Eamonn Brady MPSI provides an overview of diabetes in Ireland, including causes and treatment options

The Diabetes Federation of Ireland estimates there are over 200,000 diabetics in Ireland and that over half of these have no idea they have diabetes. Some countries have a population prevalence of up to 6 per cent for diabetes.1

What is diabetes?

The World Health Organisation (WHO) defines diabetes mellitus as “a metabolic disorder of multiple aetiology, characterised by chronic hyperglycaemia, with disturbances of carbohydrates, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both”.2 Diabetes mellitus is a condition that occurs when the body cannot use glucose normally. Glucose is the main source of energy for the body’s cells. The levels of glucose in the blood are controlled by the hormone insulin, which is made by the pancreas. Insulin helps glucose enter the cells.

Types

There are two types of diabetes, type 1 and type 2. In type 1 diabetes, the pancreas does not make enough insulin. In type 2 diabetes, the body can’t respond normally to the insulin that is made, which is often called insulin resistance. 

Type 1

This type of diabetes usually appears before the age of 40 and most often starts as a teenager. Type 1 diabetes is the least common of the two main types and accounts for between 5 and 15 per cent of all people with diabetes. You cannot prevent type 1 diabetes.

Type 2

In most cases, this is linked with obesity. Obesity results in insulin resistance, which interferes with insulin’s action on glucose uptake and its affect on fatty acids and protein metabolism.3 This type of diabetes usually appears in people over the age of 40, though in South Asian and African-Caribbean people, it often appears after the age of 25. Recently, more children are being diagnosed with the condition, some as young as seven. Type 2 diabetes accounts for between 85 and 95 per cent of all people with diabetes.

Diabetes symptoms

▸ Frequent urination.

▸ Excessive thirst.

▸ Extreme hunger.

▸ Increased fatigue.

▸ Irritability.

▸ Increased weight loss.

▸ Blurred vision.

▸ Genital itching or regular thrush.

▸ Slow healing of wounds.

Type 1 diabetes symptoms develop very quickly, usually over a few weeks. In people with type 2 diabetes, the signs and symptoms will not be so obvious or may even be non-existent. If you’re older, you may put the symptoms down to the ageing process, thus preventing diagnosis. 

Causes and risk factors

Type 1 diabetes 

Type 1 diabetes develops when the insulin-producing cells in the pancreas have been destroyed. It is not known for sure why these cells have been damaged but the most likely cause is an abnormal reaction of the body to the cells. This may be triggered by a viral or other infection. 

Type 2 diabetes

Risk factors are as follows:

Age

Risk of diabetes increases in patients aged over 40 or over 25 in African and Asian patients. 

Family and ethnicity

Having diabetes in the family increases the risk of diabetes. The closer the relative is, the greater the risk. People of Afro-Caribbean or South Asian origin are at least five times more likely to develop diabetes.

Weight

Over 80 per cent of people diagnosed with type 2 diabetes are overweight. The more overweight and inactive the person is, the greater their risk of diabetes. 

Waist size

Women: If the waist measures 31.5in (80cm) or more, the risk of diabetes increases.

Men: If the waist is 37in (94cm) or more, this means increased risk of developing diabetes. 

Gestational diabetes

Pregnant women can develop a temporary type of diabetes called gestational diabetes.  Having this, or giving birth to a large baby, can increase the risk of a woman going on to develop diabetes in the future. 

Diabetes treatment

The aim of diabetes treatment is to do what the body once did automatically, which is to mimic the insulin pattern before diabetes and to keep blood sugar under control. 

For type 1 diabetes, insulin is always part of treatment as the body does not produce any insulin. In type 2 diabetes, your body still produces some insulin, so non-drug options or drugs may be used to help the body make better use of the insulin that it still produces. 

Treatment of type 1 diabetes

There is no cure for type 1 diabetes, but it can be kept under control. Type 1 diabetes is controlled by administering insulin. This allows glucose to be absorbed into cells and converted into energy, stopping it building up in the blood. 

Treatment of type 2 diabetes

Many with type 2 diabetes can manage to control their condition simply by changing their lifestyle. Changes include:

Diet

A healthy diet is essential and it is important to eat regularly, three times a day. Special diabetic foods are not needed for a healthy diet; eating a balanced diet that is low in saturated fat, sugar and salt and high in fibre, vegetables and fruit is sufficient. Include carbohydrates, such as pasta, potatoes or sugary foods such as fruit in each meal. There is strong evidence that progression from hyperglycaemia to type 2 diabetes can be prevented or at least delayed by dietary effort. A diabetes prevention programme in the US gave a 58 per cent reduction in the incidence of diabetes when participants were provided with lifestyle intervention, including diet, compared with a 31 per cent reduction in persons treated with metformin.13 However, there are relatively few other studies evaluating the effect of dietary intervention in patients with type 2 diabetes.

Exercise

Exercise promotes a healthy circulation and maintains a healthy weight. At least half an hour of moderate activity on at least five days a week is recommended. A Cochrane review showed that exercise significantly improved glycaemic control and reduced plasma triglycerides and visceral adipose tissue, even without weight loss.5 A high level of leisure-type physical activity has been associated with a 33 per cent drop in fatal cardiovascular disease, while moderate activity showed a 17 per cent drop compared with the most sedentary group.10

Smoking

It is especially important for diabetics to quit smoking. This is because a diabetic already has a five-fold increased chance of developing cardiovascular disease or circulatory problems compared to non-diabetics. Smoking makes the chances of developing these diseases even greater. 

Alcohol

There is no need to give up alcohol completely, but it is important to drink in moderation. Do not drink on an empty stomach. Eat foods containing carbohydrates before and after drinking (as alcohol reduces glucose levels). Monitor blood glucose levels more regularly if drinking alcohol.

Medication

If lifestyle changes alone don’t reduce glucose levels, medication may be used to increase insulin production and strengthen its effect. All of the types of oral hypoglycaemic drugs and insulin are safe in older patients, although each has some limitations in older people. ‘Start low and go slow’ is a good principle to follow when starting any new medications in an older adult.

Metformin improves the effectiveness of insulin by reducing the amount of glucose released from the liver and improving the way glucose is used by muscles. It causes less weight gain than other diabetic medication. In the UKPDS, metformin reduced diabetes-associated deaths by 43 per cent over a 10-year follow-up.4 Metformin acts on the liver to lower production of glucose and reduce glycogenolysis; it has no effect on insulin release so is not associated with hypoglycaemia. Up to 3g of metformin can be administered daily.14 A 2005 Cochrane review concluded that no other antidiabetic drug showed more benefit in terms of glycaemia control, body weight or lipids than metformin in type 2 diabetes.15Gastrointestinal (GI) upset is the most common side-effect and has been reported in up to 50 per cent of patients.16Metformin is an attractive agent to use in the elderly due to a low risk of hypoglycaemia. However, it should be given with caution in older diabetic patients because of the risk of lactic acidosis. Older patients often have impaired renal function despite an apparently normal serum creatinine concentration. Weight loss and gastrointestinal side-effects may also be limiting factors in older adults taking metformin. Therefore, metformin should be used with caution in older patients.

Sulphonylureas encourage the pancreas to produce more insulin. Because they stimulate insulin secretion, they are most effective in newly- or recently-diagnosed patients who still have relatively active beta-cell function. In the UKPDS, sulphonylureas reduced diabetic-related deaths by 36 per cent.4 Sulphonylurea monotherapy is effective in 75-to-80 per cent of patients with type 2 diabetes; however treatment ‘failure’ occurs at a rate of 5-to-10 per cent of patients per annum.17 Sulfonylureas are usually well tolerated in older patients; however hypoglycaemia is the most common side-effect and more common with older, long-acting sulfonylurea drugs. However, Gliclazide MR is well tolerated in elderly patients.

Thiazolidinediones reduce the body’s resistance to insulin and are generally limited to use with metformin and sulphonylureas if other standard treatments were not working or not tolerated. They are licensed as monotherapy in obese patients if metformin is ineffective or not tolerated. They work by reducing insulin resistance in adipose tissue, muscle and liver.17 They take up to 12 weeks to exert their full affect. Thiazolidinediones are useful for some older diabetic patients because they can be given to patients who have impaired renal function. They are well tolerated in older adults and do not cause hypoglycaemia. However, limited experience, high cost and concerns regarding fluid retention, congestive heart failure, MI, and fractures limit their usefulness. Weight gain is a side-effect so they should be avoided in obese patients.

Rosiglitazone (Avandia) was withdrawn from the European market in October 2010 because new research showed it increased the risk of cardiovascular problems, including increasing the risk of myocardial infarction and heart failure. It was considered that its benefits no longer outweighed its risks. Pioglitazone (Actos) is still on the Irish market but must be used with caution in those with cardiovascular problems.

Newer medicines called DPP-4 inhibitors, such as sitagliptin (Januvia), help the body to produce more insulin in response to meals.  They work by enhancing the levels of active incretin hormones, thus enhancing insulin and reducing glucagon secretions.18 DPP-4 inhibitors don’t cause weight gain and only rarely cause hypos. 

The combination of sitagliptin and metformin has been shown to be better tolerated (14.5 per cent incidence of adverse effects) compared with a combination of sulfonylurea and metformin (30.3 per cent incidence of adverse effects). Long-term safety with this class of drug in the elderly has not been established. 

Acarbose (Glucobay) lowers blood glucose by slowing the breakdown of some carbohydrates. Acarbose reduces the digestion and absorption of starch and sucrose by competitively inhibiting the intestinal enzymes involved in the degradation of disaccharides, oligosaccharides and polysaccharides. The reduction in HbA1c is modest, however it is very unlikely to cause weight gain.19 The main side-effects, which affect over 10 per cent of patients and limit its use, are flatulence and diarrhoea.20 The gastrointestinal side-effects are due to intracolonic fermentation of the unabsorbed sugars and reduce with time. Acarbose has not been widely tested in elderly diabetic patients, but is likely to be fairly safe and effective.

Meglitinides includerepaglinide (Novonorm) and nateglinide (Starlix). Meglitinides act as postprandial glucose regulators. They increase insulin secretion by binding to specific sites within the ß cells in the pancreas. They have a rapid onset of action, meaning they need to be administered shortly (one-to-30 minutes) before meals.21 They have a short duration of action, requiring multiple daily dosing.22 Long-term data are on treatment outcomes of meglitinides are not available.23Meglitinides may play a useful role in patients with irregular meal times (ie, shift workers).23 Gastrointestinal upset is generally less than with metformin, however weight gain is greater than experienced with metformin and can be as much as 3kg in three months. Because they are metabolised by the cytochrome P450, their potential for interactions is greater than other oral antidiabetics. Their use is limited by many factors, including their inconvenient dosage regimen, ie, they must be taken immediately before meals and need multiple daily dosage. Other oral antidiabetics have more convenient dosage regimens. 

Exenatide is a synthetic peptide drug that works by increasing the secretion of insulin and reducing secretion of glucagon in response to hyperglycaemia.24It is administered by subcutaneous injection twice-daily. The two drugs available in this class in Ireland (and allowed on the GMS) are Bydureon and Byetta. GI upset (including nausea, vomiting and diarrhoea) was recorded in up to 50 per cent of patients in clinical trials.25 Hypoglycaemia occurred in over 10 per cent of patients when combined with a sulfonylurea in clinical trials, so the dose of the sulfonylurea should be reduced if combined with exenatide. Further post-marketing safety and long-term outcome data is required for this drug.

Fast-acting insulin preparations include insulin aspart (NovoRapid) and insulin lispro (Humalog). The onset of action of insulin aspart is 10-to-20 minutes and the duration of action is three-to-five hours. Insulin lispro has an onset of action of approximately 15 minutes and duration of action of two-to-five hours.26

Insulin aspart is injected subcutaneously immediately before meals or, when necessary, soon after. Insulin lispro is injected subcutaneously shortly before meals or, when necessary, soon after. Insulin aspart and insulin lispro are normally used in combination with longer-acting insulin to provide a steady glucose level throughout the day. The dose of insulin aspart or lispro needs to be individualised to the patient. The fast-acting insulins may also be used for continuous subcutaneous infusion using an insulin infusion pump. Biphasic preparations are also available (ie, NovoMix 30, Humalog Mix25). These contain fast-acting (aspart or lispro) and intermediate-acting insulin analogues.26

The long-acting insulin glargine (Lantus) is administered subcutaneously once-daily. It can be administered at any time, but it should be given at the same time each day. The dosage and timing of administration should be individualised to the patient. It shows a constant concentration-effect versus time profile which lasts approximately 24 hours. Insulin glargine is used as an additional therapy to oral hypoglycaemic agents in type 2 diabetes where oral hypoglycaemic agents do not provide adequate glucose control on their own.27 Insulin glargine was also associated with similar or less weight gain compared with isophane insulin (intermediate action).26 Patients with both type 1 and 2 diabetes experienced greater diabetic control with insulin glargine compared with isophane insulin.26

Interactions with other drugs must be taken into account when determining dose of insulin. Drugs which reduce hypoglycaemic activity and may increase insulin requirement include oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics and danazol. Substances that enhance hypoglycaemic activity and may decrease insulin requirements include oral antidiabetics, certain antidepressants (MAOIs and SSRIs), non-cardio selective beta blockers, certain ACE inhibitors (captopril, enalapril), angiotension 2 inhibitors, aspirin, alcohol, anabolic steroids, and sulphonamides. Beta blockers also mask the symptoms of hypoglycaemia and alcohol may intensify and prolong the hypoglycaemic effect of insulin. 

Insulin is sometimes underutilised in the elderly because of fear (by the doctor, patient, or family) that it is too complicated or dangerous. With the availability of long-acting insulins, ie, Lantus, Levemir, it has become easier to add once-daily insulin to oral hypoglycaemic medications in older patients who have poor glycaemic control. The quality of life of many older patients improves substantially when they take one or two daily doses of intermediate- or long-acting insulin.

Which drug to choose?

Metformin remains the most effective monotherapy, especially in obese patients. Sulfonylureas remain a good choice if the patient is not overweight. Repaglinide and acarbose are also authorised for monotherapy but are rarely used due to reasons described above. Thiazolidinediones may be used as monotherapy only in overweight patients if metformin is ineffective or not tolerated but should be avoided in patients with cardiovascular problems.

Step 2, if monotherapy is ineffective, is dual therapy, which includes metformin and/or sulfonylurea and/or thiazolidinedione. Sitagliptin (Januvia) is a popular add-on therapy to metformin due to its success and low incidence of side-effects. Meglitinides, acarbose and exenatide are also authorised for combination therapy.

Step 3 is triple-therapy (metformin and/or sulfonylurea and/or thiazolidinedione and/or meglitinides and/or acarbose). Insulin therapy may be considered with dual therapy but should be initiated by a specialist.

It must be borne in mind that metformin and sulphonureas provide a greater reduction in HbA1c than any of the newer oral antidiabetic drugs. Metformin and sulphonureas reduce HbA1c by greater than 1.5 per cent; no other oral antidiabetic drug reduces HbA1c by greater than 1.5 per cent.19,23,27Metformin and sulphonureas are central to any treatment regimen of type 2 diabetes. Metformin and sulphonureas are also less expensive than other oral antidiabetic drugs.