- Email: [email protected]
Efficacy and safety of more intensive lowering of LDL cholesterol
Correspondence
The meta-analysis of individual patient data from 26 randomised controlled trials by the Cholesterol Treatment Trialists’ (CCT) Collaboration (Nov 13, p 1670)1 showed that statin use was not associated with cancer incidence or death, neither in the five trials of more versus less intensive statin therapy nor across all 26 trials. Earlier, we published a large metaanalysis of 12 randomised controlled trials that investigated the use of pravastatin therapy for cardiovascular outcomes.2 A total of 42 902 people participated in these trials (of whom 3088 developed cancer) over about 190 000 person-years. Although in our meta-analysis the overall association between pravastatin use and cancer was not significant (risk ratio 1·06, 95% CI 0·99–1·13), the meta-regression showed that the age of study participants significantly modified the effect of pravastatin therapy on cancer risk (p=0·006). Specifically, this analysis generated the hypothesis that pravastatin therapy was associated with an increasing risk of cancer as age increased. Given the enormous public health implications of a potential association between pravastatin use and cancer, especially in older patients, to test this hypothesis with the available individual data from the CCT Collaboration would be extremely valuable. We declare that we have no conflicts of interest.
*Stefanos Bonovas, Georgios Nikolopoulos, Nikolaos M Sitaras [email protected] Department of Pharmacology, School of Medicine, University of Athens, Athens 11527, Greece (SB, NMS); and Hellenic Center for Diseases Control and Prevention, Athens, Greece (SB, GN) 1
Cholesterol Treatment Trialists’ Collaboration. 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: 1670–81.
www.thelancet.com Vol 377 February 26, 2011
2
Bonovas S, Sitaras NM. Does pravastatin promote cancer in elderly patients? A meta-analysis. CMAJ 2007; 176: 649–54.
In the first Cholesterol Treatment Trialists’ (CTT) meta-analysis,1 when looking at the proportional effects of lipid parameters on major coronary events, in the control group triglycerides did not seem to be independent predictors of coronary events, unlike LDL and HDL. These data are not published in the second CTT2 meta-analysis and we wonder whether they showed the same results. Indeed, the control groups of this huge meta-analysis might facilitate such a comparison. We think that the answer could help to settle the controversies about the fact that triglycerides might not be an independent risk factor for major coronary events3 in these thoroughly followed populations. We declare that we have no conflicts of interest.
Philippe Giral, Philippe Moulin, *David Rosenbaum [email protected] Cardiovascular Prevention Unit, AP-HP, Hôpital Pitié Salpetrière, 75013 Paris, France (PG, DR); and Endocrinology Unit, Hôpital Cardiologique, Hospices Civils de Lyon, Bron, France (PM) 1
2
3
Cholesterol Treatment Trialists’ Collaboration. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins. Lancet 2005; 366: 1267–78. Cholesterol Treatment Trialists’ Collaboration. 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: 1670–81. Bansal S, Buring JE, Rifai N, Mora S, Sacks FM, Ridker PM. Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women. JAMA 2007; 298: 309–16.
Authors’ reply The Cholesterol Treatment Trialists’ Collaborative meta-analysis of five randomised trials of more versus less intensive statin therapy and of 21 trials of statin versus control1 showed that further reductions in LDL cholesterol produced definite further reductions in the incidence of heart attack, of revascularisation, and of ischaemic stroke; each 1 mmol/L reduction
decreased the annual rate of these major vascular events by just over a fifth, approximately independently of the baseline lipid or triglyceride levels. On the basis of more than 10 000 incident cases of cancer, there was no evidence that reducing LDL cholesterol with a statin increased cancer incidence at all sites combined (rate ratio per mmol/L reduction 1·00, 95% CI 0·96–1·04; p=0·90) or at any particular site. Nor was there any evidence that the rate ratio for cancer incidence increased with increasing age: younger than 60 years, 1·02 (0·92–1·12); 60–70 years, 0·97 (0·91–1·03); older than 70 years, 1·02 (0·95–1·10); trend p=0·68. Moreover, by contrast with a previously reported comparison of rate ratios for cancer in different pravastatin trials versus mean age at trial entry,2 the individual patient data from the seven trials that compared pravastatin versus placebo did not indicate an increasing rate ratio for cancer with increasing age (trend p=0·29). In the updated meta-analysis, the annual rates of major coronary events in the aggregated control groups were slightly higher in individuals with higher baseline triglycerides: less than 1·4 mmol/L, 1·73% per year; 1·4–2·0 mmol/L, 1·92% per year; more than 2·0 mmol/L, 1·97% per year. But this trend does not necessarily mean that higher triglycerides cause higher rates of major coronary events since the distribution of other baseline prognostic factors differed substantially between these three baseline triglyceride groups. Indeed, after adjusting for baseline HDL and LDL cholesterol (and other recorded risk factors), there was no evidence of an association between raised triglycerides and risk of major coronary events (rate ratio per mmol/L higher baseline triglycerides 1·01, 95% CI 0·98–1·03). This finding is consistent with the previously reported results of a meta-analysis of 68 prospective studies involving more than 12 000 major coronary events in over 300 000 participants.3
Science Photo Library
Efficacy and safety of more intensive lowering of LDL cholesterol
715
The meta-analysis of individual patient data from 26 randomised controlled trials by the Cholesterol Treatment Trialists’ (CCT) Collaboration (Nov 13, p 1670)1 showed that statin use was not associated with cancer incidence or death, neither in the five trials of more versus less intensive statin therapy nor across all 26 trials. Earlier, we published a large metaanalysis of 12 randomised controlled trials that investigated the use of pravastatin therapy for cardiovascular outcomes.2 A total of 42 902 people participated in these trials (of whom 3088 developed cancer) over about 190 000 person-years. Although in our meta-analysis the overall association between pravastatin use and cancer was not significant (risk ratio 1·06, 95% CI 0·99–1·13), the meta-regression showed that the age of study participants significantly modified the effect of pravastatin therapy on cancer risk (p=0·006). Specifically, this analysis generated the hypothesis that pravastatin therapy was associated with an increasing risk of cancer as age increased. Given the enormous public health implications of a potential association between pravastatin use and cancer, especially in older patients, to test this hypothesis with the available individual data from the CCT Collaboration would be extremely valuable. We declare that we have no conflicts of interest.
*Stefanos Bonovas, Georgios Nikolopoulos, Nikolaos M Sitaras [email protected] Department of Pharmacology, School of Medicine, University of Athens, Athens 11527, Greece (SB, NMS); and Hellenic Center for Diseases Control and Prevention, Athens, Greece (SB, GN) 1
Cholesterol Treatment Trialists’ Collaboration. 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: 1670–81.
www.thelancet.com Vol 377 February 26, 2011
2
Bonovas S, Sitaras NM. Does pravastatin promote cancer in elderly patients? A meta-analysis. CMAJ 2007; 176: 649–54.
In the first Cholesterol Treatment Trialists’ (CTT) meta-analysis,1 when looking at the proportional effects of lipid parameters on major coronary events, in the control group triglycerides did not seem to be independent predictors of coronary events, unlike LDL and HDL. These data are not published in the second CTT2 meta-analysis and we wonder whether they showed the same results. Indeed, the control groups of this huge meta-analysis might facilitate such a comparison. We think that the answer could help to settle the controversies about the fact that triglycerides might not be an independent risk factor for major coronary events3 in these thoroughly followed populations. We declare that we have no conflicts of interest.
Philippe Giral, Philippe Moulin, *David Rosenbaum [email protected] Cardiovascular Prevention Unit, AP-HP, Hôpital Pitié Salpetrière, 75013 Paris, France (PG, DR); and Endocrinology Unit, Hôpital Cardiologique, Hospices Civils de Lyon, Bron, France (PM) 1
2
3
Cholesterol Treatment Trialists’ Collaboration. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins. Lancet 2005; 366: 1267–78. Cholesterol Treatment Trialists’ Collaboration. 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: 1670–81. Bansal S, Buring JE, Rifai N, Mora S, Sacks FM, Ridker PM. Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women. JAMA 2007; 298: 309–16.
Authors’ reply The Cholesterol Treatment Trialists’ Collaborative meta-analysis of five randomised trials of more versus less intensive statin therapy and of 21 trials of statin versus control1 showed that further reductions in LDL cholesterol produced definite further reductions in the incidence of heart attack, of revascularisation, and of ischaemic stroke; each 1 mmol/L reduction
decreased the annual rate of these major vascular events by just over a fifth, approximately independently of the baseline lipid or triglyceride levels. On the basis of more than 10 000 incident cases of cancer, there was no evidence that reducing LDL cholesterol with a statin increased cancer incidence at all sites combined (rate ratio per mmol/L reduction 1·00, 95% CI 0·96–1·04; p=0·90) or at any particular site. Nor was there any evidence that the rate ratio for cancer incidence increased with increasing age: younger than 60 years, 1·02 (0·92–1·12); 60–70 years, 0·97 (0·91–1·03); older than 70 years, 1·02 (0·95–1·10); trend p=0·68. Moreover, by contrast with a previously reported comparison of rate ratios for cancer in different pravastatin trials versus mean age at trial entry,2 the individual patient data from the seven trials that compared pravastatin versus placebo did not indicate an increasing rate ratio for cancer with increasing age (trend p=0·29). In the updated meta-analysis, the annual rates of major coronary events in the aggregated control groups were slightly higher in individuals with higher baseline triglycerides: less than 1·4 mmol/L, 1·73% per year; 1·4–2·0 mmol/L, 1·92% per year; more than 2·0 mmol/L, 1·97% per year. But this trend does not necessarily mean that higher triglycerides cause higher rates of major coronary events since the distribution of other baseline prognostic factors differed substantially between these three baseline triglyceride groups. Indeed, after adjusting for baseline HDL and LDL cholesterol (and other recorded risk factors), there was no evidence of an association between raised triglycerides and risk of major coronary events (rate ratio per mmol/L higher baseline triglycerides 1·01, 95% CI 0·98–1·03). This finding is consistent with the previously reported results of a meta-analysis of 68 prospective studies involving more than 12 000 major coronary events in over 300 000 participants.3
Science Photo Library
Efficacy and safety of more intensive lowering of LDL cholesterol
715