Control of blood glucose in type 2 diabetes involves a stepped approach to therapy ideally by a multidisciplinary team. Therapy begins with education, then a reduction in dietary fat and an increase in exercise. If control remains inadequate, the usual next steps are the addition of metformin, and later a sulfonylurea. In those who do not respond to maximal doses of these drugs, insulin therapy may be needed. Initially, intermediate-acting insulin injected at bedtime can be added. This can be increased to twice daily insulin without tablets if control is not adequate. In addition to the control of blood glucose, it is imperative to manage hypertension and dyslipidaemia and to screen for macro- and microvascular complications.
Type 2 or non-insulin dependent diabetes mellitus (NIDDM) accounts for approximately 90% of all diabetes. It is estimated to affect 3.8% of all Australians, but nearly half of these cases are undiagnosed. The incidence rates are higher in some members of the community including Aborigines, Torres Strait Islanders, Southern Europeans, Indians, Chinese and Vietnamese1 Untreated or inadequately treated type 2 diabetic patients may develop the same complications as those with type 1 or insulin dependent diabetes including eye, nerve and kidney damage. In addition, type 2 diabetes is an important risk factor for large vessel disease and is a member of a cluster of disorders which includes insulin resistance, obesity, hypertension and dyslipidaemia (Syndrome X).
Patients should be screened for diabetes if they present with a history of polyuria, polydipsia, or skin infections, especially genital candida. Everyone over 65 years of age or anyone with two or more of the following factors should be investigated for diabetes:
- age >40
- abdominal obesity
- family history of diabetes
- a history of gestational diabetes
Glycosuria, or an elevated random blood glucose (>6.0 mmol/L), should be followed up by a laboratory fasting blood glucose. If this is >7.8 mmol/L on two occasions, the diagnosis is confirmed. If the fasting glucose is between 5.5 and 7.7 mmol/L, an oral glucose tolerance test is indicated. The diagnosis is confirmed if the blood glucose concentration is >11.1 mmol/L two hours after a 75 g glucose load. Intermediate levels (8-11 mmol/L after two hours) would indicate impaired glucose tolerance and the individuals should be warned that they are at increased risk of developing type 2 diabetes. They should be advised about reducing fat intake and taking more exercise.
Following the diagnosis of diabetes, it is important to exclude hypertension, measure the fasting lipid profile and screen for the presence of complications. Approximately 10% of newly diagnosed patients with type 2 diabetes have retinopathy at the time of diagnosis. This reflects the asymptomatic nature of this type of diabetes and stresses the need for doctors to be vigilant in identifying and testing patients at risk.
The patients should not smoke. If possible, they should be referred to a diabetic educator to learn the skills necessary to live with diabetes including home blood glucose monitoring, foot care, and how to recognise the symptoms of hypo- and hyperglycaemia. Initial management must involve advice to reduce excess weight. This should be achieved with increased exercise and a reduction in fat intake. Advice about exercise should take into account the presence of ischaemic heart disease or foot problems. Dietary advice should ideally be given by a dietitian, but the general principles should be frequently reinforced by the doctor. These include avoidance of simple carbohydrates, a reduction in fat and an increase in high fibre foods.
These lifestyle changes will almost invariably result in a decrease in blood glucose. Compliance with this regimen should lead to prolonged control of type 2 diabetes. Oral hypoglycaemic drugs are generally not needed as initial therapy.
Following the Diabetes Control and Complications Trial (DCCT), targets for control based on the level of haemoglobin A1c (see 'Diabetes monitoring; use of glycated haemoglobin and glycated protein assays' Aust Prescr 1991;14:59-61) were better defined for patients with insulin dependent diabetes. There is no evidence that these targets should be any different for NIDDM. We can assume that HbA1c levels of 7% or less will be associated with a reduced risk of microvascular complications, while levels >9% will be associated with increased risks. It is advisable therefore to aim for HbA1c levels of 7% or less. HbA1c should be measured at 3-6 month intervals. Home blood glucose monitoring is important for those patients on insulin so their dose can be adjusted. My practice is to ask the patients to measure only once a day, but to rotate the time of testing before breakfast, lunch, dinner and bedtime. For the elderly on tablets, urinary glucose combined with HbA1c may be sufficient monitoring.
Oral hypoglycaemic drugs
Unfortunately, many patients are unable to maintain weight loss long term. Gradually, glycaemia and haemoglobin A1c levels rise to levels above 8.0%. After reinforcing the importance of diet and exercise, an oral hypoglycaemic drug should be tried.
Some years ago, a consensus conference of the European Association for the Study of Diabetes advised that metformin be used as the first drug in those patients who are obese (body mass index (BMI) >30.0 kg/m2). This drug lowers blood glucose by improving insulin sensitivity and by inhibiting the production of glucose by the liver. Metformin does not increase insulin levels, or cause weight gain or hypoglycaemia. It is available in 500 mg and 850 mg tablets. Treatment starts with 250 mg twice daily and is increased slowly to a maximum of 2 g per day.
Metformin frequently causes gastrointestinal adverse effects including nausea, diarrhoea and abdominal pain. These effects can be minimised if the dose is increased slowly and if the tablet is taken after food. The most serious potential adverse effect of metformin is lactic acidosis which, although rare, can be fatal. The risk is greatly increased if the drug is used in high dose in those with either renal, liver or severe cardiac failure. It can also occur due to dehydration, including fasting for surgery or radiography. Therefore, metformin should be ceased at least 48 hours before a procedure requiring fasting.
When metformin is not sufficient, as indicated by an HbA1c >8.0%, a sulfonylurea can be added. Sulfonylureas can be used as the first drug in lean type 2 patients or in those patients who cannot tolerate metformin. Five sulfonylureas are available in Australia (Table 1).
Sulfonylureas available in Australia
|Name||Tablets available||Duration of action|
|Gliclazide||80 mg||12 hours|
|Glibenclamide||2.5 and 5.0 mg||12 hours|
|Glipizide||5.0 mg||12 hours|
|Tolbutamide||500 and 1000 mg||6 hours|
|Chlorpropamide||250 mg||24-36 hours|
Sulfonylureas work by stimulating insulin secretion, although there is some evidence of extra pancreatic effects. Combining a drug that increases insulin secretion with one that improves insulin action is therapeutically worthwhile; however, the use of two different sulfonylureas together is not a logical therapeutic approach since they compete with each other for the same beta cell receptor. The dose should be increased gradually until control is adequate (HbA1c <8.0%).
The major adverse effects of sulfonylureas are hypoglycaemia and weight gain. Chlorpropamide has a very long duration of action and should be avoided in the elderly due to the risk of prolonged hypoglycaemia. Tolbutamide has the shortest duration of action and should be given 3 times daily, so compliance can be a problem.
With time, in a substantial number of patients, glucose control deteriorates even when taking maximal doses of a sulfonylurea and metformin. It has been estimated that up to 25% of overweight patients have secondary failure of oral drugs after 10 years of diabetes. Secondary failure can have many causes including progression of the disease, stress, infection, introduction of other drugs e.g. corticosteroids, non-compliance or non-adherence to diet and exercise.
There are several other oral drugs that are available or will be available soon that could be tried when treatment fails. Dexfenfluramine, a drug used for weight loss, lowers blood glucose by inhibiting hepatic glucose production. While effective in some patients, its safety when used continuously long term is not yet established. The alpha glucosidase inhibitor, acarbose, slows glucose absorption, and hence improves control by limiting postprandial hyperglycaemia. Several studies have shown reduction of HbA1c of approximately 1% following the introduction of this drug. Troglitazone improves insulin action. The role of these drugs in the management of type 2 diabetes is not clear at present.
Currently, after excluding reversible factors of treatment failure, insulin therapy is required. Type 2 diabetic patients starting insulin therapy need not be admitted to hospital. Injection technique and home glucose monitoring can be taught by the nurse educator. All patients who are capable should monitor their blood glucose at home if they are not already doing so.
One approach is to begin supplementing oral drugs with a bedtime injection of intermediate-acting insulin (e.g. isophane, insulin zinc). The aim is to lower fasting glucose to 5-6 mmol/L. In many patients, the tablets are able to control the glucose during the day. Insulin should be started at 6 units and be increased by 2-4 units every 3-4 days until daily monitoring shows that the target fasting glucose levels are achieved on most mornings. Some endocrinologists stop metformin and use only a sulfonylurea before each meal in conjunction with bedtime insulin. However, it is my practice to continue all of the oral drugs when starting insulin and to reduce these gradually if daytime hypoglycaemia occurs. Even then, I reduce the sulfonylurea first, since metformin may minimise the weight gain that often accompanies the introduction of insulin.
In my experience, about half of the patients do well on this regimen. The other half maintain adequate fasting glucose, but have high glucose concentrations during the day. In these patients, tablets are clearly not having any effect. They should be stopped and the patients changed to a full insulin regimen with twice daily insulin. It is preferable to use one of the premixed insulins, of which ratios of 20/80, 30/70 and 50/50 (short/intermediate acting) are available. Many patients find it easier to use a pen injector rather than a syringe to administer insulin. The starting dose should be between 12 and 24 units per day with two-thirds in the morning and one-third before the evening meal. Generally, the 30/70 mixture is tried first. As with the night-time insulin, the dose can be increased by 2-4 units every 3-4 days until adequate control is achieved. In obese patients who require large doses of insulin, the re-introduction of metformin may limit the weight gain and the dose of insulin required for good control.
Management of hypertension
Hypertension must be vigorously treated in type 2 diabetes since its presence is associated with a 4-5 fold increase in mortality due mainly to ischaemic heart disease. Treat patients:
- under 40 years who have blood pressure (BP) >140/90
- 40-60 years who have a BP >100 + age in years/90
- >60 years who have BP >160/90
The ACE inhibitors are used first as they may have a reno-protective effect above that resulting from blood pressure control alone. If they do not work adequately, a calcium channel blocker should be used alone or in combination with the ACE inhibitor.
In diabetes, diuretics and beta blockers should not be first-line therapy. Diuretics can worsen glucose control while beta blockers can mask the early warning symptoms of hypoglycaemia. However, there are some patients who may require these drugs and their use is not absolutely contraindicated2
Management of dyslipidaemia
The most common dyslipidaemia of diabetes is a high triglyceride and a low HDL cholesterol. This combination is atherogenic and patients should be treated as detailed in an Australian Diabetes Society position statement3, although not all these patients will qualify for subsidy under current Pharmaceutical Benefits Scheme guidelines. Briefly, thresholds for treatment depend on the HDL cholesterol level and on whether the patient has known vascular disease (Table 2).
After finding dyslipidaemia, it is important to improve control of the diabetes first since this will improve the lipid profile.
Thresholds for treatment - dyslipidaemia of diabetes3
Indications for primary prevention therapy
If HDL cholesterol level >= 1.0 mmol/L, treat if total cholesterol level >= 6.5 mmol/L or triglyceride level >= 4.0 mmol/L
If HDL cholesterol level < 1.0 mmol/L, treat if total cholesterol level >= 5.5 mmol/L or triglyceride level >= 2.0 mmol/L
Indications for therapy when pre-existing cardiovascular disease is present
If HDL cholesterol level >= 1.0 mmol/L, treat if total cholesterol level >= 5.5 mmol/L or triglyceride level >= 2.0 mmol/L
If HDL cholesterol level < 1.0 mmol/L, treat if total cholesterol level >= 4.5 mmol/L or triglyceride level >= 2.0 mmol/L
Dietary advice should be given. If, after better control and dietary advice, the levels are still outside the acceptable range (Table 2), drug therapy is advisable. The first-line drug should be a fibric acid derivative such as gemfibrozil at a dose of 600 mg twice daily. If hypercholesterolaemia is the predominant abnormality, a HMG CoA reductase inhibitor should be used.
Screening for complications
An important function of the doctor is to monitor the patient with NIDDM for both microvascular and macrovascular complications. All patients should be screened for complications at diagnosis and then at yearly intervals. Fundal examination through a dilated pupil should be done at two-yearly intervals, preferably by an ophthalmologist, and more frequently if any abnormalities are detected. Early nephropathy is best detected by measurement of microalbuminuria in 3 overnight urine samples.4 The presence of proteinuria is associated with increased risk of macrovascular disease. Neuropathy and large vessel disease should be looked for annually. The patient's feet should be carefully reviewed. Any foot problems require an early referral to a podiatrist.
- McCarty DJ, Zimmet P, Dalton A. The rise and rise of diabetes in Australia, 1996: a review of statistics, trends and costs. Canberra: Diabetes Australia, 1996
- Gilbert RE, Jasik M, DeLuise M, O'Callagan CJ, Cooper ME. Diabetes and hypertension. Australian Diabetes Society position statement. Med J Aust 1995;163:372-5.
- Best JD, Jerums G, Newnham HH, O'Brien RC. Diabetic dyslipidaemia. Australian Diabetes Society position statement. Med J Aust 1995;162:91-3.
- Jerums G, Cooper M, Gilbert R, O'Brien R, Taft J. Microalbuminuria in diabetes. Med J Aust 1994;161:265-8.