Targeting LDL cholesterol – How low do we need to get it? And at what price…?

People with diabetes are at a dramatically elevated risk for cardiovascular events and cardiovascular disease (CVD) is the main causes of death in people with type 2 diabetes.[1, 2] Though diabetes is mostly thought of as condition with an impaired glucose homeostasis, lowering elevated glucose levels does not appear to be an effective approach to mitigate this risk. To the contrary, aiming at very tight glucose control has sometimes been shown to be potentially harmful and to increase mortality and cardiovascular event rate.[3, 4]

Diabetes –It’s not all about the glucose

Putting the focus on “classic” CVD risk factors such as smoking, elevated blood pressure [5] and hyperlipidemia appears to be a more successful approach: In particular, elevated LDL-cholesterol is a major risk factor worth targeting in patients at risk. The benefits are impressive: Every 39 mg/dL (1 mmol/L) reduction of LDL-cholesterol results in a risk reduction of 21% for major vascular events [6].

These benefits are reflected by treatment guidelines in US and Europe which recommend treatment with lipid lowering drugs and treatment goals of less than 1.8 mmol/L (<70 mg/dL) LDL cholesterol for most adult patients with diabetes. [7, 8]

For decades, HMG-CoA-reductase inhibitors, better known as “statins”, have been the mainstay of cholesterol lowering treatment. Unfortunately, in some patients, LDL cholesterol targets cannot be reached by statins alone despite use of high doses, or statins are poorly tolerated due to side effects such as muscle pain or weakness, or, less commonly, myopathy[9].

LDL cholesterol – How low should we get it?

In recent years, several studies have looked into LDL cholesterol targets below 70 mg/dL and the use of combination treatment.

An updated meta-analysis published in 2010 showed that reducing LDL cholesterol to levels between 1 and 2 mmol/L using intensive statin regimens may reduce the rate of major vascular events even in individuals whose LDL-cholesterol is already relatively low. [10]

Results from the IMPROVE-IT trial seem to point into the same direction. In this trial, statin treatment was combined with ezetimibe, a marketed drug that reduces absorption of cholesterol from the small intestine. Combination treatment led to a reduction of LDL cholesterol (54 mg/dL (1.4 mmol/L) versus 70 mg/dL (1.8 mmol/L)) and less major cardiovascular events compared to statin treatment alone. [11].

A new option: PCSK9 inhibitors

A class of drugs that has recently drawn a lot of attention is the class of inhibitors of proprotein convertase subtilisin-keexin type-9 (PCSK9). Monoclonal antibodies against PCSK9 can dramatically lower LDL cholesterol levels by inhibiting degradation of the LDL-receptor in the liver, thereby increasing the capacity to clear LDL cholesterol from the extracellular fluid. Two PCSK9 inhibitors, alirocumab and evolocumab, have been approved and marketed in the US and in Europe, indicated for lowering LDL-cholesterol levels in patients where statins are not sufficiently effective or poorly tolerated.

Previously, effects on cardiovascular outcomes of PCSK9 inhibitors have only been investigated in phase 2 and phase 3 follow up studies with relatively low numbers of events. [12, 13]

Earlier this year, the much anticipated trial results from “Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk” (FOURIER) were published. FOURIER was the first dedicated cardiovascular outcomes study testing the efficacy and safety of PCSK9 inhibitor evolocumab when given as add-on to statin treatment versus statins alone. 27.564 high risk patients with a history of cardiovascular disease were included and followed up for a median of 26 months.[14]

LDL cholesterol was dramatically lowered by evolocumab to 30 mg/dL from the median baseline level of 92 mg/dL, a drop which occurred early after start of treatment and which was sustained throughout the duration of the trial. The primary endpoint of this study, a composite of cardiovascular death, stroke, hospitalization for unstable angina and coronary revascularization, occurred in 9.8% of the patients taking evolocumab versus 11.3 % of patients in the placebo group, corresponding to a risk reduction of 15 %. Risk reduction tended to increase over time, from 12% in the first year to 19% thereafter.  

The authors point out that one cardiovascular death, myocardial infarction or stroke could be prevented in 74 patients over two years treatment duration. This could result in very favorable numbers needed to treat if projected to longer treatment durations. Total and cardiovascular mortality alone, on the other hand, were not reduced in the evolocumab group.

What may FOURIER change?

So, can we expect PCSK9 inhibitors to be routinely given to a broader number of patients anytime soon?

One obstacle for a wider use if PCSK9 inhibitors will probably be the high costs which are more than tenfold above those of regimens using high intensity statins alone or in combination with ezetimibe. Costs may set limits in most countries and health care systems and may restrict their use to clearly defined high risk patient groups.

But combined data from CTT, IMPROVE-IT and FOURIER all appear to support the idea of treating LDL cholesterol to even lower targets than the ones suggested by current guidelines and may result in meaningful absolute risk reduction in people at increased risk for cardiovascular events, including people with diabetes. So maybe there is a different lesson to be learned from FOURIER: A US veterans affair study has now been published to estimate costs that would be associated with incorporating the findings of the FOURIER trial into clinical practice.[15]

The study identified US veterans who met FOURIER eligibility criteria for evolocumab. If all 154.823 people were treated, annual costs would amount to more than 2 billion USD. This number could be lowered by intensifying use of oral LDL cholesterol lowering drugs in order to lower LDL cholesterol to levels below 70 mg/dL. Titrating statin doses up to high intensity treatment would cut this number by about 20 %, adding ezetimibe would lower the number to approximately 50%, resulting in a net cost saving of 1.13 billion USD.

The authors conclude that “health care systems have considerable opportunity to increase use of evidence-based high-intensity statins and ezetimibe which may reduce the need for additional costly therapies such as evolocumab.”

References

1. Tancredi, M., et al., Excess mortality among persons with type 2 diabetes. New England Journal of Medicine, 2015. 373(18): p. 1720-1732.
2. Campbell, P.T., et al., Diabetes and cause-specific mortality in a prospective cohort of one million US adults. Diabetes care, 2012. 35(9): p. 1835-1844.
3. Boussageon, R., et al., Effect of intensive glucose lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 diabetes: meta-analysis of randomised controlled trials. BMJ, 2011. 343: p. d4169.
4. Group, A.t.C.C.R.i.D.S., Effects of intensive glucose lowering in type 2 diabetes. N Engl j Med, 2008. 2008(358): p. 2545-2559.
5. Group, U.P.D.S., Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ: British Medical Journal, 1998: p. 703-713.
6. Trialists, C.T., Efficacy of cholesterol-lowering therapy in 18 686 people with diabetes in 14 randomised trials of statins: a meta-analysis. The Lancet, 2008. 371(9607): p. 117-125.
7. Catapano, A.L., et al., 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias. European Heart Journal, 2016. 37(39): p. 2999-3058.
8. Stone, N.J., et al., 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults. Circulation, 2014. 129(25 suppl 2): p. S1-S45.
9. Collins, R., et al., Interpretation of the evidence for the efficacy and safety of statin therapy. The Lancet, 2016. 388(10059): p. 2532-2561.
10. Cholesterol Treatment Trialists, C., et al., Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet, 2010. 376(9753): p. 1670-81.
11. Cannon, C.P., et al., Ezetimibe added to statin therapy after acute coronary syndromes. New England Journal of Medicine, 2015. 372(25): p. 2387-2397.
12. Sabatine, M.S., et al., Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med, 2015. 372(16): p. 1500-9.
13. Robinson, J.G., et al., Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med, 2015. 372(16): p. 1489-99.
14. Sabatine, M.S., et al., Evolocumab and clinical outcomes in patients with cardiovascular disease. New England Journal of Medicine, 2017. 376(18): p. 1713-1722.
15. Virani, S.S., et al., Estimation of Eligibility for PCSK9 Inhibitors and Associated Costs Based on the FOURIER Trial: Insights from the Department of Veterans Affairs. Circulation, 2017: p. CIRCULATIONAHA. 117.028503.