabetic complications (1),(2). This was the largest and longest study of type 2 diabetes undertaken. Many variables were studied. Patients with newly diagnosed type 2 diabetes were randomised to either intensive drug treatment (fasting glucose < 6mmol/l) or diet alone and were monitored for an average of 10 years. After 10 years the mean HbA1c was 7.0% in the intensively treated group, versus 7.9% in the diet group. This was associated with 12% fewer diabetic related end points such as death, myocardial infarction, angina, heart failure, stroke, renal failure, amputation and eye complications in the intensive treatment group. Most of this was attributable to a 25% reduction in microvascular complications. In addition some of these patients were hypertensive and randomised to one of two groups, either tight blood pressure (BP) control ( < 150/85mmHg) or 'less tight' BP control ( < 180/105mmHg). The results demonstrated that tight BP control reduced the risk of developing microvascular disease and the consequences of this. Pharmacological intervention was demonstrated to further enhance this. Perhaps the most striking observation of the UKPDS study was the observation that type 2 diabetes is progressive in nature and there is a need to regularly review therapy, as glycaemic control is not maintained over long periods of time. Today, diabetic specialists consider the use of an insulin regimen (usually in combination with oral antidiabetic therapy) if oral medication does not produce adequate control of blood glucose. Targets for glycaemic control and blood pressure lowering in diabetes (3): HbA1c < 7.0% (SIGN) Fasting glucose 4-7mmol/l Blood pressure <130/80mmHg Biguanides act by decreasing the production of glucose by the liver (gluconeogenesis) and by increasing uptake of glucose. Metformin is the only available biguanide. It exerts its effect only in the presence of some insulin. Gastro-intestinal side-effects are common initially and include anorexia, nausea, vomiting, diarrhoea and abdominal pain. Metformin is indicated first line in obese patients and, as two thirds of all type 2 diabetes patients are obese, it is usually the drug of choice. Hypoglycaemia does not often occur and there is a lower incidence of weight gain than seen with other drugs. Metformin should be used with caution in the elderly and avoided in moderate-severe renal or hepatic failure. Sulphonylureas act by stimulating the secretion of insulin. Hypoglycaemia (usually dose related) and weight gain can be a problem. They are indicated for patients who are not overweight or in whom metformin is ineffective, not tolerated or is contra-indicated. Side-effects other than hypoglycaemia and weight gain are uncommon, but include gastrointestinal disturbances such as nausea, vomiting, diarrhoea and constipation. Caution is needed in the elderly and in patients with mild to moderate renal or hepatic impairment. Sulphonylureas are contraindicated in severe hepatic or renal impairment and in porphyria. Several sulphonylureas are available and choice is determined by duration of action, side-effects and individual patient factors. Long acting

sulphonylureas eg glibenclamide should be used with caution in the elderly due to the risk of accumulation and hypoglycaemia. Acarbose is an alpha glucosidase inhibitor, which retards glucose absorption from the intestines. Gastro-intestinal side-effects are common and include flatulence, diarrhoea, abdominal distension and pain. It may be used alone, when it has a small but significant effect, or can be used as an adjunct to metformin or sulphonylureas. Prandial glucose regulators (nateglinide, repaglinide) stimulate insulin release relative to glucose levels. They have a rapid onset and short duration of action and are taken shortly before meals. Nateglinide is licensed in combination with metformin, but repaglinide may be used alone in specific circumstances or in combination with metformin. Thiazolidinediazones (pioglitazone, rosiglitazone) boost insulin sensitivity at key sites and reduce insulin resistance. Pioglitazone is * licensed for use either as monotherapy or in combination with metformin and/or a sulphonylurea. Pioglitazone is also licenced for use in combination with insulin, however this should be initiated by a specialist only.There is evidence that they have positive effects on other components of the insulin resistance syndrome such as blood pressure and HDL cholesterol, however long term benefits have not been demonstrated as yet. * Pioglitazone is contraindicated in patients with a history of heart failure, hepatic impairment and pregnancy. * Rosiglitazone is no longer available and has had its marketing authorisation suspended across Europe on the advice of the CHM. After a review of the available data on risks and benefits of rosiglitazone they have concluded that there is an increased cardiac risk with this drug. See NICE/MHRA/CHM guidance summarised in the BNF. Dipeptidylpeptidase 4 inhibitors (DPP4 inhibitors), sitagliptin, vildagliptin and saxagliptin are newer drugs licensed for use in type 2 diabetes in combination with metformin or sulphonylureas or thiazolidinediones, when treatment with any of these agents fails to achieve adequate glycaemic control.They can be used as a second line alternative to SUs when hypoglycaemia and weight gain are a concern. They increase insulin secretion and lower glucagon secretion. Side effects include nausea, headache, peripheral oedema and tremor. Their place in therapy has been confirmed in NICE 87 guidelines and SIGN 116. GLP-1 agonists, exenatide and liraglutide are incretins which increase insulin secretion, suppress glucagon secretion and slow gastric emptying. They are given by subcutaneous injection and can be used in combination with metformin or a sulphonylurea or both. Their use is associated with weight loss and so they can be beneficial in overweight patients. Their place in therapy has been confirmed in the NICE 87 guideline and SIGN 116. The common, unpleasant side-effects of oral antidiabetic drugs may make it difficult for patients to concord with treatment. This should always be suspected if control is poor. Insulin may be substituted or added to oral antidiabetic therapy in patients who remain poorly controlled.

Summary of clinical management plan

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The following points should be considered for inclusion in a clinical management plan of a patient with diabetes: Review the diagnosis according to the SIGN recommendations on the Management of Diabetes. Identify any possible causes of diabetes which may require to be addressed, such as drug induced diabetes. Screen the patient for signs of diabetic nephropathy (urinary albumin, serum creatinine), diabetic retinal disease, diabetic foot disease, cardiovascular disease and depression, which can often be a complication of diabetes. Establish the patients views and preferences and understanding of the risks in order to promote concordance and agree a care plan. Review modifiable lifestyle factors. Set targets for control of blood glucose, blood pressure and cholesterol if appropriate. Select appropriate drug therapy, dose and dose interval Monitor the patient for evidence of effectiveness and absence of side effects. Arrange and review the appropriate regular screening for foot and eye care. It is recommended that a podiatrist review these patients regularly. In Scotland, all patients with diabetes should be offered annual Diabetic Retinopathy Screening by fundal photography Mrs Patterson is a 55 year old who smokes 20 cigarettes a day and works as a civil servant. She has a body mass index of 36 kg/m2. She presented with signs of polyuria, polydipsia and recurrent vaginal thrush. Her plasma glucose was 9mmol/l on fasting and 15mmol/l at 2 hours following an oral glucose tolerance test. She had no signs of retinal disease, nephropathy or diabetic foot disease. Her BP measurement was 170/90 mmHg and a non-fasting lipid profile revealed a cholesterol level of 7.2mmol/l, with high lipid density (HDL) of 0.9mmol/l, and triglyceride level of 4mmol/l. Mrs Patterson has no comorbidity at presentation. Outline a care plan for Mrs Patterson in the box below. Discuss diagnosis of diabetes with Mrs Patterson and provide written educational materials. Discuss implications of high blood pressure and cholesterol and the implications for overall cardiovascular risk. Emphasise positive aspects that she has no evidence of renal damage, retinal damage or foot problems. Stress the need to obtain good control of both blood pressure and glucose to reduce the risk of these developing in later years Establish the patients views and preferences and draft a care plan Her cardiovascular risk is high due to the following factors : overweight, hypertensive, smoker, high risk lipid profile and therefore she will require pharmacological intervention to reduce this risk.

Non-pharmacological measures should include diet and weight reduction, increasing her exercise. Smoking cessation should be discussed, as it would immediately reduce her cardiovascular risk. This may be supported by drug intervention. She should be advised to minimise her alcoholic intake Agree targets: HbA1c < 7.0% Fasting glucose 4-7mmol/l Blood pressure <130/80mmHg Pharmacological interventions will be necessary and may include: metformin (see BNF/NPF for dose titration) angiotensin converting enzyme inhibitor commencing on a low daily dose, titrated to target BP levels simvastatin 40mg to be taken at night (irrespective of baseline cholesterol whilst for primary prevention ) Possible side-effects should be discussed for each drug, and she should be advised to return to you if she develops these, or if any other concerns arise. Monitoring required to minimise side effects should be discussed ie U&Es for ACEI, metformin and LFTs for statin Monitor the patient for evidence of effectiveness and review the need for long term therapy. Annual screening for development of retinopathy nephropathy, neuropathy or cardiovascular disease.

the Scottish Intercollegiate Guideline Network (SIGN) recommendation on the management of diabetes