Editor's Note: Commentary based on Fan W, Philip S, Granowitz CB, Toth PP, Wong, ND. Residual hypertriglyceridemia and estimated atherosclerotic cardiovascular disease risk by statin use in U.S. adults with diabetes: National Health and Nutrition Examination Survey 2007–2014. Diabetes Care 2019;42;2307-14.

Study Summary

This paper estimates how many US patients meet the lipid and lipid-treatment criteria for patients with diabetes in the REDUCE-IT trial.¹ It studied 1,448 subjects from NHANES 2007-2014² who were age 20 or older with diabetes (defined by four standard criteria, including fasting and nonfasting glucose, A1c and/or use of glucose-lowering medications, representing 24.4 million US adults) to see how many had triglyceride (TG) ≥ 150 mg/dL and LDL-C < 100 mg/dL. Among 1,390 subjects with available lipid data, they separated subjects by presence or absence of statin use, then estimated 10-year risk of atherosclerotic cardiovascular disease (ASCVD) by the current ACC/AHA pooled cohort equation (in 889 subjects with full risk-factor information for that calculation) and finally used logistic regression to identify independent risk factors for (correlates of) TG ≥ 150. Although this paper reported borderline hypertriglyceridemia (HTG) (TG 150-199 mg/dL) and HTG (TG ≥ 200) separately, this review pools these two categories because  REDUCE-IT found both categories to have similar absolute ASCVD risk and relative risk reduction with IPE treatment. Also, their two LDL-C subcategories (≤ 70 and 70-99 mg/dL) are pooled for the same reasons.

They found that 42.6% of US adults with diabetes have TG ≥ 150 mg/dL, which extrapolated to 10.4 million patients. Among the 50.4% of patients with diabetes known to be statin users, (representing 12.3 million) the prevalence of borderline HTG plus HTG was 39.5%, extrapolating to 4.86 million patients. Although as expected, among non-statin users, somewhat fewer women than men had TG ≥ 150 (44.0% vs. 46.9%), in statin users there were more women than men (44.5% vs. 35.2%), which is surprising, given similar TG-lowering with statins between sexes. As expected, TG ≥ 150 differed among Hispanics, non-Hispanic Whites and Blacks taking statins (48.7%, 40.5% and 22.7%, respectively) or not (52.2%, 47.9% and 25.0%, respectively). Importantly, among patients with diabetes taking statins (representing 12.3 million total US patients), 71.8% had LDL-C <100 mg/dL, among whom 36.7% had TG ≥ 150, implying that about 3.2 million US patients: (1) have diabetes, (2) take statins, (3) have TG ≥ 150 and (4) have LDL-C < 100. Further, among the one-half of patients with diabetes not taking a statin, the lipid levels were comparable, suggesting that over 6 million US patients are in this high-risk category, for whom IPE should be beneficial. Ten-year ASCVD risk (by the ACC/AHA pooled cohort risk estimator) was moderately increased or elevated in 60.3% and 85.5% (with borderline HTG and HTG, respectively), even on a statin.

Two other recent publications, by overlapping authors, reinforce the above points.

1. Nichols GA, Philip S, Reynolds K, Granowitz CB, Fazio S. Increased residual cardiovascular risk in patients with diabetes and high versus normal triglycerides despite statin-controlled LDL cholesterol. Diabetes Obes Metab 2019;21;366–71.

Nichols et al,³ used West Coast Kaiser Permanente data on patients with diabetes on statins with LDL-C 40-100, who had prior ASCVD or at least one risk factor, and tallied new ASCVD events over 6 years  (January 2010 through December 2016) in patients with TG 200-499 versus TG <150 mg/dL. After full adjustment for all risk factors, rate ratios for these events were 30%, 23%, 21% and 33% higher with HTG for non-fatal myocardial infarction (MI), non-fatal stroke, coronary revascularization and unstable angina, respectively. Importantly, these data verify the estimated increase in risk described in Fan, et al, above.

2. Toth PP, Fazio S, Wong ND, Hull M, Nichols GA. Risk of cardiovascular events in patients with hypertriglyceridaemia: a review of real-world evidence. Diabetes Obes Metab 2020 22;279-89.

Toth et al,⁴ analyzed data from US adults in NHANES 2007-2014,² Kaiser Permanente data³ as well as data from the Optum Research Database. They estimated that 57 million US adults have TG ≥ 150 mg/dL, one-third of whom also have LDL-C <100 mg/dL on a statin. In the Optum database over 6 years follow-up, patients with TG ≥ 150 mg/dL had a 26% increase in ASCVD events versus those with TG <150, with a corresponding increase in healthcare costs.

Commentary

The three companion publications reviewed here are clinically important because they note how common REDUCE-IT-eligible patients⁵ are in the US, briefly, either:

1. High risk for future atherosclerotic cardiovascular disease (ASCVD) events, due to:
   1. Documented ASCVD (age ≥45, with or without diabetes)—70.7% of subjects, or
   2. Diabetes mellitus (type 1 or 2) and age ≥ 50, plus ≥ 1 other ASCVD risk factor—29.3% of subjects, and in addition all had to be taking
2. Statin therapy with controlled LDL-C (41-100 mg/dL) but elevated fasting TG (≥ 135 to 499).

Among 8,179 total patients, 4,787 (58.6%) had diabetes (98.8% being type 2), comprising all of the primary prevention cohort (2,394 with diabetes but without prior ASCVD), plus 2,393 patients in the secondary prevention cohort (with prior ASCVD and also diabetes). Thus, 3,392 (58.6%) of the secondary prevention cohort did not have diabetes.¹

REDUCE-IT tested icosapent ethyl (IPE, 98% ±2% pure eicosapentaenoic acid, EPA) 2g bid versus matching placebo (light liquid paraffin) for a median of 4.9 years follow-up.¹ The primary endpoint consisted of MI, stroke, CV death, coronary revascularization or hospitalization for acute angina. There was a striking 25% relative risk reduction (RRR) in time to a primary endpoint event (p <0.000001),¹ an unprecedented degree of benefit among cardiovascular outcome trials (CVOTs) of statin adjuncts. There was also a striking 30% reduction in total events, which were nearly twice as many as first events.⁶ Further, prespecified sub analysis of the 3,146 REDUCE-IT patients from the US showed a 31% decrease in primary events.⁷

In contrast to these dramatic results, three other statin adjuncts showed smaller ASCVD event reductions: (1) IMPROVE-IT, with ezetimibe,⁸ (2) FOURIER, with evolocumab⁹ and (3) ODYSSEY Outcomes, with alirocumab,¹⁰ showing only 6%, 15% and 15% RRR of their primary endpoints, respectively.

Interestingly, JELIS showed the second best RRR among contemporary CVOTs of statin adjuncts (19%),¹¹ and it also used a pure ethyl-ester of EPA (essentially identical to the IPE used in REDUCE-IT). Although REDUCE-IT results alone are sufficiently robust to shift the paradigm of statin adjunct use in ASCVD prevention, the finding of similar benefit with the same agent in JELIS (despite some notable differences in trial design), confirms the benefits of IPE seen in REDUCE-IT.

The three publications reviewed here characterize patients meeting the major criteria for the primary prevention cohort in REDUCE-IT: (a) with diabetes (b) taking a statin (c) with LDL-C ≤ 100 mg/dL and (d) with TG ≥ 150-499 mg/dL. Their data are important for three key reasons. First, these studies are focused on the high prevalence of diabetes, which is about 13.0% among US adults (counting those not yet diagnosed) or about 27.2 million people.¹²

Second, these publications document the high prevalence of borderline HTG (≥ 150-199 mg/dL) and HTG (≥ 200). As noted above, these two categories have similar ASCVD risk and similar risk reduction with IPE, and so can be pooled together for clinical purposes. Among all US adult patients with diabetes, about half, or roughly 13.6 million, appear to be currently taking statins, among whom a total of 39.5%, or about 5.4 million, have a TG ≥ 150. What about those patients not (yet) taking statins? REDUCE-IT excluded such subjects, so it provides no direct information about IPE effects on ASCVD in them. That said, (1) most patients with diabetes have risk that warrants statin use (69.4% of patients with diabetes having ≥ 7.5% 10-y risk by the ACC/AHA estimator²) and (2) there is no mechanistic rationale by which IPE should not have comparable ASCVD benefit in the absence of a statin. Thus, these patients could be considered IPE-eligible. Of the 13.6 million or so such US adults, the prevalence of TG ≥ 150 is 42.5%, or about 5.8 million. Adding this group to similar patients already on a statin, gives a total of about 11 million US adults with diabetes and with a TG in the range where IPE should be beneficial, even without prior ASCVD.

Third, REDUCE-IT required an LDL-C ≤ 100 mg/dL. Fan, et al, found that 71.8% of patients on statins with diabetes met this LDL-C cutoff. Although, among those not on statins, fewer had LDL-C that low, if they were started on a statin their LDL-C would likely decrease by about 30-55%, such that the prevalence of LDL-C ≤ 100 would likely be similar to that of those already taking statins. Importantly, IPE has not been and must never be considered a replacement for statins. Thus, with current data and the reasonable assumptions noted above, US adults who (1) have diabetes, (2) are on (or should be started on) a statin, (3) have TG ≥ 150 and (4) have an LDL-C ≤ 100 (or would have such when on a statin), are about 8 million in number. Despite a general lack of data on the prevalence of the additional risk-factor criteria of REDUCE-IT, it seems likely that a large majority of the nearly 8 million patients noted above would qualify.

Importantly, the above calculations do not include patients with prior ASCVD, and they are estimated to be about 18 million US adults.¹³ Since the three publications reviewed here did not exclude patients with prior ASCVD, this 18 million total with ASCVD is not fully additive to the somewhat-less-than-8 million number from these studies. Nonetheless, far less than half of prevalent ASCVD patients also have diabetes (overlapping with diabetes prevalence). Conservatively speaking, if even only 5 million of 8 million patients above would qualify for the primary prevention arm, and only 10 million of the 18 million with prevalent ASCVD had LDL-C ≤ 100 and TG ≥ 150 then roughly 15 million or so US adults could warrant IPE treatment (on top of a statin) per REDUCE-IT results.

Finally, there are two additional important considerations regarding the prevalence of elevated TG in patients with diabetes and/or prior ASCVD. First, as sometimes missed in commentaries about REDUCE-IT, the trial actually recruited patients with TG ≥ 135 mg/dL, rather than at the protocol-stated threshold of ≥ 150. Given the well-known variability of TG levels, patients were considered eligible if their TG was just 90% of the official 150 mg/dL threshold, exactly 135 mg/dL. Interestingly, 10% of subjects entered with TG 135-149 mg/dL. Importantly, they appeared to have similar ASCVD risk and similar reduction of ASCVD events as did those with entry TG ≥ 150 mg/dL. Sadly, this finding was ignored by the FDA, which chose a TG cutoff of ≥ 150 for the official indication for CVD reduction by IPE. This, however, is less important clinically due to a second key issue regarding TG levels. Although fasting specimens give TG levels which are always less variable and therefore have been favored in many settings, non-fasting sampling is much more convenient, being an informal "stress test", of possible value in assessing TG metabolism. While fasting TG is used traditionally, including in REDUCE-IT, the three publications reviewed and most other studies of TG, on the other hand, other studies have used non-fasting TG (see, for example, Pedersen SB, et al, 2016¹⁴) as many recommendations now urge (see, for example, Nordestgaard BG, et al, 2016¹⁵).

Unfortunately, the prevalence among US adults of fasting TG in the 135-149 mg/dL range is poorly understood, and there is virtually no documentation of the relationship between fasting and non-fasting TG in significant numbers of individuals. Further, this relationship varies among patients, according to various patient circumstances (e.g. recent exercise or alcohol consumption) as well as meal type, quantity and timing relative to the blood draw. Fortunately the US Food and Drug Administration (FDA) did not specify the use of a fasting sample for its TG ≥ 150 cutoff and a non-fasting TG at that level may be equivalent to a fasting TG of as low as 100 mg/dL.¹⁶ Thus, qualification for REDUCE-IT by fasting TG versus FDA labelling by non-fasting TG are likely comparable.

Importantly, IPE is rather safe in long-term use, REDUCE-IT having shown only two safety issues of note (both prespecified, adjudicated endpoints). Hospitalization for atrial fibrillation increased to 3.1% versus 2.1% (p= 0.004) and serious bleeding increased to 2.7% versus 2.1% (p=0.06) with IPE versus placebo, respectively. Importantly, there was no increase in adjudicated hemorrhagic stroke (0.3% vs 0.2%, p=0.55), serious central nervous system (CNS) bleeding (also 0.3% vs 0.2, p=0.42) or gastrointestinal bleeding (1.5% vs 1.1%, p=0.15) with IPE versus placebo, respectively, and there were no fatal bleeding episodes in either treatment arm.

Cost-effectiveness of IPE is excellent, as analyzed by two groups, using REDUCE-IT data. First, Ollendorf, et al, pooled primary and secondary prevention patients and found a cost per QALY of about $16,000.¹⁷ Weintraub, et al, used patient-level data and found a cost of only $63,793 per QALY in primary prevention subjects and net cost savings (very rarely seen with branded agents) in secondary prevention.¹⁸ Further, in the US subgroup of REDUCE-IT subjects, the same authors found a cost of only $36,118 per QALY in primary prevention and even greater cost savings in secondary prevention.¹⁹

Given the remarkable cost-effectiveness and reasonable safety of IPE, most of the roughly 15 million or so REDUCE-IT-eligible patients (with diabetes and/or prior ASCVD) in the US should be strongly considered for treatment with IPE, despite good LDL-C control on (or after starting) a statin. This rough estimate is about 30-fold higher than the approximately half-million patients estimated to be taking IPE at the end of 2019 (Amarin data on file, IQVIA Total Patient Tracker 2020).

Conclusion

IPE is effective and cost effective as a statin adjunct in US adults who are at high ASCVD risk despite statin therapy, due to (1) TG ≥ 150 mg/dL(non-fasting, or roughly ≥ 135 mg/dL fasting),  (2) LDL-C ≤ 100 mg/dL, and (3) diabetes plus other risk factors, and/or (4) prior ASCVD. The studies reviewed here have shown that millions of US patients with diabetes, and millions more without diabetes, meet these lipid cutoffs and continue to have high ASCVD risk despite appropriate statin therapy. Careful, individualized, consideration should be given to the regular practice of adding IPE to statins for ASCVD prevention in these patients.

References

1. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11-222.
2. Fan W, Philip S, Granowitz CB, Toth PP, Wong, ND. Residual hypertriglyceridemia and estimated atherosclerotic cardiovascular disease risk by statin use in U.S. adults with diabetes: National Health and Nutrition Examination Survey 2007–2014. Diabetes Care 2019;42:2307-14.
3. Nichols GA, Philip S, Reynolds K, Granowitz CB, Fazio S. Increased residual cardiovascular risk in patients with diabetes and high versus normal triglycerides despite statin-controlled LDL cholesterol. Diabetes Obes Metab 2019;21:366–71.
4. Toth PP, Fazio S, Wong ND, Hull M, Nichols GA. Risk of cardiovascular events in patients with hypertriglyceridaemia: a review of real-world evidence. Diabetes Obes Metab 2020;22:279-89.
5. Bhatt DL, Steg PG, Brinton EA, et al. Rationale and design of REDUCE-IT: reduction of cardiovascular events with icosapent ethyl–intervention trial. Clin Cardiol 2017;40:138-48.
6. Bhatt DL, Steg PG, Miller M, et al. Effects of icosapent ethyl on total ischemic events: from REDUCE-IT. J Am Coll Cardiol 2019;73:2791–802.
7. Bhatt DL, Miller M, Brinton EA, et al. REDUCE-IT USA: results from the 3146 patients randomized in the United States. Circulation 2020;141:367–75.
8. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372:2387-97.
9. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713-22.
10. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018;379:2097-2107.
11. Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open label, blinded endpoint analysis. Lancet 2007;369:1090-8.
12. National Diabetes Statistics Report (CDC website). 2020. Available at: https://www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf. Accessed 03/18/2020.
13. Benjamin EJ, Muntner P, Alonso A, et al. Heart Disease and Stroke Statistics-2019 Update: a report from the American Heart Association. Circulation 2019;139:e56-e528.
14. Pedersen SB, Langsted A, Nordestgaard BG. Nonfasting mild-to-moderate hypertriglyceridemia and risk of acute pancreatitis. JAMA Intern Med 2016;176:1834-42.
15. Nordestgaard BG, Langsted A, Mora S, et al. Fasting is not routinely required for determination of a lipid profile: clinical and laboratory implications including flagging at desirable concentration cut-points—a joint consensus statement from the European Atherosclerosis Society and European Federation of Clinical Chemistry and Laboratory Medicine. Eur Heart J 2016;37:1944–58.
16. Miller M, Stone NJ, Ballantyne C, et al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation 2011;123:2292-2333.
17. Ollendorf DA, Herron-Smith S, Fazioli K, et al. Additive Therapies for cardiovascular disease: effectiveness and value. Institute for Cost Effectiveness Research. 2019. Available at: https://icer-review.org/wp-content/uploads/2019/02/ICER_CVD_Draft_Evidence_Report_072419.pdf. Accessed 03/18/2020.
18. Cost-Effectiveness of Icosapent Ethyl in REDUCE-IT. Presented by W. Weintraub at the American Heart Association's Scientific Sessions, November 16-18, 2019.
19. Cost-Effectiveness of Icosapent Ethyl in US REDUCE-IT Patients. Presented by W. Weintraub at the American College of Cardiology/World Congress of Cardiology Virtual Annual Scientific Session (ACC20/WCC), March 28, 2020.

Clinical Topics: Arrhythmias and Clinical EP, Cardiovascular Care Team, Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Atrial Fibrillation/Supraventricular Arrhythmias, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Diet

Keywords: Diabetes Mellitus, Metabolic Syndrome, Cholesterol, LDL, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Risk Factors, Eicosapentaenoic Acid, Secondary Prevention, Mineral Oil, Hemoglobin A, Cardiovascular Diseases, Logistic Models, Fasting, Nutrition Surveys, Prevalence, Glucose, Follow-Up Studies, Secondary Prevention, Exercise Test, Atrial Fibrillation, Cost-Benefit Analysis, United States Food and Drug Administration, Cost Savings, Quality-Adjusted Life Years

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