This blog post is a summary of a lecture recently held at the 2022 Diabetes Canada Conference in Calgary, Alberta.

 

The Hidden Risk Marker in Diabetes – Triglycerides and Cardiovascular Risk

Speaker: Dr. Akshay Jain, MD, FRCPC, FACE, CCD, ECNU, DABIM, DABOM Endocrinologist Vancouver BC (Dr. Akshay Jain’s website

Triglycerides are a type of blood fat that is routinely measured in our patients living with diabetes as part of their blood cholesterol lab work.  Most often the markers of cholesterol that we focus on are LDL-C (Low Density Lipoprotein Cholesterol) due to its atherosclerotic property, linked to increased blood vessel plaquing and narrowing, and because increased levels of LDL-C increase the risk of heart attack and stroke.  Additionally, there is evidence of increased heart disease risk in those living with type 2 diabetes, both for men and women.  Combine the two and an individual’s risk is even higher.

When looking at ways to lower cardiovascular disease (CVD) risk in someone who is already following the recommended lifestyle approaches including eating a healthy diet, emphasizing whole foods, increased intake of fibre-rich foods, 2 fish meals a week, and an emphasis on unsaturated fats over saturated and trans fats, which of the following is a Canadian guideline recommendation for further lowering CVD risk?

  • Fish oil supplements
  • DPP4 inhibitor
  • Low dose ASA
  • PCSK9 Inhibitor
  • All of the above
  • None of the above

Background: Fish Oil Supplementation

Omega-3 fatty acid fish oil supplements are among the most commonly consumed fish oil supplements used by US adults and that likely is the same in Canada.  The estimated global market is 3.3 billion dollars but their effectiveness in reducing cardiovascular risk remains unverified.  Health recommendations include eating 2 fatty fish meals each week to lower your risk of heart disease.  Fish oil supplements are a way for individuals to increase their omega-3 fish oil intake and most fish oil supplements contain a blend of unsaturated and saturated fats, which have health impacts (read more about the types of fats in the diet and their food sources on the Heart and Stroke Foundation website. Most fish oil supplements contain about 30% of the Omega-3 unsaturated fats eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).  Most natural health fish oil supplements are a blend of EPA and DHA.

  • Eicosapentaenoic Acid (EPA) has been demonstrated to prevent oxidation/breakdown of LDL-C; high levels of LDL-C in the blood increase blood vessel plaquing and blood vessel narrowing as does oxidation/breakdown of LDL-C.
  • Docosahexaenoic acid (DHA) leads to the oxidation/breakdown of LDL within the blood vessels.  This further attracts platelets and promotes platelet aggregation and plaquing within the blood vessels.

A 2021 Meta Analysis did not confirm the effectiveness of EPA/DHA fish oil supplement blends on reducing cardiovascular disease (CVD) mortality, coronary heart disease (CHD) events, MACE (major adverse cardiac events), non-fatal MI (myocardial infarction/heart attack), non-fatal stroke (Safi U. Khan, MD, MS.  Deepak I Bhatt MD, MPH eclinicalMedicine2021 39DOI: 10.1016/j.eclinm.2021. 101110).

Because fish oil supplements lack proof of improving or reducing cardiovascular outcomes, the Canadian Cardiovascular Society no longer recommends the use of over-the-counter omega-3 PUFA fish oil supplements to reduce cardiovascular disease risk.

View the Canadian Cardiovascular Society Lipid Guidelines for full details. 

What should we tell our patients who want to further lower their risk of heart attack and stroke?  Evidence shows that there is an association between elevated triglycerides and an increased risk of CV events.  Fibrates and niacin are often used to lower triglycerides (TGs) but the research says they do not decrease MACE (Major Adverse Cardiovascular Events).  (Key trials: ACCORD, FIELD (fibrates), AIM-HIGH, HPS2-THRIVE (niacin). 

Triglycerides are predictive for increased CVD risk in patients with ASCVD (atherosclerotic cardiovascular disease) regardless of statin therapy or LDL-C!  Elevated TGs are associated with a 41% increased risk in coronary events. (Source: PROVE IT-TIMI 22)

Welcome to a new approach: Icosapent Ethyl (IPE)

Icosapent ethyl is distinct from over-the-counter omega-3 fish oil supplements.  Common fish oil supplements are a blend of saturated and unsaturated fats and also include proinflammatory saturated fats.  Icosapent ethyl is a blend of over 96% purified eicosapentaenoic acid.  The table below outlines the differences in the percentages of fats contained within the 2 blends of fish oils.

Common Fish Oil Supplements Icosapent Ethyl (IPE)
36% Saturated Fats <3% fatty acids (minimal saturated, pro-inflammatory arachidonic acid)
21% EPA >96% Eicosapentaenoic Acid (EPA) ethyl esters (with DHA below detection limits)
9% DHA
34% other fats

Clinical Trial: REDUCE-IT: Icosapent Ethyl vs Placebo

The REDUCE-IT trial was studying the benefits of using a purified form of EPA fish oil on reducing cardiovascular outcomes in both those who have never had a cardiovascular event (primary prevention) and those who had had a cardiovascular event (secondary prevention).

**Dr. Jain noted this was one of the top 15 impactful cardiovascular studies in the past 15 years.

Inclusion criteria for primary prevention cohort:

  1. Diabetes mellitus requiring medication AND
  2. >50 years of age AND
  3. +1 or more additional risk factors
    1. Men 55+ or women 65+
    2. Cigarette smoker or stopped smoking within 3 months.
    3. Hypertension (>140mmHg) or on antihypertensive medication
    4. HDL-C <=40 in men, <=50 in women
    5. hsCRP >3.0mg/L
    6. Renal dysfunction: Creatinine clearance >30 and <60 mls/min
    7. Retinopathy
    8. Micro or macroalbuminuria
    9. ABI <0.9 without symptoms of intermittent claudication.

Patients with diabetes and CVD are counted under the secondary prevention cohort.

It should be noted that the study inclusion criteria was quite broad and that most of our patients over the age of 50 living with diabetes would have 1 or more of these risk factors.

Prevention Cohorts
Secondary >= 45 years with established CVD (documented CAD, CVD or PAD) Fasting TG level between 1.52mmol/L and 5.63mmol/L
Primary >= 50 years with diabetes and at least 1 additional risk factor LDL-C between 1.06mmol/L and 2.59 mmol/L and on stable statin therapy for at least 4 weeks prior to randomization

 

REDUCE-IT: Key Baseline Characteristics of Study Cohorts

Icosapent Ethyl (IPE) n=4089 Placebo n=4090
Age-years 64.0 (57.0-69) 64.0 (57.0-69.0)
Female% 28.4 29.2
Non-white% 9.7 9.8
Westernized region% 71.1 71
CV risk category%
Secondary prevention cohort 70.7 70.7
Primary prevention cohort 29.3 29.3
Ezetimibe use% 6.4 6.4
Statin intensity%
Low 6.2 6.5
Moderate 61.9 63
High 31.5 30
Type 2 Diabetes % 57.9 57.8
TGs (mmol/L) 2.44 2.44
HDL-C 1.03 1.03
LDL-C 1.91 1.97
Triglyceride Category %
<1.69 10.1 10.5
1.69-2.26 29.2 29.1
>2.26 60.7 60.4
Which endpoints were shown as statistically significant for improvements in the REDUCE-IT trial using Icosapent Ethyl??

Primary Endpoint (those without cardiovascular disease)

  • CV Death
  • MI (including silent MI)
  • Stroke
  • Coronary Revascularization
  • Unstable angina

NNT = 21!  Very strong p value

Secondary Endpoint (those who had pre-existing cardiovascular disease)

  • CV Death
  • MI (including silent MI)
  • Stroke

NNT = 28!  Very strong p value

It is important to note that it is very rare to see cardiovascular disease death risk reduction with medications!

Adverse Effects

No overall treatment difference in adverse effects (AE).  Placebo was mineral oil which naturally causes more diarrhea and that was shown in the AE data.  Common side effects were diarrhea, peripheral edema, constipation, atrial fibrillation, anemia, and bleeding disorders (no fatal bleeding events in either group).

Primary Prevention Subgroup Results

The Relative Risk Reduction (RRR) was similar in primary and secondary groups meaning that the relative risk of the intervention was equally lowered in both groups.

The Absolute Risk Reduction (ARR) was less in primary than secondary groups meaning that there was additional benefit seen in those who had never had a cardiovascular event.

The safety seen in the primary prevention group was similar to the secondary prevention group.

Treatment was favorable in all subgroups:

  • Primary prevention
  • Secondary prevention
  • Region US/Canada, Netherlands, Australia, Eastern Europe, Asia-Pacific
  • Diabetes at baseline, no diabetes at baseline.

Favorable for an effect on all endpoints!!

It is interesting to note there was no meaningful between-group differences in A1c or glucose control across study visits.

Biomarkers show that from baseline to year 1 triglyceride levels were similar in REDUCE-IT, there was no change noted to LDL-Cholesterol but EPA levels in the body went up significantly.  It should be noted that IPE does not lower triglycerides and the outcomes seen in the cohorts were independent of TG levels.  It is hypothesized that the higher IPE leads to regression of plaque volume because of:

  • Less platelet aggregation
  • Less plaque progression
  • Less endothelial dysfunction
  • Less inflammation

This study has shown a significant improvement in care and patient outcomes.  So much so that major health organizations have changed their recommendations for the treatment of high triglycerides.  The following outlines two examples of the change.

The 2021 Canadian Cardiovascular Society Lipid Guidelines

Recommendations
  • The CCS recommends the use of IPE to decrease the risk of CV events in patients with ASCVD, or with diabetes and ≥ 1 CVD risk factors, who have an elevated fasting triglyceride level of 1.5-5.6 mmol/L despite treatment with maximally tolerated statin therapy (Strong Recommendation; High-Quality Evidence).
  • They do not recommend the use of over-the-counter omega-3 polyunsaturated fatty acid supplements (marketed as natural health products in Canada) to reduce CVD risk (Strong Recommendation; High-Quality Evidence).

Source: CCS Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in Adults 

The American Diabetes Association Diabetes Care Guidelines

Recommendations
  • 29 For patients with fasting triglyceride levels ≥500 mg/dL (5.6mmol/L), evaluate for secondary causes of hypertriglyceridemia and consider medical therapy to reduce the risk of pancreatitis. C
  • 30 In adults with moderate hyper-triglyceridemia (fasting or nonfasting triglycerides 175–499 mg/2.0-5.6mmol/L), clinicians should address and treat lifestyle factors (obesity and metabolic syndrome), secondary factors (diabetes, chronic liver or kidney disease and/or nephrotic syndrome, hypothyroidism), and medications that raise triglycerides. C
  • 31 In patients with atherosclerotic cardiovascular disease or other cardiovascular risk factors on a statin with controlled LDL cholesterol but elevated triglycerides (135–499 mg/dL/1.5-5.6mmol/L), the addition of icosapent ethyl can be considered to reduce cardiovascular risk. A

Hypertriglyceridemia should be addressed with dietary and lifestyle changes including weight loss and abstinence from alcohol. Severe hypertriglyceridemia (fasting triglycerides ≥500 mg/dL (5.6mmol/L) and especially >1,000 mg/dL (10.0 mmol/L) may warrant pharmacologic therapy (fibric acid derivatives and/or fish oil) and reduction in dietary fat to reduce the risk of acute pancreatitis. Moderate- or high-intensity statin therapy should also be used as indicated to reduce risk of cardiovascular events (see statin treatment section). In patients with moderate hypertriglyceridemia, lifestyle interventions, treatment of secondary factors, and avoidance of medications that might raise triglycerides are recommended.

Recommendations
  • 32 Statin plus fibrate combination therapy has not been shown to improve atherosclerotic cardiovascular disease outcomes and is generally not recommended. A
  • 33 Statin plus niacin combination therapy has not been shown to provide additional cardiovascular benefit above statin therapy alone, may increase the risk of stroke with additional side effects, and is generally not recommended. A

Source: Cardiovascular Disease and Risk Management: Standards of Medical Care in Diabetes – 2021

Summary

  • Cardiovascular risk persists for patients despite controlling LDL-cholesterol
  • Elevated triglycerides are associated with increased cardiovascular risk but to date trials have not shown benefit attributed to triglyceride lowering
  • Elevated triglyceride therefore may represent a risk marker rather than a risk factor for cardiovascular events
  • Fish oil and krill oil mixtures have not demonstrated cardiovascular benefit in clinical trials and are not indicated in management of cardiovascular risk
  • Icosapent ethyl (IPE) represents a highly purified form of eicosapentaenoic acid (EPA) with no detectable docosahexaenoic acid (DHA)
  • IPE, based on REDUCE-IT data, demonstrates cardiovascular risk reduction in statin-treated patients with elevated triglycerides with established cardiovascular disease OR diabetes plus 1 other risk factor.

 

Drug Plan Coverage in Saskatchewan

Icosapent Ethyl, branded as Vascepta, is available by prescription to patients living in Saskatchewan.  Talk with a prescriber (doctor, nurse practitioner, specialist) if you feel this drug might be suitable for your needs.  Below are the criteria for approval for Vascepta in Saskatchewan.

Saskatchewan Provincial Drug Plan Non-Insured Health Benefits
Exception Drug Status (prior approval required)

Coverage Criteria for Vascepa (icosapent ethyl):

For patients aged 45 years or older, have established cardiovascular disease (CVD) (secondary prevention), and who are concomitantly treated and maintained on a statin.

Eligible patients should have all of the following:

  • A fasting triglyceride level of 1.7 mmol/L or greater and lower than 5.6 mmol/L at baseline, measured within the preceding three months before starting treatment with icosapent ethyl; AND
  • A low-density lipoprotein cholesterol (LDL-c) greater than 1.0 mmol/L and lower than 2.6 mmol/L at baseline; AND
  • Patient must be receiving a maximally tolerated statin dose, targeted to achieve an LDL-c lower than 2 mmol/L, for a minimum of four weeks.

 

 

 

 

 

Limited use benefit (prior approval required).

Initial Request: Coverage is provided for 12 months. 

To reduce the risk of cardiovascular events (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, or hospitalization for unstable angina) in statin-treated patients with elevated triglycerides, if the following conditions are met:

  • Patient is aged 45 years and older; AND
  • Patient has established cardiovascular disease (secondary prevention); AND
  • Patient is being concomitantly treated with a statin; AND
  • Patients must have a fasting triglyceride of 1.7 mmol/L or greater and lower than 5.6 mmol/L at baseline, measured within the preceding three months before starting treatment with icosapent ethyl; AND
  • Patients must have a low-density lipoprotein cholesterol greater than 1.0 mmol/L and lower than 2.6 mmol/L at baseline and be receiving a maximally tolerated statin dose, targeted to achieve a low-density lipoprotein cholesterol lower than 2 mmol/L, for a minimum of four weeks.

Renewal at 12 months: Coverage is provided for a period of 12 months if:

  • Patient is responding to therapy; AND
  • Therapy has been shown to be effective with an improvement in condition; AND
  • Patient shows a continued medical need for the therapy; AND
  • Patient is being concomitantly treated with a statin.

 Note: Icosapent ethyl will only be reimbursed for patients being concomitantly treated with a statin.

 

 

I hope that this summary has helped you better understand the current state of the recommended use of fish oils for cardiovascular protection and provided you with an additional treatment option for some of your patients. I welcome your comments and discussion on this topic.

Michelle Archer, RD, CDE

Registered Dietitian and Certified Diabetes Educator

Diabetes Training 101 Inc.