Improving concordance in type-2 diabetes

KEY POINTS

Adherence to prescribed medication is a major barrier to achieving targets for cardiovascular risk factor management. Adverse effects can lead to patients not taking their tablets. Using medium doses of two agents in one formulation can cut incidence of side-effects associated with higher doses. Physicians need to be aware of combination agents and their properties, to optimise treatment.

 

Patients with type-2 diabetes generally require multiple interventions to address their many biochemical abnormalities, cardiovascular risk factors and associated morbidity and mortality. Guidelines recognise the growing body of evidence showing that treating risk factors can reduce the burden of diabetic vascular complications, especially cardiovascular disease,¹ so patients can be prescribed up to 10 tablets per day, often with a high dosing frequency (figure 1).

FIG 1: REDUCTION IN TYPICAL DAILY PILL BURDEN WITH FIXED-DOSE COMBINATIONS
Typical daily pill burden without FDCs ACEi = 1 Diuretic = 1 CCA = 1 Statin = 1 Metformin = 3 SU = 2 TZD = 1 Total: 10 tablets per day Number of different formulations: 7	Typical daily pill burden with FDCs ACEi+diuretic FDC = 1 CCA = 1 Statin = 1 SU = 2 TZD+metformin FDC = 2   Total: seven tablets per day Number of different formulations: five
FDC: fixed-dose combination; ACEi: angiotensin-converting enzyme inhibitor; CCA: calcium-channel agonist; SU: sulphonylurea; TZD: thiazolidinedione

Concordance with such regimens represents a significant burden for patients, especially because many may not readily accept the need for treatment. Yet compliance is critical to the successful application of evidence-based risk factor management.

Rationalising treatment
Compliance or concordance to prescribed therapies for any disease is multifactorial. We all experience the difficulties of encouraging newly diagnosed patients to make intensive lifestyle and dietary modifications as the first interventional step in gaining control over this progressive disease. This is complicated by prescribing these patients a range of tablets for a variety of conditions of which they are unaware, which may cause adverse effects and symptoms they were not experiencing before; hardly an encouragement to adhere to their regimens.

Simplifying the drug regimen by reducing the pill burden via the use of extended release formulations or combination products is a straightforward way to help improve compliance.

Addressing hypertension
Management of hypertension usually requires a combination of antihypertensive agents to achieve evidence-based BP targets.^2,3 In type-2 diabetes, agents acting on the renin-aldosterone angiotensin system form the basis of hypertension management and are combined with a diuretic or a calcium channel blocker when further target-driven control is required.

Fixed-dose combinations (FDCs) of these compounds are available in a single tablet (see box 1). Such FDCs could readily be used when the patient is already taking the component agents, or when increasing therapy when BP targets are not achieved.

BOX 1: AVAILABLE FIXED-DOSE COMBINATIONS
DRUG NAME	GENERIC INGREDIENTS	£ PER PACK (28-DAY UNLESS STATED)
Antihypertensive combinations ACE inhibitor/diuretic combinations
Acezide	Captopril/hydrochlorothiazide	50mg/25mg £13.15
Capozide	Captopril/hydrochlorothiazide	50mg/25mg £13.15
Capozide LS	Captopril/hydrochlorothiazide	25mg/12.5mg £10.46
Accuretic	Quinapril/hydrochlorothiazide	10mg/12.5mg £11.75
Carace 10 Plus	Lisinopril/hydrochlorothiazide	10mg/12.5mg £10.51
Carace 20 Plus	Lisinopril/hydrochlorothiazide	20mg/12.5mg £11.89
Zestoretic 20	Lisinopril/hydrochlorothiazide	20mg/12.5mg £14.72
Zestoretic 10	Lisinopril/hydrochlorothiazide	10mg/12.5mg £13.01
Innozide	Enalapril/hydrochlorothiazide	20mg/12.5mg £13.90
Coversyl Plus	Perindopril/indapamide	4mg/1.25mg £14.49 (30 tablets)
ARB/diuretic combinations
Co-Diovan	Valsartan/hydrochlorothiazide	80mg/12.5mg £16.44 160mg/12.5mg £21.66 160mg/25mg £21.66
CoAprovel	Irbesartan/hydrochlorothiazide	150mg/12.5mg £12.57 300mg/12.5mg £16.91 300mg/25mg £16.91
Cozaar-Comp	Losartan/hydrochlorothiazide	50mg/12.5mg £18.09 100mg/25mg £24.20
Micardis Plus	Telmisartan/hydrochlorothiazide	40mg/12.5mg £11.34 80mg/12.5mg £14.18
Olmetec Plus	Olmesartan/hydrochlorothiazide	20mg/12.5mg £12.95 20mg/25mg £12.95
ARB/calcium-channel blocker combinations
Exforge	Valsartan/amlodipine	80mg/5mg £16.44 160mg/5mg £21.66 160mg/10mg £21.66
ACE inhibitor/calcium channel blocker combinations
Triapin	Ramipril/felodipine	5mg/5mg £32.26
Triapin Mite	Ramipril/felodipine	2.5mg/2.5mg £25.55
Tarka	Trandolapril/verapamil	2mg/180mg £17.85
Cholesterol absorption inhibitor combinations
Inegy	Ezetimibe/simvastatin	10mg/20mg £33.42 10mg/40mg £38.98 10mg/80mg £41.21
Oral glucose-lowering combinations Thiazolidinedione/metformin combinations
Competact	Pioglitazone/metformin	15mg/850mg £31.56 (56 tablets)
Avandamet	Rosiglitazone/metformin	2mg/500mg £52.45 (112 tablets) 2mg/1,000mg £27.21 (56 tablets) 4mg/1,000mg £52.45 (56 tablets)
Source: MIMS June 2007

Overall, despite the number of combination products available and the evidence suggesting better compliance with FDCs than treatment with the constituent drugs, antihypertensive FDCs are not widely used in the UK. One retrospective study of patients newly diagnosed with hypertension found that 69 per cent of those taking a lisinopril plus hydrochlorothiazide FDC and 70 per cent of those taking an enalapril plus hydrochlorothiazide FDC adhered to treatment. In contrast, adherence was 58 per cent among patients prescribed lisinopril or enalapril together with a diuretic as separate tablets.3 Another study assessed compliance among 6,206 patients treated with an ACE inhibitor plus a calcium channel blocker as separate agents versus FDC therapy of benazepril plus amlodipine. After roughly 250 days, 88 per cent compliance was achieved in the FDC group, versus 69 per cent in the group receiving the agents separately.⁴

Increasingly, guidelines recommend antihypertensive FDCs of an ACE inhibitor/angiotensin receptor blocker (ARB) with a thiazide/thiazide-like diuretic in patients with type-2 diabetes when there are no cost disadvantages.5 Reducing medications and increasing adherence would also improve cost-effectiveness.

Glycaemic control
Sustained improvements in HbA1c levels are critical to reducing micro- and macrovascular risk in patients with type-2 diabetes, and rely on adherence to prescribed therapies to ensure the best response.

The Diabetes Audit and Research in Tayside Scotland (DARTS) study, which included almost 3,000 patients with type-2 diabetes, showed that 35 per cent of people receiving a once-daily sulphonylurea regimen achieved more than 90 per cent compliance, compared with 27 per cent of those receiving more than one tablet per day.⁶

The compliance benefit of once- or twice-daily dosing compared with three or four times daily dosing was shown in an analysis of data pooled from 26 studies. Once-daily dosing regimens were associated with 73 per cent compliance, twice-daily with 70 per cent compliance, versus 52 per cent for three times and 42 per cent for four times daily regimens.⁷ The importance of patient compliance was shown in a retrospective cohort study of 11,532 patients with diabetes mellitus, where non-adherent patients had higher HbA1c, BP and LDL levels.⁸

In addition, compared with adherent patients, these patients had higher all-cause hospitalisation (23.2 versus 19.2 per cent) and mortality (5.9 versus 4.0 per cent). It has been estimated that each additional oral hypoglycaemic medication taken may be associated with an increase in total HbA1c of 3.6 per cent.⁹

Several agents often required
As is the case for hypertension, glycaemic control often requires several agents to be taken as the disease progresses, with more than one-third of patients taking two or more tablets.

Metformin will probably remain the first-choice treatment in those patients who have been newly diagnosed with type-2 diabetes. However, as we strive to attain appropriate glycaemic control in this progressive condition, increasing modalities of therapy will be required.

A 12-month study demonstrated that prescribing patients a twice-daily FDC of metformin plus a glitazone improved their compliance, compared with regimens where the constituent drugs were taken separately.¹⁰

Patients moving from monotherapy with metformin or rosiglitazone to dual therapy with both showed adherence of 67 per cent at the completion of the study, whereas patients who moved to FDC therapy achieved mean adherence of 83 per cent.

If it is accepted that the metformin and glitazone FDC represents an appropriate progression in treatment, owing to the complementary modes of action of treating not only glucose levels but also the primary condition of insulin resistance (treatment of which may also directly reduce cardiovascular mortality), these combinations could represent a significant improvement in pill burden for patients.

However, physicians should be aware of the current NICE guidance regarding the use of glitazones for combination therapy with metformin or a sulphonylurea. They should prescribe accordingly when monotherapy with metformin or a sulphonylurea has failed to control blood glucose levels and the patient is unable to tolerate metformin and a sulphonylurea due to contraindications or intolerable side-effects. In such situations, a glitazone can be used to replace either of these drugs in combination therapy.

Lowering lipids
Evidence-based management of lipids supports the use of statins in patients who have been diagnosed with type-2 diabetes. However, owing to the asymptomatic nature of the disease, patients are often inclined to make decisions about the importance of their own therapy.

A recent study showed that of 60,000 patients prescribed statins, more than half discontinued their use within two years.¹¹ It is interesting to note that for the 35 per cent of patients who were persistent statin users for two years, a 30 per cent reduction in the risk of hospitalisation for acute MI was observed.

A combination product is available containing a statin and ezetimibe (see box 1) for patients with elevated cholesterol who are not achieving targets with a statin alone, or who are being treated with separate tablets containing a statin or ezetimibe.

Conclusion
There is an increasing choice of combination products that may be appropriate for glucose control and cardiovascular risk factor management in patients with type-2 diabetes, including two glitazone/sulphonylurea combinations. An ARB/calcium channel blocker combination (valsartan/amlodipine) has just become available. Prescribing physicians need to be aware of these agents and their individual properties in terms of the potential for combining cardiovascular risk factor benefits to optimise treatment. The polypill for managing cardiovascular risk is still awaited, but for the time being, there are numerous dual combination products from which to choose.

- Dr Jiten Vora is consultant physician, endocrinologist and honorary senior lecturer at Royal Liverpool University Hospitals

References
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2. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ 1998;317:703-13.
3. Dezii CM. A retrospective study of persistence with single-pill combination therapy vs. concurrent two-pill therapy in patients with hypertension. Manag Care 2000;9(9 Suppl):2-S6.
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5. Williams B, Poulter NR, Brown MJ et al. Guidelines for management of hypertension: report of the fourth working party of the British Hypertension Society, 2004-BHS IV. J Hum Hypertens 2004;18:139-85.
6. Donnan PT, MacDonald TM, Morris AD. Adherence to prescribed oral hypoglycaemic medication in a population of patients with Type 2 diabetes: a retrospective cohort study. Diabet Med 2002;19:279-84.
7. Greenberg RN. Overview of patient compliance with medication dosing: a literature review. Clin Ther 1984;6:592-9.
8. Ho PM, Rumsfeld JS, Masoudi FA et al. Effect of medication nonadherence on hospitalization and mortality among patients with diabetes mellitus. Arch Intern Med 2006;166:1836-41.
9. Krapek K, King K, Warren SS et al. Medication adherence and associated hemoglobin A1c in type 2 diabetes. Ann Pharmacother 2004;38:1357-62.
10. Vanderpoel DR, Hussein MA, Watson-Heidari T, Perry A. Adherence to a fixed-dose combination of rosiglitazone maleate/metformin hydrochloride in subjects with type 2 diabetes mellitus. Clin Ther 2004;26:2066-75.
11. Penning-van Beest FJ, Termorshuizen F, Goettsch WG et al. Adherence to evidence-based statin guidelines reduces the risk of hospitalizations for acute myocardial infarction by 40%. Eur Heart J 2007;28:154-9.