Meeting News

Multitude of treatment options puts drastically reduced LDL cholesterol within reach

PHILADELPHIA —LDL cholesterol can be reduced to even more beneficial levels than ever before by use of a number of medications, including PCSK9 inhibitors, according to a presenter at the Heart in Diabetes CME Conference.

Antonio Gotto Jr.

These pharmacologic developments can aid in treatment of patients at varying degrees of cardiovascular risk, Antonio Gotto Jr., MD, DPhil, dean emeritus at Weill Cornell Medicine, said.

“It is possible with the treatments that we have today to get LDL down almost as low as [you] want it to be,” Gotto told Endocrine Today. “The studies thus far that have been carried out where we’ve used PCSK9 inhibitors on top of maximal-tolerated statins drives LDL down 20 [mg/dL] and below, and so far, what we’ve seen has been reassuring in that the lower the better in terms of reducing cardiovascular events, and the treatments have been safe.”

Gotto presented telling data from a number of those studies, with some examining statins alone and others focusing on combinations with proprotein convertase subtilisin/kexin type 9 (PCKS9) inhibitors as they relate to not only reducing LDL levels, but also to protecting against adverse CV outcomes.

Intensifying statin treatment

According to Gotto, LDL cholesterol and risks for coronary heart disease, myocardial infarction or mortality were significantly reduced or numerically lowered in four trials that compared different doses of various statins, including intensive atorvastatin therapy, simvastatin and pravastatin, which are considered more standard therapy. These trials included the PROVE-IT TIMI, A-to-Z, TNT and IDEAL studies, which ranged between 2 and 5 years in length and looked at participants with acute coronary syndrome or CAD.

LDL cholesterol can be reduced to even more beneficial levels than ever before by use of a number of medications, including PCSK9 inhibitors.
Adobe Stock

Similarly, Gotto said, the risk for a major coronary event was reduced by 24% when LDL cholesterol was lowered by at least 1 mmol/L, or 39 mg/dL (OR = 0.76; 95% CI, 0.73-0.79), whereas there were similar decreases in risk for coronary revascularization (OR = 0.76; 95% CI, 0.73-0.8), stroke (OR = 0.85; 95% CI, 0.8-0.9) and major vascular events (OR = 0.78; 95% CI, 0.76-0.8) in metanalysis data that explored the efficacy of more-intensive statin therapies. According to Gotto, these associations held even for participants for which vascular disease was considered unlikely.

Gotto said that statin therapy can be augmented by the addition of ezetimibe, as evidenced in the IMPROVE-IT trial, which showed that the combined risk for CV death, MI, unstable angina, stroke and coronary revascularization was reduced for those taking 40 mg simvastatin in combination with 10 mg ezetimibe compared with those taking simvastatin only (HR = 0.936; 95% CI, 0.887-0.988). Gotto also said the cholesteryl ester transfer protein (CETP) inhibitor anacetrapib (Merck) reduced the incidence of a coronary event by 9% across 4 years vs. placebo in the REVEAL trial (RR = 0.91; 95% CI, 0.85-0.97).

PCSK9 inhibitors

Gotto went on to present findings from the FOURIER and ODYSSEY trials, which exhibited how PCSK9 inhibitors can further enhance the work of statins in yielding LDL cholesterol reductions and CV benefits.

In the FOURIER trial, evolocumab (Repatha, Amgen) treatment was compared with placebo in a population of individuals already using statins who had LDL cholesterol levels of at least 70 mg/dL and atherosclerotic CVD. Not only did the chances of experiencing CV death, MI, stroke, unstable angina or coronary revascularization decline by 15% at 36 months in those using the PCSK9 inhibitor (HR = 0.85; 95% CI, 0.79-0.92), participants in this group also had their LDL cholesterol levels reduced by an average of 56 mg/dL compared with those in the placebo group (P < .00001), according to Gotto, who noted that these benefits were present regardless of baseline LDL cholesterol or previous statin use and without much difference in safety outcomes between groups.

The PCSK9 inhibitor alirocumab (Praluent, Sanofi/Regeneron) was evaluated in the ODYSSEY trial. Gotto noted that such treatment also yielded a 15% reduction in instances of coronary heart disease mortality, nonfatal MI, ischemic stroke and unstable angina over 4 years in comparison with placebo when used in combination with a statin (HR = 0.85; 95% CI, 0.78-0.93). In addition, at 48 months, those taking alirocumab had an average LDL cholesterol level of 66 mg/dL compared with an average of 103 mg/dL among those taking placebo.

“All the drugs used in these studies were binding to the LDL receptor,” Gotto said. “If one looks at reducing LDL by mechanisms not involving the LDL receptor, then they don’t follow necessarily the same curve.”

With ample evidence now available that LDL cholesterol measures can be lowered substantially and safely in combination with improvements in CV events, there is a debate over what the optimal thresholds should be. Gotto said 40 mg/dL is his personal preference, but that others opt for measures of 20 mg/dL and below.

“There’s not a perfect answer to this question,” Gotto said during his presentation. “One can get the LDL down almost as low as you want, and someone has to balance the safety, the cost and the risk of the individual.” – by Phil Neuffer

References:

Gotto A. The lower LDL the better. Presented at: Heart in Diabetes CME Conference; July 12-14, 2019; Philadelphia.

Cannon CP. JAMA. 2005;doi:10.1001/jama.294.19.2492.

Cannon CP, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1410489.

CTT Collaboration. Lancet. 2010;doi:10.1016/S0140-6736(10)61350-5.

HPS3/TIMI55–REVEAL Collaborative Group. N Engl J Med. 2017;doi:10.1056/NEJMoa1706444.

Sabatine MS, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1615664.

Schwartz GG, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1801174.

Disclosure: Gotto reports he serves on the board of directors of Esperion Therapeutics, as a consultant for Kowa Pharmaceuticals and on the data safety monitoring board for Akcea Therapeutics.

PHILADELPHIA —LDL cholesterol can be reduced to even more beneficial levels than ever before by use of a number of medications, including PCSK9 inhibitors, according to a presenter at the Heart in Diabetes CME Conference.

Antonio Gotto Jr.

These pharmacologic developments can aid in treatment of patients at varying degrees of cardiovascular risk, Antonio Gotto Jr., MD, DPhil, dean emeritus at Weill Cornell Medicine, said.

“It is possible with the treatments that we have today to get LDL down almost as low as [you] want it to be,” Gotto told Endocrine Today. “The studies thus far that have been carried out where we’ve used PCSK9 inhibitors on top of maximal-tolerated statins drives LDL down 20 [mg/dL] and below, and so far, what we’ve seen has been reassuring in that the lower the better in terms of reducing cardiovascular events, and the treatments have been safe.”

Gotto presented telling data from a number of those studies, with some examining statins alone and others focusing on combinations with proprotein convertase subtilisin/kexin type 9 (PCKS9) inhibitors as they relate to not only reducing LDL levels, but also to protecting against adverse CV outcomes.

Intensifying statin treatment

According to Gotto, LDL cholesterol and risks for coronary heart disease, myocardial infarction or mortality were significantly reduced or numerically lowered in four trials that compared different doses of various statins, including intensive atorvastatin therapy, simvastatin and pravastatin, which are considered more standard therapy. These trials included the PROVE-IT TIMI, A-to-Z, TNT and IDEAL studies, which ranged between 2 and 5 years in length and looked at participants with acute coronary syndrome or CAD.

LDL cholesterol can be reduced to even more beneficial levels than ever before by use of a number of medications, including PCSK9 inhibitors.
Adobe Stock

Similarly, Gotto said, the risk for a major coronary event was reduced by 24% when LDL cholesterol was lowered by at least 1 mmol/L, or 39 mg/dL (OR = 0.76; 95% CI, 0.73-0.79), whereas there were similar decreases in risk for coronary revascularization (OR = 0.76; 95% CI, 0.73-0.8), stroke (OR = 0.85; 95% CI, 0.8-0.9) and major vascular events (OR = 0.78; 95% CI, 0.76-0.8) in metanalysis data that explored the efficacy of more-intensive statin therapies. According to Gotto, these associations held even for participants for which vascular disease was considered unlikely.

Gotto said that statin therapy can be augmented by the addition of ezetimibe, as evidenced in the IMPROVE-IT trial, which showed that the combined risk for CV death, MI, unstable angina, stroke and coronary revascularization was reduced for those taking 40 mg simvastatin in combination with 10 mg ezetimibe compared with those taking simvastatin only (HR = 0.936; 95% CI, 0.887-0.988). Gotto also said the cholesteryl ester transfer protein (CETP) inhibitor anacetrapib (Merck) reduced the incidence of a coronary event by 9% across 4 years vs. placebo in the REVEAL trial (RR = 0.91; 95% CI, 0.85-0.97).

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PCSK9 inhibitors

Gotto went on to present findings from the FOURIER and ODYSSEY trials, which exhibited how PCSK9 inhibitors can further enhance the work of statins in yielding LDL cholesterol reductions and CV benefits.

In the FOURIER trial, evolocumab (Repatha, Amgen) treatment was compared with placebo in a population of individuals already using statins who had LDL cholesterol levels of at least 70 mg/dL and atherosclerotic CVD. Not only did the chances of experiencing CV death, MI, stroke, unstable angina or coronary revascularization decline by 15% at 36 months in those using the PCSK9 inhibitor (HR = 0.85; 95% CI, 0.79-0.92), participants in this group also had their LDL cholesterol levels reduced by an average of 56 mg/dL compared with those in the placebo group (P < .00001), according to Gotto, who noted that these benefits were present regardless of baseline LDL cholesterol or previous statin use and without much difference in safety outcomes between groups.

The PCSK9 inhibitor alirocumab (Praluent, Sanofi/Regeneron) was evaluated in the ODYSSEY trial. Gotto noted that such treatment also yielded a 15% reduction in instances of coronary heart disease mortality, nonfatal MI, ischemic stroke and unstable angina over 4 years in comparison with placebo when used in combination with a statin (HR = 0.85; 95% CI, 0.78-0.93). In addition, at 48 months, those taking alirocumab had an average LDL cholesterol level of 66 mg/dL compared with an average of 103 mg/dL among those taking placebo.

“All the drugs used in these studies were binding to the LDL receptor,” Gotto said. “If one looks at reducing LDL by mechanisms not involving the LDL receptor, then they don’t follow necessarily the same curve.”

With ample evidence now available that LDL cholesterol measures can be lowered substantially and safely in combination with improvements in CV events, there is a debate over what the optimal thresholds should be. Gotto said 40 mg/dL is his personal preference, but that others opt for measures of 20 mg/dL and below.

“There’s not a perfect answer to this question,” Gotto said during his presentation. “One can get the LDL down almost as low as you want, and someone has to balance the safety, the cost and the risk of the individual.” – by Phil Neuffer

References:

Gotto A. The lower LDL the better. Presented at: Heart in Diabetes CME Conference; July 12-14, 2019; Philadelphia.

Cannon CP. JAMA. 2005;doi:10.1001/jama.294.19.2492.

Cannon CP, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1410489.

CTT Collaboration. Lancet. 2010;doi:10.1016/S0140-6736(10)61350-5.

HPS3/TIMI55–REVEAL Collaborative Group. N Engl J Med. 2017;doi:10.1056/NEJMoa1706444.

Sabatine MS, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1615664.

Schwartz GG, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1801174.

Disclosure: Gotto reports he serves on the board of directors of Esperion Therapeutics, as a consultant for Kowa Pharmaceuticals and on the data safety monitoring board for Akcea Therapeutics.

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