Putting the FOURIER Findings in Perspective
By Kevin C Maki, PhD
Background and Methods
Earlier this year the results from the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial were published in the New England Journal of Medicine1 in conjunction with their presentation at the American College of Cardiology Scientific Sessions. For the trial, 27,564 patients with atherosclerotic cardiovascular disease (ASCVD) and low-density lipoprotein cholesterol (LDL-C) at least 70 mg/dL while on statin therapy were randomly assigned to receive 140 mg of evolocumab or placebo by subcutaneous injection every 2 weeks. Evolocumab is a proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor that lowers LDL-C and cholesterol carried by other apolipoprotein B-containing lipoproteins by reducing the rate at which hepatic LDL receptors are catabolized.
The primary and key secondary composite outcomes were:
- Primary: cardiovascular (CV) death, myocardial infarction, stroke, hospitalization for unstable angina, coronary revascularization;
- Key secondary: CV death, myocardial infarction, stroke.
The median baseline LDL-C level was 92 mg/dL, which was reduced by an average of 59% compared to placebo at 48 weeks to a median value of 30 mg/dL. Levels of non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein B, were also reduced by 52% and 49%, respectively.
The primary outcome was reduced by 15% (95% confidence interval [CI] 8 to 21%) and the key secondary endpoint was reduced by 20% (95% CI 12 to 27%) with evolocumab vs. placebo over an average follow-up period of 2.2 years. In the placebo group, the primary and key secondary outcomes occurred in 11.3% and 7.4% of subjects, respectively. Efficacy results were consistent across subgroups, including men and women and quartiles of baseline LDL-C. The effect appeared to grow over time. Beyond 12 months, the reduction in the key secondary outcome with evolocumab was 25%, compared to 16% during the first 12 months. Other than injection site reactions (2.1% vs. 1.6%), no significant differences in adverse events were present between treatment groups.
The results from FOURIER bolster the case for the view that “lower is better” when it comes to LDL-C and related atherogenic lipoprotein variables such as non-HDL-C and apolipoprotein B. The trial had a shorter follow-up time (2.2 years) than most statin trials, which have averaged roughly 5 years of treatment. The event rate in FOURIER was relatively high (about 3-5% per year in the placebo group).
The reduction in LDL-C from a median baseline level of 92 to an on-treatment level of 30 mg/dL is a reduction of about 62 mg/dL (1.6 mmol/L). The results from the Cholesterol Treatment Trialists’ (CTT) analysis of data from statin trials2,3 would predict a reduction in risk of roughly 33% over five years for major vascular events [1 – (0.78^1.6) = 0.328], assuming a hazard ratio of 0.78 per 1.0 mmol/L reduction in LDL-C. However, the follow-up period was shorter than 5 years, so we have to look at the CTT analysis for shorter timeframes for comparison. The definition of major vascular event in the CTT analysis included the combined outcome of major coronary event, non-fatal or fatal stroke, or coronary revascularization. This outcome has elements of both the primary and key secondary outcomes in FOURIER. For simplicity, I will focus on the key secondary outcome in FOURIER of CV death, myocardial infarction or stroke for comparison to the CTT results with statin therapy.
During years 0-1, the hazard ratio in the CTT analysis was 0.90 per mmol/L of LDL-C reduction.2 The corresponding hazard ratios for years 1-2 and 2-3 were 0.78 and 0.74, respectively.2 I will use 0.78 in my calculations for simplicity, since this corresponds to the overall result from the CTT analysis. For the first year, the predicted risk reduction in FOURIER based on the CTT values would be 15.5% [1 – (0.90^1.6) = 0.155]. This corresponds very closely to the 16% reduction in the key secondary outcome during the first 12 months. Beyond 12 months, the effect in FOURIER was a 25% reduction in risk. This is slightly below the predicted 32.8% reduction predicted by the CTT relationship, but certainly not far enough below the predicted value to conclude that the relationship is not similar.
In his presentation at the American College of Cardiology meeting, the Principal Investigator, Dr. Marc Sabatine, compared the results from year 2 of follow-up in FOURIER and the CTT analysis for the outcomes of major coronary events and stroke.3 They were very similar, as you can see by examining the hazard ratios and 95% CIs, which are shown below:
- Major coronary events
- CTT: 0.78 (0.70 to 0.86)
- FOURIER: 0.80 (0.71 to 0.90)
- CTT: 0.77 (0.66 to 0.91)
- FOURIER: 0.77 (0.63 to 0.94)
Thus, once the relatively short follow-up period is taken into account, the results from FOURIER are consistent with those from the CTT analysis, and are generally supportive of a linear relationship between LDL-C reduction and lower CV event risk, extending to lower levels than had previously been studied in large CV outcomes trials.
The findings from FOURIER are consistent with those from a pooled analysis of 10 trials in the development program for another PCSK9 inhibitor, alirocumab.4 In that analysis, a 39 mg/dL reduction in LDL-C (roughly 1 mmol/L) was associated with a hazard ratio of 0.76 (95% CI 0.63 to 0.91) compared with control for major adverse CV events. Similar results were obtained for non-HDL-C and apolipoprotein B reductions. When expressed per 50% reduction from baseline, the relative risk reductions for LDL-C, non-HDL-C and apolipoprotein B were 29%, 29% and 32%, respectively.
The results from FOURIER have generated confusion because the risk reduction reported was less than some had expected. The CV benefits of LDL-C reduction take some time to become fully apparent. Thus, after taking into account the comparatively short follow-up period of 2.2 years, it is clear that the FOURIER results are aligned with previous results from statin trials, as represented by the CTT analysis, as well as the findings from the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), in which the small incremental reduction of about 0.4 mmol/L in LDL-C when ezetimibe was added to statin therapy translated into additional CV event risk reduction of 7-10%.5 Accordingly, the FOURIER results further strengthen the evidence that reducing LDL-C (and related variables such as non-HDL-C and apolipoprotein B) will reduce CV event risk in high-risk patients.
Additional evidence is expected to become available in 2018 from a trial with the other PCSK9 inhibitor currently cleared by the Food and Drug Administration, ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment with Alirocumab. Assuming that the results from that trial confirm those from FOURIER, the debate will continue to focus not on who might benefit from therapy, but rather for whom PCSK9 inhibitor therapy is justified, given the cost of approximately $14,000 per year.
1. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713-1722.
2. The 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;366:1267-1278.
3. The 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;376:1670-1681.
4. Ray KK, Ginsberg HN, Davidson MH, et al. Reductions in atherogenic lipids and major cardiovascular events: a pooled analysis of 10 ODYSSEY trials comparing alirocumab with control. 2016;134:1931-1943.
5. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387-2397.
Another CETP Inhibitor Fails to Show Cardiovascular Benefit, Despite Reducing LDL Cholesterol and Raising HDL Cholesterol: Implications of the ACCELERATE Trial
By Kevin C Maki, PhD
Cholesteryl ester transfer protein (CETP) is an enzyme that modulates the transfer of cholesterol esters from high-density lipoprotein (HDL) particles to apolipoprotein (apo)-B containing particles, including very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) particles. CETP inhibitor drugs, by blocking this action, raise the level of HDL cholesterol (HDL-C) and lower the level of LDL cholesterol (LDL-C).
Previous outcomes trials with two CETP inhibitors, torcetrapib and dalcetrapib, failed to show cardiovascular disease (CVD) event risk reduction.1 Torcetrapib use was associated with increased CVD event risk, which was believed to be secondary to off-target effects, including raising blood pressure and aldosterone levels and lowering serum potassium concentration. Whereas torcetrapib raised HDL-C by 70% and lowered LDL-C by 25%, dalcetrapib was a weak CETP inhibitor and raised HDL-C by only 30%, while having no effect on LDL-C. A CVD outcomes trial with dalcetrapib was stopped for futility, showing no evidence of benefit or harm regarding CVD event risk.
The ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes) trial evaluated the effects of evacetrapib 130 mg/d vs. placebo, when added to standard therapies in ~12,000 men and women with high CVD risk secondary to having clinical atherosclerotic CVD with a history of a recent acute coronary syndrome, cerebrovascular atherosclerosis, peripheral atherosclerosis, or diabetes mellitus with known coronary disease).2
After randomization, the effects of evacetrapib compared to placebo on mean or median changes from baseline to the 3-month timepoint in lipoprotein-related parameters were as follows (all p < 0.001):
- HDL-C: +134.8%;
- LDL-C: -37.1%;
- Triglycerides (TG): -6.0%;
- Apo B: -19.3%;
- Lipoprotein (a): -22.3%.
There were also small changes (all p < 0.01), relative to placebo, in systolic/diastolic blood pressure (+1.2/+0.5 mm Hg) and C-reactive protein (8.6%).
Despite substantial changes in potentially favorable directions in lipoprotein-related variables, no difference was present for the primary efficacy outcome of the first occurrence of any component of the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina: hazard ratio (HR) 1.01, 95% confidence interval (CI) 0.91 to 1.11, p = 0.91. After an interim analysis with 82% of the final projected number of events, the trial was stopped early for futility. No significant benefits were present for any of the individual components of the primary outcome, nor for a secondary composite that excluded hospitalization for unstable angina.
Comment. The third failure of a CETP inhibitor to show CVD event risk reduction may sound the death knell for this class of lipid-altering agents. The reasons for the lack of benefit in ACCELERATE are unclear. Although HDL-C concentration is a strong inverse predictor for CVD event risk, the mechanisms responsible for this consistent finding are uncertain. There are numerous ways that the HDL-C level can be raised, some of which could be beneficial, while others may be only cosmetic.
More disturbing than the lack of benefit associated with a rise in HDL-C, is the fact that LDL-C, TG, apo B and lipoprotein (a) were all lowered, yet this did not reduce CVD event risk. Reduced CVD event risk has been observed with other agents that lower apo B-containing lipoproteins such statins, ezetimibe and proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors, so why did changes in these values with evacetrapib fail to lower risk?
Niacin lowers apo B-containing lipoproteins and lipoprotein (a), while also raising HDL-C, and it failed to demonstrate CVD event risk reduction in both the HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) study (co-administered with laropiprant) and in the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes) trial .3 However, there were issues in both trials regarding whether the subjects enrolled were appropriate candidates for niacin therapy.3 For example, more than two-thirds of the subjects in HPS2-THRIVE had baseline non-HDL-C of less than 100 mg/dL. Such individuals would not be likely to have been prescribed niacin in clinical practice.
Interventions that lower LDL-C and apo B-containing lipoproteins through mechanisms that involve inducing an upregulation in hepatic LDL receptor activity, including statins, ezetimibe and PCSK9 inhibitors have all been shown to reduce CVD event risk. Lowering LDL-C and apo B-containing lipoproteins with evacetrapib had no effect on risk. Should we infer from these results that lowering LDL-C and apo B-containing lipoproteins through mechanisms that do not upregulate hepatic LDL receptor activity will not reduce CVD risk? Alternatively, is it the case that evacetrapib had some off-target effect(s) that offset the benefits of LDL-C and apo B-containing lipoprotein reduction, as has been hypothesized for torcetrapib? Evacetrapib did produce modest increases in blood pressure and C-reactive protein. These changes were small enough that they are unlikely to have been sufficient to directly offset the expected CVD benefits from reductions in LDL-C and apo B-containing lipoproteins. However, they could be indicators of other adverse neuroendocrine and/or inflammatory effects. At present, it is not possible to determine whether the explanation for the lack of benefit with evacetrapib was attributable to one of these, or perhaps some other explanation.
- Barter PJ, Rye KA. Targeting high-density lipoproteins to reduce cardiovascular risk: what is the evidence? Clin Ther. 2015;37:2716-2731.
- Lincoff AM, Nicholls SJ, Riesmeyer JS, et al.; ACCELERATE Investigators. Evacetrapib and cardiovascular outcomes in high-risk vascular disease. N Engl J Med. 2017;376:1933-1942.
- Mani P, Rohatgi A. Niacin therapy, HDL cholesterol, and cardiovascular disease: is the HDL hypothesis defunct? Curr Atheroscler Rep. 2015;17:521.
Debates Rage on About the Health Effects of Low-Calorie Sweeteners – Newly Published Study Shows No Effect of Sucralose on Carbohydrate Metabolism
By Kevin C Maki, PhD
A study published recently in the journal Regulatory Toxicology and Pharmacology by Grotz and colleagues investigated the effects of sucralose consumption on glucose homeostasis in healthy men and women.1 Sucralose is one of six high-intensity sweeteners approved by the United States’ Food and Drug Administration (FDA) as food additives. The approved high-intensity (low-calorie) sweeteners include: saccharin, aspartame, acesulfame potassium (Ace-K), sucralose, neotame, and advantame.2 Sucralose is one of the largest selling of the high-intensity sweeteners on the market, although consumption in the US has declined in recent years along with sales of diet soda, which were more than 20% lower in 2016 than in 2009.
There has been significant controversy about effects of high-intensity sweeteners on health, which seems to have intensified lately. One of the findings that has generated debate is the relatively recent discovery of gut receptors for sweet taste, which has triggered concern that high-intensity sweeteners might have previously unappreciated effects on metabolism through their interactions with these receptors.1,3 Researchers at Purdue University have also hypothesized that when people consume high-intensity sweeteners, the body produces physiologic responses in anticipation of the arrival of sugar and calories, which could increase appetite and partially or fully offset the reduction in energy consumption of substituting a high-intensity sweetener for calorie-containing sugars.4
The newly published study by Grotz et al.1 was conducted a number of years ago, and the data were submitted to the FDA as part of the food additive petition for sucralose in 1996, but had never appeared in the peer reviewed literature. Given the recent concerns expressed regarding the potential for high-intensity sweeteners to influence glucose homeostasis through their effects on sweet taste receptors in the gut, the investigators felt it would be useful to publish the results to make them more readily available to the scientific community.
The study was a randomized, double-blind parallel trial in which 48 healthy, normoglycemic males were randomly assigned to receive capsules containing either a cellulose placebo or 333.3 mg of sucralose, three times daily with meals. The intake of 1000 mg/d in the sucralose group (n = 25) far exceeds the expected consumption from foods and beverages. For perspective, diet sodas sweetened with sucralose typically contain ≤40 mg per serving. A packet of Splenda® contains 12 mg of sucralose, which is 300-1000 times as sweet as sucrose.
The subjects underwent assessments of serum chemistry, hematology and glycated hemoglobin (HbA1C) levels, as well as fasting and post-oral-glucose-load (75 g) concentrations of insulin, glucose and C-peptide at baseline (twice), weeks 7 and 12 during the treatment period, and again 4 weeks after the end of the 12-week treatment period. There were no significant differences between the placebo and sucralose groups for changes from baseline in HbA1C, or in fasting and post-glucose-load levels of glucose, insulin or C-peptide. No differences were observed in clinical chemistry or hematology values.
Comment. Given the widespread consumption of high-intensity sweeteners by large segments of the United States’ population, it is important to understand their effects on physiologic processes with implications for human health. The results from this study in healthy men suggest that even very large intakes have no influence on indicators of glucose homeostasis. Similar results have been obtained in patients with obesity or type 2 diabetes mellitus.1 Furthermore, reviews of the effects of high-intensity sweeteners, including sucralose, on appetite, gut hormones and gut motility have concluded that there is no evidence for material effects in humans.3,5 It is important for research on the physiological and psychological effects of high-intensity sweeteners to continue. However, the results of this study and others suggest that sucralose has no adverse effects on glucose homeostasis. Given evidence that sugar-sweetened products appear to have adverse effects on glucose homeostasis,6 the use of products sweetened with sucralose (and other high-intensity sweeteners) may be an acceptable option for those who would like to limit their intakes of added sugars and calories.7
Grotz VL, Pi-Sunyer X, Porte, Jr. D, et al. A 12-week randomized clinical trial investigating the potential for sucralose to affect glucose homeostasis. Regul Toxicol Pharmacol. 2017;88:22-33.
- S. Department of Health and Human Services. U.S. Food & Drug Administration. High-Intensity Sweeteners. Accessed at https://www.fda.gov/food/ingredientspackaginglabeling/foodadditivesingredients/ucm397716.htm on 11 July 2017.
- Magnuson BA, Roberts A, Nestmann ER. Critical review of the current literature on the safety of sucralose. Food Chem Toxicol. 2017;106 (Part A):324-355.
- Swithers SE, Martin AA, Davidson TL. High-intensity sweeteners and energy balance. Physiol Behav. 2010;100:55-62.
- Bryant C, Mclaughlin J. Low calorie sweeteners: evidence remains lacking for effects on human gut function. Physiol Behav. 2016;164 (Pt B):482-485.
- Maki KC, Nieman KM, Schild AL, et al. Sugar-sweetened product consumption alters glucose homeostasis compared with dairy product consumption in men and women at risk of type 2 diabetes mellitus. J Nutr. 2015;145:1-8.
- Peters JC, Wyatt HR, Foster GD, et al. The effects of water and non-nutritive sweetened beverages on weight loss during a 12-week weight loss treatment program. Obesity. 2014;22:1415-1421.