Prescribing Review - Type 2 Diabetes


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Preventing Type 2 Diabetes
Several large studies have shown that preventing or delaying onset of type 2 diabetes is possible in those at risk. In overweight people with impaired glucose tolerance or raised fasting plasma glucose, intensive lifestyle intervention aimed at weight loss, healthy eating and physical activity more than halved the progression to diabetes compared with brief information provided annually (NNT for intensive lifestyle support over 3 years = 7, metformin = 14)¹. Although not licensed for preventative use, the potential role of drugs has received attention recently. Conclusions were as follows: the threshold for drug use in otherwise healthy people must be high; no trial has shown that prevention with drugs improves outcomes important to patients; lifestyle changes are at least equally effective, much safer and cheaper². Recommendations in NICE Clinical Guideline 43 - Obesity are highly relevant, covering both population measures and specific interventions for individuals³.

Initiating treatment and treatment targets
Interventions to reduce the risk of CV complications are largely the same as for people without diabetes and are based on overall CV risk, i.e. smoking cessation, blood pressure control, cholesterol reduction, antiplatelet drugs, increased activity, weight loss and dietary modification (including increased fruit, vegetables and oily fish, reduced saturated fat and salt, moderate alcohol intake). Standard risk calculators have limited validity for people with type 2 diabetes⁴ and clinical judgement is required. Risk calculators based on outcome data for people with type 2 diabetes may be more appropriate⁵. For those at high risk (10 year CVD risk > 20%), priority should be given to controlling blood pressure and reducing cholesterol with statins⁶. Table 1 compares Quality and Outcomes Framework (QOF) figures for patients reaching QOF treatment targets with data collected from primary care sources for the National Diabetes Audit (NDA) for 2004/05. Differences are probably due to the effect of QOF exception reporting. NICE recommends targets for blood pressure of < 140/80 mmHg or < 135/75 mmHg if microalbuminuria or proteinuria is present, and that HbA1c should be between 6.5-7.5%, according to individual vascular risk.

Table 1 Patients with type 2 diabetes reaching treatment targets (QOF versus NDA)

Empowering people with diabetes is a core component of the National Service Framework (NSF) delivery strategy and NICE Technology Assessment 60 recommends that structured patient education, such as DESMOND (Diabetes Education and Self-Management for Ongoing and Newly Diagnosed), be made available to all people with diabetes at the time of diagnosis and subsequently as required. An important feature of empowerment is reaching agreement on personally meaningful, realistic and achievable targets.

Blood Pressure
A difference of 10/5 mmHg between a group randomised to tight blood pressure control (achieved 144/82 mmHg) and a group randomised to less tight control (achieved 154/87 mmHg) resulted in large and significant reductions in diabetes related death, heart failure, stroke and deterioration in visual acuity⁷. Among the more than 13,000 people with diabetes enrolled in ALLHAT, neither amlodipine nor lisinopril was superior to chlortalidone in reducing the rate of end-stage renal disease, myocardial infarction or fatal CHD⁸. Thiazide diuretics are included in current NICE guidance as first line options for people with type 2 diabetes without microalbuminuria or proteinuria. ACE-inhibitors are recommended for people with microalbuminuria or proteinuria. Angiotensin receptor antagonists should be substituted only when ACE-inhibitors are truly not tolerated, because there are more outcome data for the latter.

Lipids
Statins are recommended where there is evidence of CV disease and for primary prevention when clinical judgement is that 10 year estimated risk is = 20%. Among the 5,963 people with diabetes (90% with type 2 diabetes) enrolled in the Heart Protection Study a fixed 40mg dose of simvastatin was safe and effective, and reduced major coronary events and strokes by about a quarter⁹. It has not been established that more aggressive lipid lowering therapy is warranted¹⁰. NICE recommends using the statin with the lowest acquisition cost.

Blood Glucose
Although observational studies suggest an association between persistent hyperglycaemia and macrovascular complications in type 2 diabetes, evidence that hypoglycaemic agents reduce these is limited. A recent systematic review and meta-analysis¹¹ found that improved glycaemic control translated into reductions in peripheral vascular disease and stroke but concluded that the prevention of cardiac events must be effected by means of antihypertensive, lipid-lowering, and platelet inhibiting measures. Metformin is the only hypoglycaemic agent shown to reduce deaths and prevent both microvascular and macrovascular complications. Unless contraindicated, it is the first line choice for all people whose blood glucose is inadequately controlled with lifestyle interventions. A generic sulphonylurea (e.g. gliclazide) is normally recommended when metformin is contraindicated and for those people who do not tolerate it. Tolerability can be improved by slow titration (over 3-6 weeks)¹². Combining metformin and a sulphonylurea is suitable for those whose blood glucose is inadequately controlled with monotherapy. Modified release and combination preparations are considerably more expensive than alternatives and have not been shown to be more effective, safer or better tolerated. Rosiglitazone and pioglitazone (glitazones) should only be used in combination with either metformin or a sulphonylurea where one or the other is contraindicated or not tolerated¹³. Recent studies, raising the possibility that rosiglitazone may increase the risk of myocardial infarction and CV death¹⁴ and suggesting no effect of pioglitazone on a composite CV outcome, emphasise that effectiveness in reducing blood glucose may not always translate into meaningful benefits for patients. Studies confirming that glitazones increase the risks of heart failure and osteoporotic fracture, and regulatory concern regarding macular oedema, underline this. The role of other newer drugs such as sitagliptin and exenatide has yet to be established.

Insulin therapy is usually considered if maximum tolerated doses of two oral agents combined with maximum achievable lifestyle modification do not adequately control blood glucose. Triple therapy including a glitazone might be considered if insulin is not acceptable, but considerable caution is required. Decisions in primary care will usually be based on specialist advice. 30% of people with type 2 diabetes may require insulin¹⁵. Choice of insulin for type 2 diabetes is based on local experience, patient factors and cost. Continuing metformin may lessen the number of injections required, reduce the dose of insulin needed and minimise weight gain. If metformin is not tolerated, a sulphonylurea should be continued. Night time isophane insulin or twice daily biphasic insulins are typically used for type 2 diabetes. There is little evidence to suggest that glargine or detemir reduce HbA1c compared with isophane insulin in patients with type 2 diabetes or that either reduces severe hypoglycaemia¹⁶. It seems reasonable to consider that NICE guidance not to prescribe insulin glargine for people with type 2 diabetes unless they suffer from recurrent hypoglycaemia, require assistance with insulin or would otherwise need twice daily basal injections with oral antidiabetic drugs also applies to detemir. Biphasic analogue insulins have not been shown to have any consistent advantages over other pre-mixes¹⁷. Inhaled insulin may be suitable for the very small number of people with type 2 diabetes who, in addition to requiring fast-acting insulin, have proven phobia to injections or persistent injection site problems.

There is a continuing debate about blood glucose self-monitoring by people with type 2 diabetes who do not require insulin. Some observational studies have suggested benefit but results of randomised controlled trials (RCT) have been inconclusive. One large RCT found evidence of harm. No significant improvement in glycaemic control was found in a recent trial comparing HbA1c monitoring by health professionals with either less intensive or more intensive blood glucose self-monitoring for 12 months¹⁸.

PRESCRIBING DATA
(Reporting quarter = January-March 2007, index quarter = January-March 2002)
The cost of prescribing hypoglycaemic drugs has more than doubled over the last 5 years. There has been little change in the relative proportions of oral antidiabetic drugs and insulins prescribed, but expenditure on oral drugs has increased to a greater extent (see charts 1 and 2).

Metformin prescribing has doubled over the last 5 years, accounting for 54% (2.4 million items) of antidiabetic drug items and 28% of cost (£13.8 million). There has been an 18% increase in prescribing of sulphonlyureas to 1.4 million items; cost has fallen by 12% to £8.2 million. Gliclazide accounts for a quarter of all antidiabetic drug prescribing (1.1 million items) and 11% of cost (£5.5 million); it is the most commonly prescribed sulphonylurea. Rosiglitazone prescribing and spending has risen almost three-fold in the last 5 years to 307,000 items and £14.0 million (28% of all spending on oral antidiabetic drugs). Pioglitazone accounts for 132,000 items at a cost of £5.3 million. Prescribing of the combination drug, rosiglitazone with metformin, stands at 153,000 items and accounts for 15% of all spending on oral antidiabetic drugs (£7.3 million). In total the glitazones and the combination of glitazones with metformin represent 54% of all expenditure on antidiabetic drugs but only 13% of items.

Intermediate- and long-acting insulins account for 74% of all insulin prescribing and 73% of cost. Insulin glargine is the most commonly prescribed long-acting insulin: 248,000 items (27%) at £14.2 million (32%). Biphasic insulins account for 478,000 items at £22.4 million. Prescribing of blood glucose testing strips has risen by 30% to 1.4 million items costing £32 million.

• Intensive support for lifestyle modification can prevent or delay progress to type 2 diabetes.

• Multifactorial management of cardiovascular risk reduces preventable morbidity and mortality.

• Lowering lipids and blood pressure is associated with substantial cardiovascular benefit.

• Metformin also reduces macrovascular complications.
• Self-monitoring of blood glucose may be of little or no value for the majority of people with type 2 diabetes.

¹Diabetes Prevention Program Research Group. N Engl J Med 2002; 346:393-403.
²Montori VM, Isley WL, Guyatt GH. Waking up from the DREAM of preventing diabetes with drugs. BMJ 2007;334:882-884
³NICE. Obesity. Clinical Guideline 43. December 2006.
⁴Technology Appraisal 94: Statins for the prevention of cardiovascular events. NICE 2006.
⁵The UKPDS Risk Engine. [Online]. Available here
⁶Huang ES, Meigs JB, Singer DE. The effect of interventions to prevent cardiovascular disease in patients with type 2 diabetes mellitus. Am J Med 2001; 111: 633-42
⁷UK Prospective Diabetes Study (UKPDS) Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998; 317: 703-713
⁸The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic. The antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). JAMA 2002;288:2981-97.
⁹Heart Protection Study Collaborative Group. MRC/BHF heart protection study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7-22.
¹⁰Ravnskov U, Rosch PJ, Sutter MC, and Houston MC. Analysis and comment: Should we lower cholesterol as much as possible? BMJ 2006; 332: 1330-1332. ¹¹Stettler C, Allemann S, Jüni P, Cull CA, Holman RR, Egger M, et al. Glycaemic control and macrovascular disease in type 1 and type 2 diabetes mellitus: Meta-analysis of randomised controlled trials. Am Heart J 2006; 152:27-38
¹²Diabetes Type 2 - blood glucose management. [Online]. Clinical Knowledge Summaries 2006. Available from: URL: http://cks.library.nhs.uk/diabetes_glycaemic_control/
¹³NICE. Guidance on the use of glitazones for the treatment of type 2 diabetes. Technology Appraisal Guidance 63. August 2003.
¹⁴Nissen SE, Wolski MPH. Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes. NEJM 2007; 356: 2457-2471
¹⁵NICE. Guidance on the use of long-acting insulin analogues for the treatment of diabetes - insulin glargine. Technology Appraisal 53. December 2002.
¹⁶MeRec Bulletin; Vol 17: No 4: The role of newer insulins in diabetes: Summary. National Prescribing Centre 2007.
¹⁷Garber AJ. Premixed insulin analogues for the treatment of diabetes mellitus. Drugs 2006; 66: 31-49
¹⁸Farmer A, Wade A, Goyder E, Yudkin P, French D, Craven A, et al. Impact of self monitoring of blood glucose in the management of patients with non-insulin treated diabetes: open parallel group randomised trial. BMJ, Jun 2007; doi:10.1136/bmj.39247.447431.BE