Poor response to statins predicts growth in plaque

For about one in five patients with known atherosclerotic coronary artery disease, standard-dose therapy with statins did not result in significant lowering of LDL cholesterol.

Furthermore, the results of this large pooled data sample showed that for statin hyporesponders, statin therapy did not prevent progression of intravascular plaque volume as measured by grayscale intravascular ultrasound.

Patients exhibit a wide range of response to standard statin dosing, and the effect of minimal LDL-C lowering on atherosclerotic disease progression had not previously been determined, according to Dr. Yu Kataoka of the University of Adelaide, Australia, and his colleagues (Arterioscler. Thromb. Vasc. Biol. 2015 [doi:10.1161/ATVBAHA.114.304477]).

Investigators pooled data from seven clinical trials that examined 647 total patients with angiographically confirmed CAD who were initiated on statins and followed by serial intravascular ultrasound. The present study analyzed baseline characteristics, serial lipid profile, and atheroma burden for the group.

In all, 130 patients of the 647 (20%) had minimal LDL-C lowering with statin therapy, showing nonsignificant lowering or even an increase in LDL-C levels during the study period. This group of hyporesponders differed in being slightly younger, more obese, less likely to have hypertension and dyslipidemia, and less likely to be receiving beta-blockers than were the statin responders. Other patient characteristics were similar between the two groups. A variety of agents were used, including atorvastatin, rosuvastatin, simvastatin, and pravastatin. Concurrent administration of other antiatherosclerotic agents was permitted and was similar between the groups. Atheroma burden at baseline was also similar between the two groups.

Measuring serial changes in atheroma burden showed a significant difference between statin responders and hyporesponders. The adjusted change in atheroma volume was –0.21% for the responders, compared with +0.83% for the hyporesponders (P = .006). Lumen volume decreased 11.64 mm³ for the responders, while the reduction was 16.54 mm³ for the hyporesponders (P = .006). Of those who responded to lipid therapy with LDL-C lowering, 29.8% had substantial atheroma regression, while 25.9% had substantial plaque progression; among hyporesponders, however, just 13.8% experienced significant plaque regression, while 37.7% had significant atheroma progression, both significant differences.

Dr. Kataoka and his colleagues emphasized that the factors contributing to poor statin response are not well understood. They noted that for this study, the pooled trials all showed adherence rates over 90%, eliminating patient compliance as a variable. Rigorous statistical techniques were used to control for comorbidities and coadministered medications. There are known genetic polymorphisms and phenotypic variations in statin metabolism, though these were not reported here. Although the results were not statistically significant, C-reactive protein levels were higher for the hyporesponse group, suggesting that another factor may be individual response to the anti-inflammatory effect that is among the known pleiotropic effects of this drug class.

In an interview, lead author Stephen Nicholls noted that many clinicians are still reluctant to treat to full effect. Citing the concept of “clinical inertia,” Dr. Nicholls pointed out that “Even when statins are prescribed, they are often at lower doses than ideal. That translated to more plaque growth, which leads directly to more heart attacks and more revascularization procedures.”

Study limitations included the potential residual confounding effects of pooling data from seven discrete clinical trials, though mixed modeling techniques attempted to correct for this effect. The present study also reported atheroma burden, but not actual clinical events. The study authors noted, however, that they had previously reported a direct relationship between atheroma progression and the occurrence of cardiovascular events.

Dr. Nicholls has received speaking honoraria and research support from many pharmaceutical companies, and from Infraredx. Dr. Steven E. Nissen of the Cleveland Clinic was a coinvestigator and has received research support from and is a consultant/adviser to numerous pharmaceutical companies; all honoraria or consulting fees go directly to charity so that he receives neither income nor a tax deduction. The other authors report no conflicts.

For about one in five patients with known atherosclerotic coronary artery disease, standard-dose therapy with statins did not result in significant lowering of LDL cholesterol.

Furthermore, the results of this large pooled data sample showed that for statin hyporesponders, statin therapy did not prevent progression of intravascular plaque volume as measured by grayscale intravascular ultrasound.

Patients exhibit a wide range of response to standard statin dosing, and the effect of minimal LDL-C lowering on atherosclerotic disease progression had not previously been determined, according to Dr. Yu Kataoka of the University of Adelaide, Australia, and his colleagues (Arterioscler. Thromb. Vasc. Biol. 2015 [doi:10.1161/ATVBAHA.114.304477]).

Investigators pooled data from seven clinical trials that examined 647 total patients with angiographically confirmed CAD who were initiated on statins and followed by serial intravascular ultrasound. The present study analyzed baseline characteristics, serial lipid profile, and atheroma burden for the group.

In all, 130 patients of the 647 (20%) had minimal LDL-C lowering with statin therapy, showing nonsignificant lowering or even an increase in LDL-C levels during the study period. This group of hyporesponders differed in being slightly younger, more obese, less likely to have hypertension and dyslipidemia, and less likely to be receiving beta-blockers than were the statin responders. Other patient characteristics were similar between the two groups. A variety of agents were used, including atorvastatin, rosuvastatin, simvastatin, and pravastatin. Concurrent administration of other antiatherosclerotic agents was permitted and was similar between the groups. Atheroma burden at baseline was also similar between the two groups.

Measuring serial changes in atheroma burden showed a significant difference between statin responders and hyporesponders. The adjusted change in atheroma volume was –0.21% for the responders, compared with +0.83% for the hyporesponders (P = .006). Lumen volume decreased 11.64 mm³ for the responders, while the reduction was 16.54 mm³ for the hyporesponders (P = .006). Of those who responded to lipid therapy with LDL-C lowering, 29.8% had substantial atheroma regression, while 25.9% had substantial plaque progression; among hyporesponders, however, just 13.8% experienced significant plaque regression, while 37.7% had significant atheroma progression, both significant differences.

Dr. Kataoka and his colleagues emphasized that the factors contributing to poor statin response are not well understood. They noted that for this study, the pooled trials all showed adherence rates over 90%, eliminating patient compliance as a variable. Rigorous statistical techniques were used to control for comorbidities and coadministered medications. There are known genetic polymorphisms and phenotypic variations in statin metabolism, though these were not reported here. Although the results were not statistically significant, C-reactive protein levels were higher for the hyporesponse group, suggesting that another factor may be individual response to the anti-inflammatory effect that is among the known pleiotropic effects of this drug class.

In an interview, lead author Stephen Nicholls noted that many clinicians are still reluctant to treat to full effect. Citing the concept of “clinical inertia,” Dr. Nicholls pointed out that “Even when statins are prescribed, they are often at lower doses than ideal. That translated to more plaque growth, which leads directly to more heart attacks and more revascularization procedures.”

Study limitations included the potential residual confounding effects of pooling data from seven discrete clinical trials, though mixed modeling techniques attempted to correct for this effect. The present study also reported atheroma burden, but not actual clinical events. The study authors noted, however, that they had previously reported a direct relationship between atheroma progression and the occurrence of cardiovascular events.

Dr. Nicholls has received speaking honoraria and research support from many pharmaceutical companies, and from Infraredx. Dr. Steven E. Nissen of the Cleveland Clinic was a coinvestigator and has received research support from and is a consultant/adviser to numerous pharmaceutical companies; all honoraria or consulting fees go directly to charity so that he receives neither income nor a tax deduction. The other authors report no conflicts.

For about one in five patients with known atherosclerotic coronary artery disease, standard-dose therapy with statins did not result in significant lowering of LDL cholesterol.

Furthermore, the results of this large pooled data sample showed that for statin hyporesponders, statin therapy did not prevent progression of intravascular plaque volume as measured by grayscale intravascular ultrasound.

Patients exhibit a wide range of response to standard statin dosing, and the effect of minimal LDL-C lowering on atherosclerotic disease progression had not previously been determined, according to Dr. Yu Kataoka of the University of Adelaide, Australia, and his colleagues (Arterioscler. Thromb. Vasc. Biol. 2015 [doi:10.1161/ATVBAHA.114.304477]).

Investigators pooled data from seven clinical trials that examined 647 total patients with angiographically confirmed CAD who were initiated on statins and followed by serial intravascular ultrasound. The present study analyzed baseline characteristics, serial lipid profile, and atheroma burden for the group.

In all, 130 patients of the 647 (20%) had minimal LDL-C lowering with statin therapy, showing nonsignificant lowering or even an increase in LDL-C levels during the study period. This group of hyporesponders differed in being slightly younger, more obese, less likely to have hypertension and dyslipidemia, and less likely to be receiving beta-blockers than were the statin responders. Other patient characteristics were similar between the two groups. A variety of agents were used, including atorvastatin, rosuvastatin, simvastatin, and pravastatin. Concurrent administration of other antiatherosclerotic agents was permitted and was similar between the groups. Atheroma burden at baseline was also similar between the two groups.

Measuring serial changes in atheroma burden showed a significant difference between statin responders and hyporesponders. The adjusted change in atheroma volume was –0.21% for the responders, compared with +0.83% for the hyporesponders (P = .006). Lumen volume decreased 11.64 mm³ for the responders, while the reduction was 16.54 mm³ for the hyporesponders (P = .006). Of those who responded to lipid therapy with LDL-C lowering, 29.8% had substantial atheroma regression, while 25.9% had substantial plaque progression; among hyporesponders, however, just 13.8% experienced significant plaque regression, while 37.7% had significant atheroma progression, both significant differences.

Dr. Kataoka and his colleagues emphasized that the factors contributing to poor statin response are not well understood. They noted that for this study, the pooled trials all showed adherence rates over 90%, eliminating patient compliance as a variable. Rigorous statistical techniques were used to control for comorbidities and coadministered medications. There are known genetic polymorphisms and phenotypic variations in statin metabolism, though these were not reported here. Although the results were not statistically significant, C-reactive protein levels were higher for the hyporesponse group, suggesting that another factor may be individual response to the anti-inflammatory effect that is among the known pleiotropic effects of this drug class.

In an interview, lead author Stephen Nicholls noted that many clinicians are still reluctant to treat to full effect. Citing the concept of “clinical inertia,” Dr. Nicholls pointed out that “Even when statins are prescribed, they are often at lower doses than ideal. That translated to more plaque growth, which leads directly to more heart attacks and more revascularization procedures.”

Study limitations included the potential residual confounding effects of pooling data from seven discrete clinical trials, though mixed modeling techniques attempted to correct for this effect. The present study also reported atheroma burden, but not actual clinical events. The study authors noted, however, that they had previously reported a direct relationship between atheroma progression and the occurrence of cardiovascular events.

Dr. Nicholls has received speaking honoraria and research support from many pharmaceutical companies, and from Infraredx. Dr. Steven E. Nissen of the Cleveland Clinic was a coinvestigator and has received research support from and is a consultant/adviser to numerous pharmaceutical companies; all honoraria or consulting fees go directly to charity so that he receives neither income nor a tax deduction. The other authors report no conflicts.