Ask The Experts

Are PCSK9 inhibitors the next “statin” for patients with diabetes?

Understanding the potential for proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors to improve CVD outcomes in patients with diabetes.

Proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors and statins have notable similarities and differences.  Like statins, PCSK9 inhibitors reduce low-density lipoprotein (LDL) cholesterol, but with about 1.5 to 2 times greater potency.  In fact, the PCSK9 inhibitor, evolocumab (Repatha), a monoclonal antibody, was shown in the FOURIER trial, to significantly reduce the risk of cardiovascular events by lowering LDL cholesterol1 in patients with preexisting stable vascular disease.

Are PCSK9 inhibitors needed to reduce CVS risk in people with diabetes?

Furthermore, as with statins, a pre-specified subgroup analysis in FOURIER showed even greater absolute benefit of evolocumab in diabetic subjects,2 given their higher baseline rate of cardiovascular events. Comparable results have been reported based on preliminary data from the phase 3, ODYSSEY Outcomes trial among those received twice weekly alirocumab (Praluent) injections.3

However, PCSK9 inhibitors are injectable biologic agents whose annual cost is 50- to 100-fold greater than that of generic statins, which may be a limiting factor for many patients. Also, while these drugs appear very safe, without the side effect profile for increased risk of muscle symptoms or new-onset diabetes inherent to statins, they have been used in humans for only 4 or 5 years, including in clinical trials. Therefore, any long-term effects remain uncertain. 

In contrast, we now have 30-plus years of experience with statins, and are confident of their safety and reliability in the vast majority of patients, especially those with diabetes. Whether PCSK9 inhibitors eventually rival or replace statins will depend on a number of factors, including acquiring longer term experience in randomized trials and in the clinical setting, with continued demonstration of benefit and tolerability, and reduction of barriers to accessibility.

Is this group of meds only effective to lower LDL or is there a benefit for other lipids such as Lp(a)?  

Through their mechanism of action, PCSK9 inhibitors prevent or delay the degradation of cell surface LDL receptors; these receptors are the central regulator of plasma LDL cholesterol levels.4 PCSK9 inhibitors reduce LDL cholesterol by up to 60-70% from baseline levels, including the already shifted baseline levels in statin-treated patients.1,3 Because apo B containing lipoproteins are removed from plasma by LDL receptors, plasma apo B levels are reduced by up to 50%. 

Plasma triglycerides, which are carried in very-low density lipoproteins (VLDL) are also reduced somewhat—perhaps 15-20%— with PCSK9 inhibitors. The family of particles comprising “non-HDL cholesterol” is thus reduced by about 40-50% with PCSK9 agents, while HDL cholesterol is only minimally (~5%) increased.4,5

An important component of non-HDL is lipoprotein(a) (Lp[a]), which is an atherogenic lipoprotein particle that resembles LDL.6  Elevated Lp(a) levels have generally but not universally been associated with increased CVD risk in both type 1 and type 2 diabetes mellitus.7-9 An extremely interesting effect of the PCSK9 inhibitors is a reduction of plasma Lp(a) by ~25%.4,5  This is quite unique among lipid-lowering agents. Statins either have no effect on Lp(a) or sometimes may even increase levels. Only niacin was noted previously to lower Lp(a) levels, and the use of this medication has waned over the past few years. 

Because PCSK9 inhibitors are neutral with respect to their effects on glycemia and HbA1c, they cannot substitute for or replace hypoglycemic agents such as metformin, gliptins or SGLT2 inhibitors. However, the FOURIER subgroup analysis unequivocally shows that these drugs have a marked cardiovascular benefit in diabetes that is mediated entirely through their ability to lower LDL cholesterol and is independent of any glucose modulation.  Furthermore, there was no increased risk of developing diabetes with the use of evolocumab.

In Which Patients and When Might PCSK inhibitors Be Prescribed? 

At the moment, PCSK9 inhibitors are most appropriately considered to be add-on agents to maximally tolerated statins. The least controversial high-risk target patient population for PCSK9 inhibitors includes those with:

  1. Familial hypercholesterolemia
  2. Significant atherosclerotic CVD and elevated LDL cholesterol despite maximally tolerated statin therapy

Patients with diabetes who in addition have either of these conditions would represent a particularly high-risk subgroup for which PCSK9 inhibitors would merit serious consideration.

For patients with newly diagnosed diabetes, the current algorithm for lipid management to reduce cardiovascular risk recommends initiating treatment with a statin.10  If the patient’s treated LDL cholesterol is higher than acceptable, ezetimibe is the next agent to add, because of tolerability, low cost, ease of administration and evidence for cardiovascular benefit, especially in patients with diabetes.

Should there still be room for improvement of LDL cholesterol, a PCSK9 inhibitor is then a worthwhile and reasonable consideration.  If there’s still room for improvement of LDL cholesterol, a PCSK9 inhibitor is then a worthwhile and reasonable consideration.  

Almost all clinical trials with PCSK9 inhibitors have been conducted with background statin therapy, so to practice evidence-based medicine, these agents should be used together with background statins.   

A patient’s response following treatment to reduce LDL-C should be assessed within three months of initiating treatment. Although it appears that ultra-low levels of LDL-C that result from PCSK9 inhibition are well-tolerated, the dose of statin may be lowered if LDL cholesterol is so low as to be virtually undeterminable, such as < 15 mg/dL (< 0.4 mmol/L).

Continue Reading:
LDL—How Low to Go In People With Diabetes?
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