NPC Archive Item: CV risk reduction in diabetes: law of cumulative benefits, diminishing returns

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15th July 2010

This modelling study demonstrates the “law of cumulative benefits” or conversely a “law of diminishing returns” with regard to the intensification of BP-lowering and lipid-modification therapy in patients with diabetes. It suggests a personalised, shared-care approach based on baseline CV risk could maximise a patient’s net benefit from treatment.

Level of evidence:
Level 3 (other evidence) according to the SORT criteria.

Action
Health professionals should continue to follow NICE guidance on the management of type 2 diabetes. NICE guidance recommends reducing BP to below 140/80 mmHg (below 130/80 mmHg if there is kidney, eye or cerebrovascular damage). Simvastatin 40mg is the usual choice and dose of statin, with an increase to 80mg if the total cholesterol is more than 4mmol/L and also the LDL-cholesterol is more than 2mmol/L on treatment. In people with type 2 diabetes and existing or new cardiovascular (CV) disease, or increased albumin excretion, NICE advises considering intensifying lipid lowering treatment to achieve a total cholesterol of less than 4mmol/L or an LDL-cholesterol of less than 2mmol/L. However, in line with good medical practice, such a decision should take into account the patient’s informed preference, including the benefits and risks of treatment.

Health professionals may wish to consider the implications of this modelling study and the earlier ACCORD BP and lipids trials with respect to the risks and benefits of intensifying antihypertensive and lipid-modification treatment, especially if aiming for BP and lipid targets below or at the lower end of the standard target levels set by NICE.

What is the background to this?
As the NICE full guideline for diabetes emphasises, people with type 2 diabetes are at increased CV risk, which is reduced by lowering BP and using suitable lipid modification. Clinical trials have shown that antihypertensives and statins provide significant CV benefits on average for people with type 2 diabetes. However, the recent ACCORD studies have highlighted that intensive BP control and intensive treatment with combination lipid-lowering treatments offered no survival advantage overall, and perhaps caused harm, to patients with type 2 diabetes. This mathematical modelling study aimed to examine the benefits and harms among patients with diabetes of treating high cholesterol levels to a target LDL-cholesterol of 100mg/dL (2.6mmol/L) and blood pressure to a target of 130/80mmHg. Patients were modelled to receive up to five titrations of statin therapy and eight titrations of antihypertensive therapy.

What does this study claim?
Compared with no treatment, treating  to an LDL-cholesterol target of 2.6mmol/L resulted in gains of 1.50 quality-adjusted life-years (QALYs) of lifetime treatment-related benefit. Treating to a BP target of 130/80mmHg resulted in a gain of 1.35 QALYs of lifetime treatment-related benefit. These QALYs declined to 1.42 and 1.16, respectively, after accounting for treatment-related harms. Most of the total benefit was limited to the first few steps of medication intensification or to tight control for a limited group of very high-risk patients. Because of treatment-related harms (such as treatment specific adverse events and the burdens and safety risks from polypharmacy), and the diminishing benefits of combination therapy, intensifying treatment beyond the first step (simvastatin 20mg to 40mg/day) for the LDL-cholesterol target or the third step (thiazide plus ACE inhibitor plus beta-blocker) for the BP target resulted in either limited benefit or net harm for patients with below-average risk. See table below for intensification regimens.

So what?
Like all modelling studies, this study has limitations largely because of the numerous assumptions that had to be made regarding treatment benefits and harms. However, as the related editorial points out, the lessons to be gleaned from this simulation could be profound.

The editorial suggests that over the years, practice guidelines have advocated increasingly tighter control of blood glucose and CV risk factors. However, this model suggests that the diminishing benefits of more aggressive therapy might not only be inefficient but potentially harmful. The principle around the “law of cumulative benefits” or conversely the “law of diminishing returns” has been discussed in some detail in workshop 3 of the Information Mastery 4 – communicating risks and benefits section of NPC. With each preventative drug added, the absolute benefit gained becomes increasingly less. This paper refers to previous work suggesting , for example, that adding a second antihypertensive produces a 16% lower systolic BP reduction and a 35% lower diastolic BP reduction than would be expected if the treatment effects were additive. Conversely, additive drugs are likely to have more adverse effects (because third, fourth, and fifth-line drugs and high doses tend to be less well tolerated) and a high polypharmacy burden. When the benefits of treatment are small or accrue mainly to a subset of patients, treatment harms such as adverse effects can significantly lessen or negate the benefit of treatment.

The other important finding from this modelling study was that the benefit patients receive from preventative interventions is strongly related to their baseline absolute risk of the outcome. Patients with diabetes with the highest risk of CV disease accounted for nearly all of the benefits of treating to targets. Average risk patients (nearly three-quarters of the population) received very little benefit. In addition, while the benefits of treatment accrue preferentially to those at greater likelihood of the outcome, the risks of treatment are distributed more evenly among those treated. By accounting for treatment related harms, the authors identified numerous examples where intensifying treatment would be contraindicated on the basis of risk-benefit considerations, and many more instances where the expected benefits would be so small that shared patient-clinician decision making would be most appropriate.

Shared decision making is an important theme running through much of our work on NPC, see the Information Mastery 4 – communicating risks and benefits section and our work around patient decision aids.

NICE guidance on the management of type 2 diabetes recommends reducing BP to below 140/80 mmHg (below 130/80 mmHg if there is kidney, eye or cerebrovascular damage). For all type 2 diabetes patients apart from those at low CV risk, statins are recommended. Simvastatin 40mg is the usual choice and dose of statin, with an increase to 80mg if the total cholesterol is more than 4mmol/L and also the LDL-cholesterol is more than 2mmol/L on treatment. In people with type 2 diabetes and existing or new cardiovascular disease, or increased albumin excretion, NICE advises considering intensifying lipid lowering treatment to achieve a total cholesterol of less than 4mmol/L or an LDL-cholesterol of less than 2mmol/L. However, in line with good medical practice, such a decision should take into account the patient’s informed preference, including the benefits and risks of treatment.

Study details
Timbie JW, et al. Variation in the net benefit of aggressive cardiovascular risk factor control across the US population of patients with diabetes mellitus. Arch Intern Med 2010;170:1037–44

Design and patients
Mathematical modelling study to examine the effect among patients with diabetes mellitus of treating high cholesterol levels to a target of LDL-cholesterol 100mg/dL (2.59 mmol/L) and blood pressure to a target of 130/80mmHg. Sample comprised individuals 30 to 75 years old with diabetes mellitus participating in the National Health and Nutrition Examination Survey III. Used Monte Carlo methods to simulate a treat-to-target strategy. Patients received up to 5 titrations of statin therapy and 8 titrations of antihypertensive therapy. Treatment adverse effects and polypharmacy risks and burdens were incorporated using disutilities. Health outcomes were simulated using a Markov model.

Intervention and comparison
Intensification regimens differed according to each patient’s baseline medication.

Intensification treatment
Baseline treatment Step 1 Step 2 Step 3 Step 4 Step 5 Step 6 Step 7 Step 8
LDL-C
None Add simva 20mg Intensify to simva 40mg Switch to atorva 40mg Intensify to atorva 80mg Switch to simva 80mg / ezetimibe 10mg
Non-statin Add simva 20mg Intensify to simva 40mg Switch to atorva 40mg Intensify to atorva 80mg Switch to simva 80mg / ezetimibe 10mg
Low-dose statin Intensify to simva 40mg Switch to atorva 40mg Intensify to atorva 80mg Switch to simva 80mg / ezetimibe 10mg
BP
None Add thiazide Add ACE Add BB Add CCB Intensify thiazide Intens. ACE Intens. BB Intensify CCB
Thiazide Add ACE Add BB Add CCB Intensify thiazide Intensify ACE Intens. BB Intens. CCB
ACE inhibitor Add thiazide Add BB Add CCB Intensify thiazide Intensify ACE Intens. BB Intens. CCB
Beta-blocker Add thiazide Add ACE Add CCB Intensify thiazide Intensify ACE Intens. BB Intens. CCB
Calcium channel blocker Add thiazide Add ACE Add BB Intensify thiazide Intensify ACE Intens. BB Intens. CCB

Outcomes and results
Treating to targets resulted in gains of 1.50 for LDL-cholesterol) and 1.35 (for BP) QALYs of lifetime treatment-related benefit, which declined to 1.42 and 1.16 QALYs after accounting for treatment-related harms. Most of the total benefit was limited to the first few steps of medication intensification or to tight control for a limited group of very high-risk patients. However, because of treatment-related disutility, intensifying beyond the first step (LDL-cholesterol) or third step (BP) resulted in either limited benefit or net harm for patients with below-average risk.

Sponsorship
Supported in part by the VA Health Services Research and Development Service and the Michigan Diabetes Research and Training Centre

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