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Early diagnosis and intensive treatment to maintain optimal glycaemic control reduce the
morbidity and mortality associated with type 2 diabetes. To sustain glucose concentrations as
near normal as possible — and make the Quality and Outcomes Framework diabetes targets
achievable — generally requires use of more than one antidiabetic agent, which necessitates
attention to licensing indications, as Dr Caroline Day explains.
diabetes is now being diagnosed in younger population groups, including children3. To reduce At least 95 per cent of people with diabetes in the UK have type 2 diabetes. It has long been associated with maturity, corpulence, the onset and severity of diabetes-related inactivity and ageing, and more recently an excess complications, it is important to rapidly achieve and prevalence has been observed in some ethnic groups. maintain good glycaemic control and to treat other In 1993, a survey suggested a diabetes prevalence of conditions that increase vascular risk4. 3.1 per cent in people >15 years old, which more than doubled (6.5 per cent) in those >75 years1. A report covering the period 1991–2001 noted a >50 per cent increase in prevalence of type 2 diabetes over that The value of good diabetes management has been decade2. Although the proportion of older people in recognised by the new General Medical Services the population increased during that time, so too had (nGMS) contract allocating the condition nearly the prevalence of excess adiposity — a well one-fi fth of the total clinical points available within recognised risk factor for type 2 diabetes. The the Quality and Outcomes Framework (QOF)5,6. ‘obesity epidemic’ has no regard for age, and type 2 Achieving these points is based mainly on attaining february 2007 / midlife and beyond / geriatric medicine
specifi c targets for glycaemic control, parameters for Table 1. Oral antidiabetic agents
increased vascular risk such as blood pressure and Classes of oral antidiabetic agents, their main modes of action and glucose lowering monitoring of microvascular disease6. The provision of evidence-based treatment targets by learned societies has become increasingly common as guides for the provision of optimal treatment. The nGMS QOF targets use the carrot and stick principle to encourage appropriate investigations, monitoring and delivery of treatment. Whether care provision has been improved by the nGMS contract is debatable, but comparing 2004/5 with 2005/6 the total QOF points achieved have risen from >90 per cent to >95 per cent across England, Scotland, Wales and Northern Ireland with concomitant increases in *not widely used in UK = decrease = increase points achieved for diabetes (>93 per cent to ~98 per cent) and associated vascular risk areas7.
morbidity — both microvascular and macrovascular — continuously decrease with progression to normoglycaemia. The Joint British Societies’ (JBS2) guidelines has recommended an HbA ≤6.5 per The aim of treatment is to achieve glycaemic control cent while the National Institute for Health and that is as near to normal as possible as this reduces the Clinical Excellence (NICE) has opted for a less incidence, progression and severity of complications. demanding HbA of 6.5–7.5 per cent11,12. However, Indeed, the value of intensive intervention has been the American Diabetes Association (ADA) and highlighted by the United Kingdom Prospective European Association for the Study of Diabetes Diabetes Study (UKPDS), which has shown that over (EASD) consensus document states the goal for treatment should be as near to normal (HbA <6.1 substantially reduces morbidity and mortality8. The cost effectiveness of obtaining and sustaining optimal glycaemic control should not be underestimated, The QOF clinical indicator DM20 sets an HbA1c especially when considering that at least 25 per cent of of ≤7.5 per cent and recommends individual patient patients have vascular complications at the time of targets should be set at 6.5–7.5 per cent, but QOF diagnosis of type 2 diabetes9. The insidious onset of recognises that reaching tighter levels of control is type 2 diabetes mitigates against early detection, thus diffi cult and has also set a less stringent target people may have degenerating glucose control — (DM7) of ≤10 per cent to encourage and reward impaired fasting glucose (IFG) or impaired glucose efforts to ‘achieve the impossible’6. However, some tolerance (IGT), type 2 diabetes — for a decade patients will not achieve QOF targets and exception prior to diagnosis in which time vascular damage reporting prevents a practice being penalised for factors outside its control (eg, adverse response to statins, informed opt-out). The clustering of cardiovascular risk factors (including glucose intolerance) that constitute the metabolic syndrome should create an index of suspicion for the presence of co-morbidities in Type 2 diabetes is a progressive disease characterised people being treated for at least one of the risk by insulin resistance and deteriorating ß-cell factors. For example, in a primary care setting function. The conventional approach to treatment is screening for type 2 diabetes among older based on lifestyle modifi cation (eat less, move more) hypertensive and ischaemic heart disease (IHD) onto which is added oral antidiabetic drugs that patients without diabetes revealed two per cent and target different lesions of the condition and when 2.5 per cent respectively with type 2 diabetes and a adequate insulin secretion can no longer be further 18.5 per cent and 12.4 per cent respectively sustained, insulin therapy is introduced (Table 1). had IGT and/or IFG10. Identifi cation and treatment The ADA-EASD consensus document recommends of patients early in the pathogenesis of type 2 initiating treatment with metformin in addition to diabetes greatly improves their prognosis.
lifestyle modifi cation and moving to the next treatment strategy if an HbA of <seven per cent It is well recognised that diabetic mortality and cannot be achieved and maintained13. At diagnosis geriatric medicine / midlife and beyond / february 2007
Table 2. Main precautions associated with oral antidiabetic agents
aif liver or renal disease select SU with appropriate pharmacokinetics and monitor. Caution drug interactions if liver or renal disease select SU with appropriate pharmacokinetics and monitor. Cau bexcluded by renal impairment, serious liver disease and any condition predisposing to hypoxia,ccheck liver function (eg, serum alinine transaminase) before treatment and at intervals thereafterdavoid in intestinal disease etake with meals and titrate slowly to reduce gastrointestinal effectsfmonitor glucose with all antidiabetic drugs, especially during titration to avoid hypoglycaemiagcheck creatinine and vitamin B12 or haemoglobin annually CHF = congestive heart failure/disease, GI = gastrointestinal, LFT = liver function test an HbA <eight per cent may be effectively treated therapy may be helpful14,15,16. The most common triple by monotherapy with a sulphonylurea or metformin combination is metformin plus a sulphonylurea plus a (especially in overweight patients) whereas an HbA thiazolidinedione. It is important that triple therapy is >10 per cent is indicative of hyperglycaemia that is not used in lieu of insulin therapy, which is necessary unlikely to be lowered to the target range using if there is rising hyperglycaemia on two agents, monotherapy. Provided the individual does not have possibly accompanied by unintentional weight loss, late-onset type 1 diabetes, early use of combination therapy may achieve an adequate fall in HbA 4,13. appropriateness of the agent, the presence of When monotherapy ceases to maintain adequate contraindications and possible adverse events glycaemic control the use of two antidiabetic agents associated with the added drug. Main precautions with different modes of action can produce associated with oral antidiabetic agents are shown in complementary and additive benefi ts that will Table 2. When introducing a drug to achieve optimal improve glycaemic control and other aspects of glycaemic control, it is recommended the agent be cardiovascular risk14-16. The addition of a second agent titrated to maximal effi cacy/tolerated dose to reduce typically reduces HbA by a further 0.6–1.5 per the risk of adverse events such as hypoglycaemia. cent14. When adding another oral agent it is important Titration strategies for monotherapy and to consider the time period you would expect to combination therapy are carefully documented in achieve maximal effect. For example, sulphonylureas Bailey and Feher15. An advantage of combination show a rapid effect evident on the fi rst day of therapy therapy is that glycaemic control may be achieved with the near-maximal effect of a single dose being with lower doses of both agents than with either as achieved in two weeks15. Meglitinides target monotherapy, thereby reducing the potential for side postprandial hyperglycaemia, have a faster onset and shorter duration of action, exhibiting near maximal effi cacy by one week. In contrast, the thiazolidinediones (rosiglitazone and pioglitazone) act via PPARg (peroxisome proliferator activated Most people with type 2 diabetes will also be receptor gamma) and therefore have a more slowly receiving a statin, possibly low-dose aspirin and generated glucose lowering effect and may take from antihypertensives — to reduce vascular risk — and six weeks to three months to exert maximal effi cacy in older people are likely to receive treatment for people who respond to this treatment (up to 30 per other chronic conditions as well as therapies for cent of patients may be non-responders)15–17. intercurrent illness. The increasing pill burden raises the issue of compliance. Among patients If combination therapy with two differently acting prescribed a free combination of metformin and a agents does not achieve glycaemic control, triple sulphonylurea only 13 per cent showed adequate february 2007 / midlife and beyond / geriatric medicine
Table 3. Approved combination therapy drugs
Only four such preparations have received regulatory approval for UK marketing (Table 3). Insulin resistance is an underlying feature of type 2 diabetes initially compensated by unsustainable hyperinsulinaemia. Eventually the islet ß-cells lose the ability to respond adequately to oral agents and insulin replacement therapy is necessary to achieve glycaemic control. The range of insulins, insulin *Actoplus Met **Avandaryl and ***Duetact in USA injection devices and the advent of inhaled insulin have made insulin therapy less daunting and provides an opportunity to more closely mimic physiological concordance, and only about one-third of patients insulin secretion15,17,23. Hypoglycaemia is the main side on metformin or sulphonylurea monotherapy were effect associated with insulin therapy and this taking adequate medication14,19,20. This highlights potential may compromise — but should not preclude the importance of building a positive therapeutic — its use in the elderly, particularly those living alone. alliance so both patient and physician are ‘singing Patient education is critical to the success of insulin therapy and it is recommended that family/carers are similarly informed15,18.
The selection of an appropriate insulin regimen is Patients on a once-daily sulphonylurea regimen an important issue which often warrants consultation showed greater adherence compared with those on >2 with a specialist, particularly in the care of the elderly doses per day20, highlighting the value of simple amongst whom treatment is more likely to be dosing strategies. Several preparations are suited to complicated by the presence of co-morbidities such as once-daily dosing; for example, metformin SR which renal and hepatic impairment15,17. It is generally can be useful for overcoming metformin-associated recommended that insulin therapy is initiated with a low dose (eg, 10–12 units/day) in association with administration of the sulphonylureas gliclazide MR or regular glucose monitoring to avoid hypoglycaemia. glimepiride produced a mean HbA of ≤7.5 per cent The dose is gradually up-titrated by 2–4 units/day to within nine weeks and by 27 weeks about 50 per cent achieve target control. If HbA is <eight per cent it is of patients achieved an HbA <7 per cent21. advisable to start on a lower dose of six units/day17. Hypoglycaemia is a recognised risk in the battle to optimise glycaemic control and it is the main side Insulin resistance in type 2 diabetes necessitates effect of sulphonylurea therapy. Use of sulphonylureas higher insulin dosages compared to people with type in the elderly is therefore a caution since they are 1 diabetes. In some patients insulin therapy is added more likely to live alone and have less regular meal to ongoing oral treatments — for example, insulin to habits. In this study signifi cantly fewer patients on a sulphonylurea regimen may reduce insulin dose gliclazide MR (3.7 per cent) than glimepiride (8.9 per and improve control while ß-cell function remains, cent) noted hypoglycaemic symptoms and no third or addition of metformin to insulin therapy may party assistance was required21; a further study using improve glycaemic control, reduce the weight gain gliclazide MR over two years also exhibited a good and insulin dose15-17. Detailed approaches to safety profi le, notably in the elderly and in patients initiating insulin therapy in primary care have been described by Hirsch et al24 and PCT guidelines can be accessed via the National Diabetes Support Team website25. Some oral agents are not licensed for use with insulin so it is important to consult the current Fixed-dose combination tablets offer the convenience of two differently acting agents in a single tablet, thereby reducing the pill burden14. The cautions attached to each of the component medications need to be considered when moving Improvements in glycaemic control are associated from monotherapy to 2.4.1 combination treatment. with improvements to components of the metabolic february 2007 / midlife and beyond / geriatric medicine
Key points
References
• Type 2 diabetes is a progressive disease.
therapies? Diabetes & Primary Care 2006; 8(3), 124-132
• Maintaining glycaemic control as near normal as possible reduces morbidity and mortality.
• Presence of a cardiovascular risk factor should prompt investigation for associated conditions.
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• Conditions which increase vascular risk should be Practice 2005; 55: 589-95
• Advancing age does not preclude treating to target.
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Excess adiposity is associated with type 2 diabetes as recognised by DM2 and production of a practice obesity (BMI ≥30) register for patients ≥16 years now warrants eight QOF points (OB1)6. Obesity is a major Diabetes & Primary Care 2006; 19(4); 263-4
cause of insulin resistance and weight loss, with or 8(4): 204-6
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complications. However, circumstances might warrant deviating from treating to target as part of individualising patient care. Non-governmental consensus publications, provide targets for optimal treatment outcomes. Such targets provide a gold standard for treatment and should not be undermined by lesser targets which, though easier to achieve, do not necessarily serve the best Dis 2006; 6(4): 147-148
Confl ict of interest: none declared.
Vasc Dis 2006; 6: 121-5
geriatric medicine / midlife and beyond / february 2007

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