420 -Hypertriglyceridemia Management, DM Peripheral Neuropathy, Grief

From the American College of Cardiology (ACC)

1) Management of ASCVD Risk in Persistent Hypertriglyceridemia

In 2018, the American Heart Association (AHA) and ACC, in collaboration with several medical societies, released a guideline on the management of blood cholesterol along with a guidance on risk assessment for both primary and secondary prevention. These guidelines also introduced the concept of “risk enhancers” to personalize risk assessment. Based on the available evidence at the time of publication, the 2018 guideline recommended the use of elevated triglycerides as a “risk-enhancing factor” in primary ASCVD prevention.

Since the publication of the 2018 guidelines, the results of REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Interventional Trial) were published. REDUCE-IT used a triglyceride risk-based approach by including patients with ASCVD or those with diabetes mellitus plus additional ASCVD risk factors and elevated triglycerides (median triglycerides of 216 mg/dL). In this trial, the addition of high-dose icosapent ethyl (IPE) to statin therapy led to a significant relative and absolute reduction in the risk of ASCVD events and cardiovascular mortality. The results of REDUCE-IT have since been incorporated into more recent guidelines and scientific statements and IPE (Vascepa) has since received FDA approval for ASCVD risk reduction in specific patient populations. The results of outcomes trials with other omega-3 fatty acid preparations have subsequently been published, although only REDUCE-IT has shown cardiovascular benefits.

Based on the unique aspects of lifestyle intervention in hypertriglyceridemia and the evolving evidence of significant benefit in CV risk reduction with a triglyceride risk-based approach, the ACC determined that consensus recommendations patients with persistent hypertriglyceridemia were needed. Therefore, an Expert Consensus Decision Pathways (ECDPs) writing committee was convened to address current gaps in care for high-risk patients with mild to moderate (fasting triglycerides ≥150 mg/dL or non-fasting triglycerides ≥175 mg/dL and <500 mg/dL) and severe hypertriglyceridemia (fasting triglycerides ≥500 mg/dL and especially triglycerides ≥1,000 mg/dL).

These recently published consensus recommendations are provided for clinicians and patients regarding unique aspects of lifestyle interventions for management of hypertriglyceridemia and the use of statins and triglyceride risk-based non-statin therapies for ASCVD risk reduction in the following patient groups with persistent hypertriglyceridemia: 1) patients with established ASCVD; 2) patients with diabetes mellitus and additional risk factor(s); 3) high-risk primary prevention patients; and 4) patients with severe hypertriglyceridemia. It should be noted that this process did not involve formal systematic reviews, grading of evidence, or synthesis of evidence.

The common emphasis in all four algorithms is to begin by evaluating patients for secondary causes of hypertriglyceridemia. Notable secondary causes include: poorly controlled diabetes, CKD, uncontrolled hypothyroidism, alcohol abuse, diets high in saturated fat, sugar, or high-glycemic-index foods, sedentary lifestyle, beta-blockers, thiazide and loop diuretics, oral estrogens, atypical antipsychotic medications, overweight/obesity, and metabolic syndrome/insulin resistance.

The next steps, also common to all algorithms, are to optimize diet and lifestyle changes that lower triglycerides, optimize glycemic control, and optimize statin therapy. Lifestyle modification (ie, adherence to a heart-healthy diet, regular physical activity, avoidance of tobacco products, limited alcohol consumption, and maintenance of a healthy weight) remains a critical component of ASCVD risk reduction, both before and in concert with the use of lipid-lowering medications. Referral to a registered dietitian nutritionist is strongly recommended to improve understanding of heart-healthy dietary principles and individualize nutrition recommendations for patients with hypertriglyceridemia.

With regard to statin therapy, statins provide 10-30% dose-dependent reduction in triglycerides in patients with elevated triglyceride levels. Trial data have demonstrated that patients with elevated triglyceride levels are at increased risk of ASCVD events and can achieve ASCVD risk reduction with statin therapy.

For patients whose triglyceride targets are not achieved with these interventions, the committee called particular attention to the role of omega-3 fatty acids (docosahexaenoic acid/DHA and eicosapentaenoic acid/EPA) for the management of hypertriglyceridemia. Prescription products (EPA+DHA or EPA-only) presently include Lovaza (DHA and EPA) and Vascepa (icosapent ethyl/IPE). Doses of 4 g/d (>3 g/d total EPA+DHA) have been shown to be an effective option for reducing triglycerides as monotherapy or as an adjunct to other lipid-lowering agents. At these does, there has been found to be a higher incidence of atrial fibrillation (1 in 71 patients on Vascepa), which provides another reason why aggressive lifestyle intervention and statin therapy are the preferred initial management options.

The authors noted that nonprescription fish oil products are classified as dietary supplements and are not interchangeable with prescription omega-3 products if the intention is to lower CV risk. Unlike the prescription omega-3 fatty acid products, the supplements are not approved by the FDA to treat elevated triglyceride levels. In addition, the manufacturing process for supplements is not regulated to the same degree as the manufacturing process for prescription medications so that the content and quality of the supplements vary. Some supplements may contain impurities, including saturated fat and oxidized lipids, contaminants, or other ingredients that may be harmful.

Mark’s Comments:

This was a good article for me to review, as I’ve noted I’ve fallen into a habit of often only tacitly noting mildly elevated triglyceride levels when reviewing lipid profiles. It was “heartening” to note the ACC’s emphasis on addressing secondary causes and implementing lifestyle changes as the initial management for these patients, as well as the measured language regarding pharmacological therapy, and in particular omega-3 fatty acid products. Note that the lowest present monthly price on GoodRx is $25 for Lovaza and $84 for Vascepa.

References:

• Salim S, et al. 2021 ACC Expert Consensus Decision Pathway on the Management of ASCVD Risk Reduction in Patients With Persistent Hypertriglyceridemia. J Am Coll Cardiol 2021 Aug,78(9):960-993. Link
• Grundy S.M. et al. "2018 ACC/AHA guideline on the management of blood cholesterol: a report of the ACC/AHA Task Force on Clinical Practice Guidelines". J Am Coll Cardiol 2019;73:e285-e350 Link

From the Literature

2) Treatments for Painful Diabetic Peripheral Neuropathy

A recent network meta-analysis has attempted to clarify which medications work best for painful diabetic peripheral neuropathy (DPN) – a common complication of diabetes. This review searched multiple databases and found 43 studies that included over 7700 patients. The review itself was well done and the quality of the studies included was overall good. There was adequate representation of subjects by gender and geography.

The study looked for the outcomes of “50% reduction in pain” and “30% reduction in pain” as well as total dropouts for adverse effects.

Nortriptyline had the greatest probability of achieving both 50% and 30% pain reduction outcomes when compared with placebo, however in the pairwise analyses (direct or indirect comparisons with other agents), gabapentin and duloxetine also fared well on these outcomes. Desvenlafaxine, duloxetine, lacosamide, oxcarbazepine, and pregabalin had more withdrawals than placebo, and in the pairwise comparisons, valproic acid led the pack for withdrawals due to adverse events.

The American Diabetes Association Standards for Diabetes recommendations for painful diabetic neuropathy line up well with the results of this meta-analysis:

“Pregabalin, duloxetine, or gabapentin are recommended as initial pharmacologic treatments for neuropathic pain in diabetes. Tricyclic antidepressants, venlafaxine, carbamazepine, and topical capsaicin, although not approved for the treatment of painful DPN, may be effective and considered for the treatment of painful DPN.”

John’s Comments:

Remember that these medications only treat the neuropathic pain – they don’t improve the overall condition or improve sensation in the feet. Yearly clinician foot exams, educating patients to check their feet daily, and referring to our podiatry colleagues to help us manage problem feet are all important components of the care for patients with diabetic peripheral neuropathy. Antidepressants and seizure medications seem to be the consistently useful medications to control neuropathic pain.

References:

• Relative Efficacy and Safety of Pharmacotherapeutic Interventions for Diabetic Peripheral Neuropathy: A Systematic Review and Bayesian Network Meta-Analysis. Pain Phys. 2020 Dec 31;1;24(1;1):E1–14. Link
• American Diabetes Association. 11. Microvascular Complications and Foot Care: Standards of Medical Care in Diabetes—2021. Diabetes Care. 2021 Jan 1;44(Supplement 1):S151–67. Link

From PeerRxMed (www.PeerRxMed.org)

3) We All Need to Grieve … No One Should Grieve Alone

“Your loss is not a test, a lesson, something to handle, a gift, or a blessing. Loss is simply what happens to you in life. Meaning is what you make happen.” David Kessler, author of Finding Meaning: The Sixth Stage of Grief

How do you grieve? Or for many of us, perhaps the better question is “do you grieve?” Though we typically associate grieving with the death of a loved one, that is a very narrow view of loss and grief. Indeed, loss comes in many forms, including changes in relationships, changes in physical health, and changes in life circumstances, and we’ve certainly had plenty of all of those over the past 18 months since COVID-19 became a household word.

My experience is that many physicians and other healthcare professionals don’t grieve effectively, if they even consciously grieve at all. Note that last sentence didn’t say “correctly,” but rather “effectively.” That is certainly true for me. Indeed, we rarely allow ourselves permission to experience the wide range of complex and often “unlovely” emotions that can accompany loss, including anger, shock, guilt, and even relief. Instead, we often dismiss, bury, or deny them rather than providing ourselves the space and grace to process them.

It’s almost as if we in healthcare have been taught somewhere along the way that grief is not necessary for us because either we don’t experience it in the same way as others or we’re not negatively impacted by loss like others are – that somehow we are either immune to it or have been able to transcend it. And that those of us who do experience it and express that grief are somehow weak, too enmeshed, or even “unprofessional.”

In the process, we deny our humanity and instead of learning how to grieve, we experience emotional consequences of suppressed and unresolved grief, including irritability, anger, guilt, fear, confusion, and emotional distance. You are likely seeing these being expressed by many of our colleagues presently – and perhaps by yourself as well.

This week, remember that loss is being experienced by all of us and what we do with it matters, so be sure to check in with those around you to see how they’re processing that loss – how they’re grieving, starting with your PeerRxMed partner (if you don’t have one, consider signing up!). And allow them to check in with you as well. Then together, let’s discover the meaning that might come from grief, remembering that we all need to grieve, and no one should grieve alone.

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Mark and John

Carilion Clinic Department of Family and Community Medicine

Feel free to forward Take 3 to your colleagues. Glad to add them to the distribution list.

Email: mhgreenawald@carilionclinic.org