Bempedoic acid in conjunction with statin therapy for dyslipidemia management

Bempedoic acid in conjunction with statin therapy for dyslipidemia management

By Aly Becraft, MS; Kevin C. Maki, PhD

Use of statins to reduce risk of cardiovascular disease is an effective treatment strategy,1 but the statin doses required to adequately reduce low density lipoprotein cholesterol (LDL-C) and non-high-density-lipoprotein cholesterol (non-HDL-C) levels and achieve optimal cardiovascular disease risk reduction are not well tolerated by some patients, and even maximal statin therapy may be inadequate to achieve sufficient cholesterol-lowering in some patients.2-8  Bempedoic acid is a promising prodrug that may be useful as an adjunct therapy to stains for lowering LDL-C. Its activation is reliant on very-long-chain acyl-CoA synthetase 1, which is present in the liver, but absent from most other tissues.8 Once activated, it is thought to act via the same cholesterol biosynthesis pathway as statins; however, its target, ATP citrate lyase (ACL), is further upstream in the pathway than the target for statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase.8 The liver specific activation of bempedoic acid differentiates it from statins. Because muscle cells do not express the activating enzyme for bempedoic acid, it is less likely to have skeletal muscle-related side effects.  This makes it an attractive adjunct therapy to statins since the most commonly reported side effects with statins include myalgias and other muscle-related complaints.8 Bempedoic acid has also been studied in combination with ezetimibe in patients with and without statin intolerance.9,10 It was shown to reduce LDL-C more than ezetimibe alone, and to have a similar tolerability profile. In a trial of patients with a history of statin intolerance and LDL-C ≥100 mg/dL, bempedoic acid added to background lipid-modifying therapy that included ezetimibe reduced LDL-C by 28.5% more than the addition of placebo (p < 0.001).10 Until recently, the efficacy and safety of bempedoic acid had been evaluated in relatively small groups and in trials of short duration.9-13

Ray et al.14 published results from the Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen (CLEAR) Harmony trial. This 52-week, randomized, double-blind, placebo-controlled trial evaluated the safety and efficacy of bempedoic acid for reducing LDL-C. In this phase 3, parallel group trial, a total of 2230 patients were enrolled; 1488 were assigned to receive bempedoic acid and 742 received a placebo. Patients qualified for the study if they had either atherosclerotic cardiovascular disease (97.6% of subjects) or heterozygous familial hypercholesterolemia (3.5% of subjects), were taking stable doses of maximally tolerated statin therapy, and had fasting LDL-C levels of at least 70 mg/dL (mean ± standard deviation 103.2 ± 29.4 mg/dL) . The primary end points were safety-related, including incidence of adverse events and changes in laboratory variables. Secondary end points included changes from baseline to 12 weeks in LDL-C, non-HDL-C, total cholesterol, apolipoprotein B and high-sensitivity C-reactive protein.

Of the enrolled patients, 78.1% completed the intervention and 94.6% continued the trial through week 52, providing a total of 1248 patient-years of exposure to bempedoic acid. Adverse events were reported in approximately 79% of both treatment groups, with a majority of events (>80%) graded as mild to moderate in severity. Common adverse event incidence and major adverse events occurred with similar frequency in both groups; however, the number of patients who discontinued treatment due to adverse events was higher in the bempedoic acid group compared to the placebo group (10.9% vs 7.1%; p = 0.005). Incidence of gout in the bempedoic acid group was modestly increased compared to placebo (1.3% vs 0.3%; p = 0.03). Interestingly, the incidence of new-onset diabetes or worsening diabetes was lower among subjects receiving bempedoic acid compared to placebo (3.3% vs. 5.4%; p = 0.02), although the total number of events was low.

Treatment with bempedoic acid significantly (p < 0.001) reduced LDL-C levels compared to placebo at week 12 (18.1% from baseline) and week 24 (16.1% from baseline). All other measured cardiometabolic risk factors were also significantly reduced (p < 0.001 for all comparisons) from baseline at week 12 with bempedoic acid compared to placebo. The effects of bempedoic acid were sustained with minimal attenuation through the end of the trial (week 52). Efficacy was observed to be greater among women than men (p = 0.03) but was not significantly different across other subgroups, including type or intensity of background lipid-lowering therapy.

Comment: The present trial provides evidence for the safe and efficacious longer term (1-year) , use of bempedoic acid as an adjunct therapy to statins. Although discontinuation of the trial was higher among subjects in the bempedoic acid group, adverse events appeared to occur at similar frequency in both groups. Increased gout occurrence with the bempedoic acid treatment may be related to metabolite competition with uric acid for renal transporters involved in their excretion14 and the incidence of gout in this trial was modest.

Compared to placebo, use of bempedoic acid in conjunction with statin therapy modestly reduced the levels of LDL-C and other lipoprotein lipid and biomarker levels from baseline to week 12 and throughout the remainder of the 52-week trial. Bempedoic acid works via the same cholesterol synthesis pathway as statins;8 however, doubling statin dosage reduces LDL-C levels by ~6%,15 less than half of the reported effect from the present trial. Furthermore, bempedoic acid treatment did not appear to cause or exacerbate skeletal muscle-related side effects associated with statin use, further signifying its efficacy and tolerability as a prospective statin adjunct. Of note, the trial population was predominantly white (~96%), and more racial diversity is needed in future evaluations of bempedoic acid safety and efficacy. In addition, 73% of patients were male; therefore, the present findings of greater treatment efficacy in women should also be explored in future studies with a greater proportion of women subjects.

In February 2019, the manufacturer, Esperion Therapeutics, Inc. (Ann Arbor, MI), submitted two New Drug Applications to the US Food and Drug Administration for approval of bempedoic acid and a bempedoic acid/ezetimibe combination tablet as once daily oral therapies for the treatment of patients with elevated LDL-C who need additional LDL-C lowering despite the use of currently accessible therapies. Esperion expects to receive notification on whether the submissions have been accepted for review in May of 2019.

References

  1. Ford ES, Ajani UA, Croft JB, et al. Explaining the decrease in U.S. deaths from coronary disease, 1980–2000. N Engl J Med. 2007;356:2388-98.
  2. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495-1504.
  3. Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology. Circ Res. 2016;118:547–563.
  4. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129:Suppl 2:S1-S45.
  5. Jacobson TA, Ito MK, Maki KC, et al. National lipid association recommendations for patient-centered management of dyslipidemia: full report. J Clin Lipidol. 2015;9:129-69.
  6. Danese MD, Gleeson M, Kutikova L, et al. Management of lipid-lowering therapy in patients with cardiovascular events in the UK: a retrospective cohort study. BMJ Open. 2017;7:e013851.
  7. Steen DL, Khan I, Ansell D, Sanchez RJ, Ray KK. Retrospective examination of lipid-lowering treatment patterns in a real world high-risk cohort in the UK in 2014: comparison with the National Institute for Health and Care Excellence (NICE) 2014 lipid modification guidelines. BMJ Open. 2017;7:e013255.
  8. Pinkosky SL, Newton RS, Day EA, et al. Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis. Nat Commun. 2016;7:13457.
  9. Thompson PD, MacDougall DE, Newton RS, et al. Treatment with ETC-1002 alone and in combination with ezetimibe lowers LDL cholesterol in hypercholesterolemic patients with or without statin intolerance. J Clin Lipidol. 2016;10:556-67.
  10. Ballantyne CM, Banach M, Mancini GBJ, et al. Efficacy and safety of bempedoic acid added to ezetimibe in statin intolerant patients with hypercholesterolemia: a randomized, placebo-controlled study. Atherosclerosis. 2018;277:195-203.
  11. Ballantyne CM, Davidson MH, Macdougall DE, et al. Efficacy and safety of a novel dual modulator of adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase in patients with hypercholesterolemia: results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. J Am Coll Cardiol. 2013;62:1154-62.
  12. Thompson PD, Rubino J, Janik MJ, et al. Use of ETC-1002 to treat hypercholesterolemia in patients with statin intolerance. J Clin Lipidol. 2015;9:295-304.
  13. Ballantyne CM, McKenney JM, MacDougall DE, et al. Effect of ETC-1002 on serum low-density lipoprotein cholesterol in hypercholesterolemic patients receiving statin therapy. Am J Cardiol. 2016;117:1928-33.
  14. Ray KK, Bays HE, Catapano AL, Lalwani ND, Bloedon LT, Sterling LR, Robinson PL, Ballantyne CM. Safety and efficacy of bempedoic acid to reduce LDL cholesterol. N Engl J Med. 2019;380:1022-32.
  15. Nicholls SJ, Brandrup-Wognsen G, Palmer M, Barter PJ. Meta-analysis of comparative efficacy of increasing dose of atorvastatin versus rosuvastatin versus simvastatin on lowering levels of atherogenic lipids (from VOYAGER). Am J Cardiol. 2010;105:69-76.
Photo by Louis Reed

New Trial Suggests Light Therapy may be a Promising Intervention for Treatment of Depression with Type 2 Diabetes

New Trial Suggests Light Therapy may be a Promising Intervention for Treatment of Depression with Type 2 Diabetes

By Aly Becraft, MS; Kevin C Maki, PhD

One in 11 adults have diabetes worldwide,1 with an estimated 25% of people with diabetes also suffering from depression.2 Co-occurrence of these diseases has been shown to increase risk for diabetes complications,3 potentially due to a lack of motivation to properly manage the disease.4,5 Therefore, people with diabetes and depression need effective therapies for both conditions in order to remain properly treated.

Often, depression simultaneously occurs with impaired sleep, leading to biological rhythm disturbances.6 While pharmacological interventions can be successful, some antidepressant drugs may have unfavorable effects on glycemic control in people with type 2 diabetes (T2D).7 Light therapy is an alternative or adjunctive treatment for depression with minimal side effects.8 It is thought to act by modifying the phase relationships between the biological clock and the light-dark cycle to restore appropriate sleep-wake cycles9 and has proven effective for treating seasonal depression (seasonal affective disorder) as well as some cases of non-seasonal depression.10-12 In 2017, an estimated 12% of global health expenditures were spent on diabetes,1 thus, if efficacy can demonstrated, light therapy would be a cost-effective treatment for T2D patients suffering from depression. In addition to altering mood states, sleep deficiency may also be related to changes in glucose metabolism and decreased insulin sensitivity.13 Previous studies have reported that partial sleep deprivation induced insulin resistance in healthy subjects and patients with type 1 diabetes.13-15 Therefore, the restoration of biological rhythmicity in individuals with impaired sleep may have the potential to improve glucose regulation.

Brouwer et al., (2019) report results from a randomized, double-blind, placebo-controlled trial which was published in Diabetes Care and investigated whether mood and insulin sensitivity could be improved via light therapy in clinically depressed patients with T2D.16 In this parallel-arm study, a total of 79 adults with depression and T2D were included in the outcome measures. Forty received light therapy (broad-spectrum, white-yellow light, 10,000 lux), while 39 received placebo therapy (monochromatic green light, 470 lux). Light therapy was provided in the homes of participants over 4 weeks for 30 minutes each morning. Participants were assessed for changes in depressive symptoms, and a subset of participants who agreed to hyperinsulinemic-euglycemic clamp (HEC) procedure were evaluated for insulin sensitivity. Both measures were assessed at baseline and after the 4-week intervention. Several secondary measures were also evaluated including anxiety symptoms, diabetes stress, self-reported insomnia, objective sleep duration, sleep efficiency, and mid-sleep time, as well as glycated hemoglobin (HbA1C) levels, fasting blood glucose, self-reported hypo-glycemic events and body weight.

After the intervention, light therapy did not significantly reduce depressive symptoms, and similarly, had no effect on insulin sensitivity in the primary analysis. However, per-protocol analyses were conducted to exclude 13 participants that changed glucose-lowering medication during the protocol, which resulted in 51 remaining participants.  In the per-protocol analysis, participants had a 26% greater reduction in depressive symptoms in response to light therapy (P=0.031). In addition, subgroup analysis suggested that patients with higher insulin resistance responded positively to light therapy (P=0.017), and there was a trend toward positive response in patients using insulin vs non-insulin glucose lowering medication (P=0.094). No significant differences in secondary measures were found between the treatment and placebo groups.

Comment.  Overall, the results of this study were inconclusive, but the per-protocol analysis was suggestive of improvements in depressive symptoms, which is a hypothesis-generating finding that should be investigated in additional research. Furthermore, the reduction in depressive symptoms observed in patients with higher insulin resistance may indicate greater efficacy of light therapy in this subset. A similar observation by Dimitrova et al., (2017) suggested that higher BMI, a factor strongly associated with insulin resistance, may be a baseline predictor for light therapy response in patients with seasonal depression.17 Although improvements in insulin sensitivity have been previously demonstrated in two case studies in response to light therapy,18,19 this effect was not established in the present study. This study shows potential for light therapy as a treatment for depression with T2D, but more research is needed with larger samples, longer duration of therapy and/or greater daily light exposure to more fully evaluate the effects of this therapy.

 

References:

  1. Cho NH, Shaw JE, Karuranga S, et al. International Diabetes Federation (IDF) diabetes atlas: global estimates of diabetes prevalence for 2017 and projections for 2045. DiabetesRes Clin Pract. 2018;138:271-281.
  2. Goldney RD, Phillips PJ, Fisher LJ, Wilson DH. Diabetes, depression, and quality of life: a population study. Diabetes Care. 2004;27(5):1066-1070.
  3. Petrak F, Baumeister H, Skinner TC, et al. Depression and diabetes: treatment and health-care delivery. Lancet Diabetes Endocrinol. 2015;3:472-485.
  4. Gonzalez JS, Peyrot M, McCarl LA, et al. Depression and diabetes treatment nonadherence: a meta-analysis. Diabetes Care. 2008;31:2398-2403.
  5. Lin EH, Katon W, Von Korff M, et al. Relationship of depression and diabetes self-care, medication adherence, and preventive care. Diabetes Care. 2004;27:2154-2160.
  6. van Mill JG, Hoogendijk WJ, Vogelzangs N, et al. Insomnia and sleep duration in a large cohort of patients with major depressive disorder and anxiety disorders. J Clin Psychiatry. 2010;71:239-246.
  7. Deuschle M. Effects of antidepressants on glucose metabolism and diabetes mellitus type 2 in adults. Curr Opin Psychiatry. 2013;26:60-65.
  8. Wirz-Justice A, Benedetti F, Terman M. Chronotherapeutics for affective disorders: a clinician's manual for light and wake therapy, 2nd. Karger Medical and Scientific Publishers. 2013.
  9. Wirz-Justice A. Biological rhythm disturbances in mood disorders. Int Clin 2006;21:S11-5.
  10. Tuunainen A, Kripke DF, Endo T. Light therapy for non-seasonal depression. Cochrane Database Syst Rev. 2004;(2):CD004050.
  11. Perera S, Eisen R, Bhatt M, et al. Light therapy for non-seasonal depression: systematic review and meta-analysis. BJPsych Open. 2016;2:116-126.
  12. Mårtensson B, Pettersson A, Berglund L, Ekselius L. Bright white light therapy in depression: a critical review of the evidence. J Affect Disord. 2015;182:1-7.
  13. Spiegel K, Tasali E, Leproult R, Van Cauter E. Effects of poor and short sleep on glucose metabolism and obesity risk. Nat Rev Endocrinol. 2009;5(5):253.
  14. Donga E, van Dijk M, van Dijk JG, et al. A single night of partial sleep deprivation induces insulin resistance in multiple metabolic pathways in healthy subjects. J Clin Endocrinol Metab. 2010;95(6):2963-2968.
  15. Donga E, van Dijk M, van Dijk JG, et al. Partial sleep restriction decreases insulin sensitivity in type 1 diabetes. Diabetes Care. 2010;33:1573-1577.
  16. Brouwer A, Nguyen HT, Rutters F, et al. Effects of light therapy on mood and insulin sensitivity in patients with type 2 diabetes and depression: results from a randomized placebo-controlled trial. Diabetes Care. 2019.
  17. Dimitrova TD, Reeves GM, Snitker S, et al. Prediction of outcome of bright light treatment in patients with seasonal affective disorder: discarding the early response, confirming a higher atypical balance, and uncovering a higher body mass index at baseline as predictors of endpoint outcome. J Affect Disord. 2017;222: 126-132.
  18. Nieuwenhuis RF, Spooren PF, Tilanus JJ. Less need for insulin, a surprising effect of phototherapy in insulin-dependent diabetes mellitus. Tijdschr Psychiatr. 2009;51:693-697.
  19. Allen NH, Kerr D, Smythe PJ, et al. Insulin sensitivity after phototherapy for seasonal affective disorder. Lancet. 1992;339:1065-1066.

 

 

Photo by Duy Hoang