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Time Stamps

• 02:17 Check a non-HDL-C or ApoB if TGs are ≥150 mg/dL
• 07:18 Address waist circumference and lifestyle before meds for high TGs
• 10:52 Dr. Watson’s 3-day carbohydrate responsiveness trial
• 17:07 Order a fasting or nonfasting lipid panel?
• 19:00 When do you reach for TG-lowering medications?
• 25:26 Don’t miss familial chylomicronemia syndrome (FCS)

Show Notes

Elevated TGs rarely travel alone!

• TGs = a metabolic clue!
  • When TGs are high, look for what came with them:
    • insulin resistance/diabetes
    • visceral adiposity
    • alcohol
    • kidney disease
    • hypothyroidism
    • medications
• Ask yourself: Are the TGs themselves the problem, OR do they reveal a bigger metabolic issue? 

Consider checking ApoB when LDL looks reassuring but you’re still worried about residual cardiovascular risk!

• Think “cargo vs. trucks”:
  • Cholesterol and TGs = cargo
  • Lipoprotein particles = trucks carrying the cargo (LDL, VLDL/remnants, IDL, and Lp(a))
  • LDL-C = how much cholesterol cargo is being carried inside LDL particles
  • ApoB ≈ how many atherogenic trucks are on the road
    • Each atherogenic lipoprotein particle carries one apoB molecule
      • So apoB approximates the number of circulating atherogenic particles. 
    • ApoB is relatively minimally affected by fasting status.
• Non-HDL = amount of cholesterol cargo across all atherogenic trucks
• LDL and apoB usually track together
  • BUT they can become discordant– particularly with elevated TGs*, diabetes, and metabolic syndrome. 
• When LDL looks reassuring BUT the patient’s TGs, diabetes/metabolic phenotype, or ASCVD history makes you think “there have to be more trucks here!”
  • CHECK apoB! It can uncover residual atherogenic particle burden
• When LDL and apoB disagree: cardiovascular risk tends to track more closely with the number of trucks (apoB) than with the cholesterol cargo (LDL) alone

When should you check apoB?

• When it changes your management!
  • The 2026 guideline suggests considering apoB measurement in the following situations:
    • Already on lipid-lowering therapy:
      • apoB is reasonable when LDL/non-HDL are at goal but knowing the residual atherogenic particle burden could influence treatment (Class 2a)
    • Not on lipid-lowering therapy:
      • apoB may be reasonable when it would help clarify ASCVD risk, inform whether to start therapy, or evaluate a suspected inherited lipid disorder (Class 2b)]
    • How is calculated LDL-C actually calculated?Most lipid panels do not directly measure LDL-C. Instead, they estimate LDL-C from total cholesterol, HDL-C, and triglycerides.
      • • Friedewald equation:
          LDL-C = total cholesterol − HDL-C − triglycerides/5
          It assumes that the triglyceride-to-VLDL-cholesterol ratio is always 5. That shortcut becomes less reliable when triglycerides are elevated or LDL-C is low and is traditionally not reported when triglycerides are ≥400 mg/dL.
        • Martin/Hopkins equation:
          Uses an adjustable triglyceride-to-VLDL-cholesterol factor based on the patient’s triglyceride and non-HDL-C levels rather than always dividing triglycerides by 5. This generally improves accuracy, particularly at low LDL-C levels and with elevated triglycerides.
        • Sampson/NIH equation:
          Uses a more complex equation incorporating triglycerides and non-HDL-C. It was designed to improve LDL-C estimation in patients with low LDL-C or hypertriglyceridemia and was validated with triglycerides up to 800 mg/dL.
• * The 2026 guideline recommends the Martin/Hopkins or Sampson/NIH equation rather than Friedewald for LDL calculation for accuracy, especially if TGs >150 mg/dL

Don’t have apoB? Look at non-HDL!

• Non-HDL (amount of cholesterol cargo across all atherogenic trucks) = total cholesterol – HDL
  • You already have it on a standard lipid panel
• If LDL is at goal but non-HDL is high, LDL isn’t telling you the full story → apoB can add another layer to risk!

How should apoB inform risk and treatment goals?

• LDL-C and non-HDL-C are the main targets in the 2026 guideline
  • ApoB is useful for identifying residual risk when those measures may underestimate particle burden
• For primary prevention, apoB ≥120 mg/dL is a 2026 ACC/AHA risk-enhancing factor and can help push a borderline treatment decision toward lipid-lowering therapy
• Risk-based apoB treatment goals:
  • Clinical Context: Borderline- or intermediate-risk primary prevention
    • Optional ApoB Treatment Goal: <90 mg/dL
  • Clinical Context: High-risk primary prevention, including diabetes or 10-year PREVENT-ASCVD risk ≥10%
    • Optional ApoB Treatment Goal: <70 mg/dL
  • Clinical Context: Clinical ASCVD, not at very high risk
    • Optional ApoB Treatment Goal: <70 mg/dL
  • Clinical Context: Very-high-risk ASCVD
    • Optional ApoB Treatment Goal: <55 mg/dL

Address waist circumference and lifestyle before medicine for high TGs!

• Before reaching for medications, the updated guidelines emphasize controlling TGs by focusing on:
  • Low added sugars
  • Reduced alcohol and saturated fat
  • Exercise
  • 5-10% weight loss if overweight/obese
• Waist circumference (measured at the top of the iliac crest with the tape parallel to the floor)
  • Simple proxy for abdominal adiposity and can identify cardiometabolic risk that BMI alone may miss!
    • Consider measuring it alongside BMI
      • Particularly at baseline and when tracking the response to lifestyle interventions!
  • NOTE: Patient can have a “normal” BMI and still carry excess visceral fat and higher cardiometabolic risk
    • Waist circumference catches what BMI alone can miss
• Reference cutoffs from the Obesity Society/ADA consensus
  • Men ≥40 in (102 cm) in men 
  • Women ≥35 in (88 cm) in women (Asian patients have lower cutoffs)
    • Though there’s no single number the guidelines insist on. 
      • No single cutoff fully captures risk; ethnicity, sex, body composition, and changes over time all matter!
• Clinically, the TREND may be more useful than cutoff: is waist circumference  (alongside weight/BMI) decreasing as the patient’s metabolic health improves?

Dr. Watson’s 3-day carbohydrate responsiveness trial 

• Patients often blame dietary fat, but refined carbohydrates, alcohol, and insulin resistance can be major drivers of elevated TGs
• Dr. Watson’s lipid clinic = 3-day trial to show patients to see how refined carbohydrates and alcohol may affect their triglycerides!
  • Obtain a baseline lipid panel 
  • Limit total carb consumption to <100 g/day for 3 days while strictly avoiding all alcohol
  • Repeat the lipid panel on day 3 under the same fasting or non-fasting conditions
• Important caveat: the exact 3 day duration, less than 100 g carb/day limit, and the clinical response threshold all represent Dr. Watson’s clinical approach and aren’t formally validated, but the physiologic premise is well supported in RCTs on diet control
• Always do a medication review, common offenders that raise TG:
  • Atypical antipsychotics*
  • Oral estrogens
  • Thiazides
  • HIV protease inhibitors
  • Isotretinoin
  • Propranolol
  • Immunosuppressants (sirolimus, tacrolimus)
  • Propofol (in the peri-op or ICU setting)
• TIP: *Consider co-administering metformin; some evidence to suggest metformin may help mitigate antipsychotic-associated weight gain and metabolic abnormalities.
• Check lipids alongside glucose/A1c at baseline, 12 weeks, 1 year, then annually

Order a fasting or nonfasting lipid panel?

• Nonfasting lipid panels are appropriate for most patients
  • TGs are the component most affected by recent food intake!
• A nonfasting sample arguably better reflects what the body is exposed to most of the day
• Consider fasting lipids when:
  • Nonfasting TG elevated (≥400 mg/dL)
  • Suspected genetic TG/lipid disorder
  • Fasting TG or LDL would change treatment
• When trending TGs over time, compare apples to apples– if the prior level was fasting, you should compare against another fasting level

When do you reach for TG lowering medications? 

• For primary prevention, don’t let TG 150-499 mg/dL automatically trigger a TG-lowering drug. First ask: What is this patient’s ASCVD risk?
• Use PREVENT-ASCVD to stratify risk first:
  • Low: <3%
  • Borderline: 3 to < 5%
  • Intermediate: 5 to < 10%
  • High: ≥10%

Why do TGs matter if they aren’t in PREVENT?

• PREVENT already captures some of the risk associated with the dyslipidemic phenotype through HDL and non-HDL-C
  • Persistent TG elevation = risk enhancer!
    • Especially for borderline/intermediate risk that can push discussion towards lipid-lowering therapy
• Optimize LDL-C lowering first!
  • Statins remain the foundation of pharmacotherapy for ASCVD risk reduction in patients with elevated TGs.
• If LDL-C remains above the patient’s risk-based goal on maximally tolerated statin therapy, intensify LDL-C lowering with an appropriate evidence-based nonstatin before reflexively reaching for a TG-specific drug

When to think about icosapent ethyl (prescription EPA)? 

• The 2026 guideline gives icosapent ethyl a selective Class 2b recommendation
  • Meaning it may be reasonable in certain high-risk patients
• Who for?
  • Adults with clinical ASCVD 
  • Adults age ≥50 with type 2 diabetes plus at least one additional ASCVD risk factor
    • Who have persistent triglycerides of 150–499 mg/dL AND LDL-C <100 mg/dL, DESPITE maximally tolerated statin therapy!
• REDUCE-IT showed benefit in high-risk statin-treated patients!
  • But no second placebo-controlled outcomes trial using the same formulation in a comparable population has confirmed the magnitude of benefit
    • Rrials of other omega-3 formulations have generally not reproduced it!
  • In the placebo group (which got mineral oil) LDL-C increased 10.2% at 12 months 
    • Inflammatory/atherogenic biomarkers also rose (including hsCRP ~21.9%!)
      • Raised concern that mineral oil may not have been biologically inert
      • Although does not fully explain REDUCE-IT’s cardiovascular benefit
  • CAUTION: Icosapent ethyl also increased
    • Hospitalizations for atrial fibrillation or flutter (3.1% versus 2.1%)
    • Produced a numerical increase in serious bleeding, 2.7% versus 2.1%
• The guidelines specifically recommend prescription purified EPA, not OTC fish oil, and explicitly recommend against relying on dietary supplements!
• Ask yourself: Does this patient resemble the high-risk population in whom icosapent ethyl was studied, or am I simply treating an elevated TG number?

Fibrates are not for cardiovascular risk reduction. They’re reserved for pancreatitis prevention!

• Fibrates lower TGs, but trials have NOT shown consistent overall cardiovascular benefit when they are added to contemporary statin therapy
• PROMINENT is the cleanest example:
  • Pemafibrate lowered TGs substantially without reducing cardiovascular events 
• Fibrates remain useful for lowering markedly elevated triglycerides
  • Especially when reducing pancreatitis risk is the priority!

When does pancreatitis become the priority?

• For persistent triglycerides of 500–999 mg/dL, and especially ≥1,000 mg/dL,
  • Despite dietary intervention, considers a fibrate or prescription omega-3 fatty acid 
• At ≥1,000 mg/dL, a very-low-fat diet and prompt correction of secondary factors become particularly important!
• Guideline: TG-lowering therapy specifically for TGs ≥1,000 mg/dL
  • Though pancreatitis risk begins rising above 500 and climbs sharply above 1,000
• Fenofibrate is generally preferred!
  • Especially when combined with a statin. 
  • CAUTION: Gemfibrozil inhibits pathways involved in the hepatic uptake and metabolism of several statins!
    • Increasing the risk of myopathy and rhabdomyolysis in combo with statin

Don’t miss familial chylomicronemia syndrome (FCS)

• Consider persistent chylomicronemia when fasting triglycerides repeatedly approach or exceed approximately 885–1,000 mg/dL
  • Some emerging therapy trials use a ≥500 mg/dL cutoff, especially when accompanied by 
    • Recurrent triglyceride-associated pancreatitis
    • Otherwise unexplained severe abdominal pain
    • Onset early in life
    • Limited response to standard triglyceride-lowering therapies.
• Most adults with severe chylomicronemia have multifactorial chylomicronemia syndrome (MCS) rather than FCS! 
  • FCS is an ultrarare
    • Usually autosomal-recessive disorder involving severe impairment of the lipoprotein-lipase pathway
• How to diagnosis? Mix of:
  • triglyceride pattern
  • age at onset
  • pancreatitis history
  • secondary factors
  • treatment response
  • laboratory clues such as a relatively low apoB 
• Genetic testing can confirm FCS and may help determine treatment access, but it is not always available or conclusive
  • A negative test does not exclude every clinically compatible case. 
  • Referral to a lipid specialist is appropriate when FCS is suspected.
• Two newer therapies targeting apoC-III now have a role for FCS:
  • Olezarsen (Tryngolza): a monthly antisense oligonucleotide, initially approved for adults with FCS in December 2024. 
    • In June 2026, its indication was expanded to adults with severe hypertriglyceridemia to reduce triglycerides and the risk of acute pancreatitis.
  • Plozasiran (Redemplo): a small-interfering RNA therapy administered every three months, approved in November 2025 as an adjunct to diet to reduce triglycerides in adults with FCS.

Transcript

Dr. Karol Watson: So obviously, normal, normal, normal triglycerides by all lipid panels is less than 150. But when you think about it, true, true normal fasting triglyceride is probably 70 or so. You really should not be making a lot of triglycerides, but if it’s less than 150, you’re fine. If it’s above 150 but less than 500, you’re in that high cardiovascular risk profile.

Dr. Shreya Trivedi: That’s Dr. Karol Watson, professor of cardiology at UCLA and a nationally recognized expert in cardiovascular disease prevention. And we asked you to expand on what you really meant by that truly normal fasting triglyceride being closer to 70.

Dr. Karol Watson: It’s like glucose. We say a hundred is a cutoff, but most fasting glucoses are lower than that. And they give us the same kind of theme. It’s not bad that you’re at 150, but that tells you there’s probably some insulin resistance underlying that. And if I blink or if you have one bad day, you’re going to be over the limit.

Dr. Shreya Trivedi: Hi everyone. Welcome to an awesome episode on Updates in Triglycerides. I am Dr. Shreya Trivedi, and I’m joined by…

Dr. Harini Shah: Hi! I’m Dr. Harini Shah, a PGY3 resident at UCLA. 

Dr. Shreya Trivedi: I think we all spend a lot of time talking about LDL cholesterol, but the new 2026 ACC/AHA lipid guidelines put triglycerides back in the spotlight. This episode thankfully was made possible by an independent medical education grant from the National Triglyceride Association. And today we’re going to break down the updates in triglycerides that are actually going to change our practice.

Dr. Karol Watson: Don’t just think of triglycerides in isolation. They’re like cockroaches. They never exist alone. They always have these bad things running with them, like high insulin or insulin resistance, et cetera. Think about that because that’s driving your risk as much as the triglycerides themselves. So they’re a marker of risk in as much as just an actual risk themselves.

Dr. Shreya Trivedi: Triglycerides and cockroaches. Unfortunately, I will remember that forever. So yes. Yes. At this point, I think whenever I see that triglycerides elevated, I’m going to look around and see who else came to the party. Insulin resistance, visceral adiposity, diabetes, triglycerides are a metabolic clue.

Check a non-HDL-C or ApoB if TGs are ≥150 mg/dL

Dr. Harini Shah: Shreya, one update I didn’t fully appreciate before reading these guidelines is actually how helpful ApoB is when it comes to triglycerides.

Dr. Karol Watson: For most people, your LDL level and your ApoB level are about the same if your triglycerides are normal. But if your triglycerides are high, your ApoB will be out of proportion high compared to your LDL. So it’s important to look at that.

Dr. Harini Shah: So here’s the teaching point. Elevated triglycerides, especially once they’re above 150, can really make the LDL on a routine lipid panel look falsely reassuring.

Dr. Karol Watson: Remember ApoB, it’s the protein portion of every single atherogenic lipoprotein. LDL, chylomicrons, VLDL, IDL, LP level A, all of them have one ApoB molecule because in the body the overwhelming predominant atherogenic lipoprotein is LDL. For most people, your LDL level and your ApoB level are about the same if your triglycerides are normal. But if your triglycerides are high, your ApoB will be out of proportion high compared to your LDL. So it’s important to look at that.

Dr. Shreya Trivedi: Yeah, I also think I didn’t really appreciate that until we broke down the guidelines and worked on the episode. And then to solidify things a little bit more, we also sat down with Dr. Roger Blumenthal, a preventative cardiologist at Johns Hopkins and the chair of the 2026 ACC/AHA Lipid Guidelines Writing Committee.

Dr. Roger Blumenthal: I think that most people feel that the ApoB measurement is most helpful when the triglycerides are above average. And if you have someone whose triglycerides are 200 or above, then if you use the standard Friedewald equation, the LDL cholesterol may be falsely low.

Dr. Shreya Trivedi: And yes, for the cardiology levers out there, we will definitely link that equation in another equation in the show notes. But the idea and the premise is that the LDL values are actually calculated rather than directly measured. So as the triglycerides rise, that calculation becomes less accurate, and someone’s LDL may appear lower than a patient’s true atherogenic burden.

Dr. Harini Shah: And so when should we consider ApoB testing? Turns out it’s a two-way recommendation to check ApoB after you’ve used lipid-lowering therapy to achieve your target LDL and your triglycerides are still above 150. Those elevated triglycerides basically signal excess atherogenic risk that might not be captured otherwise. But then, Shreya, if you dig deeper, particularly in the management section on triglycerides in the guidelines, it does say that it’s reasonable to check an ApoB over LDL in patients with triglycerides above 150 milligrams per deciliter to help guide your decision-making.

Dr. Shreya Trivedi: Awesome. Awesome. Okay. So once we get that ApoB, what do we actually then do with that information?

Dr. Harini Shah: Yeah, sure. I went looking for a single universal ApoB cutoff, but I found that it really depends on whether you’re talking primary or secondary prevention. Briefly, though, for primary prevention, let’s say an ApoB is really high, like 120 mgs per deciliter or higher; that’s definitely considered a risk-enhancing factor that can support starting a statin.

Dr. Shreya Trivedi: Okay. So ApoB greater than 120 is like an LDL higher than 135, 140, so no bueno and another reason to lean on starting that statin.

Dr. Harini Shah: And so just like LDL, you can actually trend ApoB with lower targets as cardiovascular risk increases. So for the lower targets, even our lipid experts told us that they look up those cutoffs in practice, which was very validating because I had already opened the table approximately six times while writing this episode.

Dr. Shreya Trivedi: Yeah, fair, fair. Yeah, I can already think of so many patients who kind of had an LDL where that number didn’t actually match the one-liner of cardiovascular events they had. And I wonder if checking ApoB might’ve changed how I interpreted their residual cardiovascular risk.

Dr. Harini Shah: Oh, and by the way, if you can’t check an ApoB, the guidelines do say you can also check non – HDL cholesterol, which is already on your lipid panel normally and is a free alternative.

Dr. Shreya Trivedi: Ah, nice. Good to know. So if the triglycerides are elevated, we can look at an apoB as well as a non – HDL cholesterol to better characterize that cardiovascular risk. And yes, we will put in the show notes the what are equivalent LDL, apoB, and non – HDL targets.

Dr. Harini Shah: Yeah. And just to summarize, sometimes the LDL is giving us a decidingly flattering version of the story if the triglycerides are above 150. And in that case, as you said, Shreya, the ApoB or the non – HDL cholesterol can really tell us more about the overall atherogenic burden.

Dr. Shreya Trivedi: Yep. And we will get more into treating that ApoB and triglycerides in just a little bit.

Address waist circumference and lifestyle before meds for high TGs

Dr. Shreya Trivedi: Okay. Say we have a lipid panel and we’ve checked their ApoB, their non – HDL cholesterol. We kind of have a better sense of their cardiovascular risk. Those triglycerides are still like 200, 300s. Where should our mind go to next?

Dr. Harini Shah: My first instinct, Shreya, used to be to ask, okay, “What meds should I add now?” But interestingly, the new lipid guidelines really flipped that thinking for me.

Dr. Roger Blumenthal: I think we have a lot of innovative medications for high triglycerides, but it’s much better to control the triglycerides with better glycemic control and weight loss and better lifestyle habits.

Dr. Harini Shah: The guidelines focus on lifestyle targets, the typical things like promoting weight loss and increasing physical activity, but Dr. Blumenthal also brought up something that I did not realize was as prioritized in the triglyceride world.

Dr. Roger Blumenthal: I think the guidelines, again, emphasize the importance of going over a patient’s dietary and exercise habits, as well as getting a baseline measure of their visceral adiposity via low-tech waist circumference. And you’d be surprised how many people, if they come back six months, 12 months later on, they think they’ve been doing a good job, and they say, “Doc, let’s double-check the waist circumference measurement and let’s see if I’m really making some success.”

Dr. Shreya Trivedi: So fun fact, waist circumference performs comparably to actual measures of adiposity on imaging. So both the AHA and our recent lipid guidelines recommend actually measuring a waist circumference alongside a BMI for all your patient visits.

Dr. Roger Blumenthal: They also, again, emphasize that really at each visit we should take out a little tape measure, get to the top of the iliac crest and measure parallel to the floor. And so give people an idea that their body mass index may be within normal limits, but they have a protuberant abdomen. It means that they have an excess of visceral adiposity and they’re at higher risk. And a lot of people think, well, being overweight doesn’t really make that much difference. 

Dr. Harini Shah: This is a really good reminder that while BMI being normal could be reassuring, it’s unfortunately not a cardiometabolic hall pass. We could still be missing visceral adiposity.

Dr. Shreya Trivedi: Yes, yes. BMI is tricky indeed. And we asked Dr. Blumenthal if there is a waist circumference cutoff that he’s really trying to aim for, but his answer was simple. Less visceral adiposity, the better.

Dr. Harini Shah: And measuring waist circumference over time can be a practical way to track progress that BMI alone may miss.

Dr. Shreya Trivedi: Exactly. And then for those of you that like numbers like me, I did go searching, and the Obesity Society does use less than 40 inches for men and less than 35 inches for women. But I think what is honestly the more practicing thing for me is to just start measuring abdominal circumference, just trying to have a measuring tape on hand in the clinic, tracking waist circumference alongside the BMI over time, I think is going to be a big shift.

Dr. Harini Shah: Yeah. So to summarize, waist circumference is something to track over time to see whether visceral adiposity is improving. And the premise of that is visceral adiposity is increasingly recognized as an independent cardiovascular risk factor.

Dr. Watson’s 3-day carbohydrate responsiveness trial 

Dr. Shreya Trivedi: Okay. I thought this one was fascinating because I think so many of us and our patients kind of immediately blame triglycerides on dietary fat. But most people, it’s more about the excess refined carbs or the underlying insulin resistance that are bigger drivers of that elevated triglyceride.

Dr. Harini Shah: And there’s so many ways to approach dietary counseling, but we wanted to highlight one strategy from Dr. Watson’s lipid clinic because it’s so simple, practical, and really gives patients that rapid feedback.

Dr. Karol Watson: The first way of managing it for everyone will be lifestyle. Everyone. For every single high triglyceride referral we get to our lipid clinic, everyone gets a three-day lifestyle trial to see if they’re diet responsive.

Dr. Shreya Trivedi: Wow. Three days? I think a lot of us fall in the pattern saying, “Okay, work on your diet. We’ll check your lipids in three months or so.” This is so interesting. And I will have to say what Dr. Watson and some other lipidologists around the country do isn’t in the guidelines, but we just found it so thought-provoking in managing elevated triglycerides that we just wanted to learn more.

Dr. Karol Watson: The three-day trial we give is an extreme carbohydrate-reduced trial, and I’m talking less than a hundred grams a day, which is really restrictive. And again, it’s not because we expect them to stay on less than a hundred grams per day forever; it’s because we want to see if they’re diet-responsive.

Dr. Harini Shah: Finally, a lifestyle intervention designed for my attention span.

Dr. Shreya Trivedi: Oh yeah. And a lot of people, right? It’s hard to sustain things over three months.

Dr. Harini Shah: Yeah, I love this. And just to say it out loud, during those three days, patients are also asked to abstain from alcohol.

Dr. Shreya Trivedi: Right. And again, I think most people assume triglycerides are more driven by too much fat, but here we’re really focusing on carb restriction, less than a hundred grams a day.

Dr. Karol Watson: We want to see that there is a significant reduction in triglycerides with this, and it’s going to vary depending on how much insulin resistance an individual has, but some people can get a 50% or more reduction. And let’s think about it. Triglycerides: it’s one glycerol attached to three fatty acids. Glycerol is derived from glucose. If you starve the body of the substrate, you literally can’t make it if that is the basis for your hypertriglyceridemia. There are some people who don’t have that as a basis. They have as a basis a true lipid disorder, like inability to make lipoprotein lipase or something else, and then that won’t work. But for most people, the overwhelming majority, high triglycerides are carbohydrate-driven.

Dr. Harini Shah: Oh, how I love when biochem becomes unexpectedly useful.

Dr. Shreya Trivedi: Glycerol molecules. 

Dr. Harini Shah: Yeah. But even more, I love the idea of a three-day trial that gives both the patient and the clinician feedback right away.

Dr. Shreya Trivedi: Yes. And we did go back and ask Dr. Watson, what does an adequate response entail? She said she’s happy with over 20% reduction in serum triglycerides with the carb control, but often she sees greater than 50% reduction with a three-day carb-responsive trial. And if the triglycerides are not responsive to carb control, then it should prompt us to think about another underlying cause, right? Is there a genetic disorder? Is there a primary lipid disorder driving this?

Dr. Harini Shah: Is it, for example, hypothyroidism where you’re not clearing triglycerides as efficiently, or maybe it’s kidney disease like nephrotic syndrome or CKD, which can impair chylomicron clearance? Or is it insulinopenic diabetes, maybe like type one or super late-stage type two where you have no intrinsic insulin production and so you lose that insulin’s activation of lipoprotein lipase. And then lastly, could it just be Cushing’s or exogenous steroids?

Dr. Shreya Trivedi: Yeah, steroids are so common and given for too many COPD exacerbations. Well, no, they need it. I’ll take that back. Yes. Yes. Steroid packs here and there are very common, so definitely good to do that medication review. And there’s a bunch of other secondary causes from the medication perspective too, right?

Dr. Harini Shah: Yeah. I just wanted to bring up a couple high-yield points here from my personal practice. I have noticed that atypical antipsychotics, particularly olanzapine or clozapine, can raise triglycerides pretty quickly after you start them. And what I found is that switching to a more metabolically friendly agent that’s not olanzapine or clozapine, and of course working alongside a psychiatrist in the meantime, can definitely bring them down dramatically. And then there’s also evidence for starting metformin alongside that atypical antipsychotic to blunt some of those triglyceride-raising effects. I actually know some psychiatrists who do this upfront, in fact. I just had a patient last week who was on oral estrogen. We saw a pretty high in the 200s of triglycerides, and we switched to transdermal estrogen. We were able to bring that triglycerides down to mid 100s. Yeah, it was amazing. Such a quick fix, but it really changed the risk profile for that person.

Dr. Shreya Trivedi: Nice. Look at you doing awesome cardiovascular prevention. I think my takeaway from this section is just this overall idea of carb responsiveness, and it’s so awesome if you’re in a system where you’re able to do a rapid three-day carb control trial that generates information, not just lowering the triglycerides, and especially if your patient has more than a 20% reduction in their triglyceride, that points more to a diet-driven disease, but then a lack of response should prompt some careful searching of secondary causes, will have more comprehensive listener show notes, medications, or is this a primary lipid disorder? 

Order a fasting or nonfasting lipid panel?

Dr. Shreya Trivedi: Okay, so we talked a lot about what patients eat. So I think another very practical question is, should we be checking triglycerides fasting or not fasting?

Dr. Karol Watson: People are so focused on this fasting lipid panel, I have to have it to make sure my LDL’s accurate. Nothing really changes much with fasting except triglycerides. Your triglycerides will tell you exactly what you ate in the last 12 hours, and that’s why the new guidelines say obtain a lipid panel, fasting or non-fasting, because the one thing that will change is triglycerides.

Dr. Harini Shah: Yeah, so for most patients, a non-fasting lipid panel is totally fine and arguably could give us a snapshot of what their body’s exposed to for most of the day.

Dr. Karol Watson: I actually want to see what your body sees, and let’s be frank, we’re fasting for a seven-hour period while we’re sleeping the rest of the day. We’re kind of eating all day.

Dr. Harini Shah: But the guidelines do spell out a few times when fasting is preferred, for example, a family history of premature ASCVD, which is defined as a first-degree male relative with an event before 55 or a female before 65, and then also in suspected genetic or triglyceride metabolism disorders. And then finally, if your non-fasting triglyceride comes back at 400 or higher, generally, the guidelines recommend repeating a fasted lipid panel at that point because it would change our management.

Dr. Shreya Trivedi: Yeah, definitely. I think a triglyceride over 400 is a little too high for my comfort. Then the last practical point about fasting versus non-fasting is that when you are trending triglycerides, try to compare apples to apples. So if your patient’s last triglyceride was fasting, ideally compare it to another fasting one.

When do you reach for TG-lowering medications? 

Dr. Shreya Trivedi All right, so we talked about risk assessment, lifestyle, fasting, non-fasting. The next natural question is: when are we reaching for medications, and which medications should we reach for?

Dr. Harini Shah: So the updated guidelines clearly tell us the answer. For primary prevention among adults 40 to 75 without ASCVD or diabetes, but who have persistent triglycerides between 150 and 499, rather than starting a medication, the first step is actually calculating a PREVENT score.

Dr. Shreya Trivedi: What? I was not expecting that answer, but that makes a lot of sense. Okay. So PREVENT, I think, as we all kind of know now, helps us risk stratify patients from low risk, borderline, intermediate to high risk. But Harini, I can’t help but wonder if triglycerides are so important, how come they’re not in the actual PREVENT score?

Dr. Harini Shah: Great question, Shreya. Much of the risk associated with triglycerides is already reflected in non – HDL and HDL cholesterol, which PREVENT does include. However, persistent triglyceride elevation can still help with the treatment discussion. Let’s say our patient score comes back borderline, which is three to under 5%. In that case, an elevated triglyceride level would be considered a risk enhancer and provide another reason to consider a statin for that person.

Dr. Shreya Trivedi: Yeah. Awesome. And I think that highlights another real shift for me: when we are thinking about medication for triglycerides, we’re still first reaching for a statin.

Dr. Karol Watson: Statin therapy is to treat elevated cardiovascular risk. So whatever your risk is driven by, if it’s elevated, a statin is indicated. This is not just a cholesterol-lowering drug; this is a risk-reducing agent, the best risk-reducing agent we have.

Dr. Harini Shah: So for a person with elevated triglycerides, it’s not about lowering the number or reaching for fibrates or a fish oil. Instead, the guidelines tell us we should optimize someone’s risk first by intensifying their LDL-lowering treatment.

Dr. Karol Watson: The first thing is important to point out is that LDL is still the primary target of therapy. LDL, don’t forget about that.

Dr. Shreya Trivedi: Yeah, I think for me, the guidelines really clarify the order of operations because for example, based on the guidelines, if someone’s already on a max statin and has residual risk and has an elevated triglyceride, the answer is not to go to a triglyceride-specific medication. The answer is go to ezetimibe or go to a PCSK9 inhibitor. And here I thought omega-3 fish oil might be the next step, particularly the one that’s been studied the most, icosapent ethyl, but that is incorrect.

Dr. Harini Shah: Speaking of omega-3, AKA icosapent ethyl, or some call EPA for short, yeah, the recommendation is way more selective than I expected. Icosapent-ethyl landed at a class 2B recommendation, meaning, “It may be reasonable in certain patients.” Most relevant is if your patient is 50 or older, has known ASCVD or diabetes with another risk factor, already on a max statin with an LDL at  goal, but those darn triglycerides keep being over 150.

Dr. Shreya Trivedi: Yeah, just to quickly zoom in on EPA and omega-3s a little bit more, there was this REDUCE-IT trial, which I think is a great one to do for a journal club because the headline is that there was an impressive cardiovascular benefit, but the placebo was mineral oil-based, and so that was a little bit controversial because it did worsen some of the lipid inflammatory markers in the placebo group. And then on top of that, even there was some concern about higher rates of AFib and bleeding, and so putting all that uncertainty together, I think the guideline authors landed on a “maybe reasonable” rather than a stronger recommendation, but I’m sure there’s future trials coming that’ll help us understand what’s best for our patients.

Dr. Harini Shah: And just to clarify, the guidelines do specifically recommend prescription purified EPA or icosapent ethyl, not over-the-counter fish oil.

Dr. Karol Watson: And if you look at a lot of the over-the-counter fish oils, most of them are not more than 30 to 50% true fish oil, and the remainder is actually crazy stuff like saturated fats. The only the really expensive bougie fish oil capsules use things like olive oil, everybody else uses regular old kind of allergenic oils and that we don’t like.

Dr. Shreya Trivedi: It is very eye-opening that some of the over-counter oils contain the exact thing we’re trying to avoid for our patients, and then it’s also no surprise that the guidelines very explicitly recommend against using any dietary supplements. So yeah, definitely worth asking our patients, “Hey, what supplements are you taking? What natural remedies are you taking?”

Dr. Harini Shah: So Shreya, what happens once triglycerides climb above 500? It sounds like at this point, the goal shifts pretty dramatically here. We’re no longer just thinking about ASCVD risk. We’re also trying to prevent pancreatitis.

Dr. Karol Watson: Fibrates are not for cardiovascular risk reduction. That’s really important to point out, but in people at real risk for pancreatitis, they’re the agents we go to. The problem is the fibrate-statin combination can be more dangerous for rhabdomyolysis, and all of these patients are at high cardiovascular risk, so we don’t want to forego the statin, so we have to be very careful. And it’s Fenofibrate rather than gemfibrozil, which is the preferred fibrate in that case

Dr. Shreya Trivedi: Okay, so here, what I’m going to remember, if the triglycerides are between 150 to 499, I’m thinking ASCVD risk first, right? Optimize, look at the PREVENTS score, optimize LDL-lowering therapy with the statin, reverse something like icosapent ethyl for more selected high-risk patients, and once the triglycerides are over 500, particularly above 1,000, then the priority really shifts towards pancreatitis prevention. That’s why we reach for things like fibrates, particularly fenofibrate, to minimize any interactions with statins, and prescription omega-3 therapies become much more important.

Don’t miss familial chylomicronemia syndrome (FCS)

Dr. Harini Shah: Our last section features someone whose story really brought to life our last few updates in the guidelines.

Aaron Bowman: And I’ve always known that something is wrong. There’s never been a time in my life where I didn’t feel some type of stomach discomfort, and that goes back to my earliest memories. And for years, I would be lower energy, stomach problems, and brain fog. School was quite hard for me because grasping and retaining information, and now we know that is what they call brain fog. I just remember all through school, I wouldn’t participate in sports. If I could get out of PE, I would. If I could take easier classes, I would, because my stomach hurt all the time, my joints hurt, and I couldn’t retain information. I was nauseous all the time. On my best days, I would have a mid-grade flu all day, and that was my best days. So imagine being born and trying to get through life, having the flu every single day. It was rough, and also the embarrassment of having to go to the bathroom three or four times a day at school, right? The teachers were like, “What’s going on? You’re always going to the bathroom.” Well, it’s like I have diarrhea all the time, and that’s just part of this disorder.

Dr. Harini Shah:  That was Aaron Bowman, who lives with familial chylomicronemia syndrome, or FCS, which is what we’ll call it. That’s a rare genetic disorder that causes lifelong, often profound hypertriglyceridemia.

Aaron Bowman: Hi, I’m Aaron Bowman, an FCS patient and an overall good human being. Every single doctor said a couple things to me, “Eat better, exercise more.” Okay? The symptoms would persist or get worse, a lot worse, and I would go to a new doctor, and they’d be like, “Eat better, exercise more.”

Dr. Shreya Trivedi: Yeah. And before his diagnosis was made, he spent years seeing doctor after doctor searching for an explanation, and I was really struck to hear not about how rare FCS is, but more so in his story, how easy it was to be dismissed.

Aaron Bowman: If any of those doctors said, “Oh man, we’re finding a surprisingly high amount of fat in your blood,” well, let’s go through this logically. It’s that you don’t drink, right? What do you eat every day? Okay. A couple doctors got to that point with me, not the fat in the blood, but they’re just like, “I want you to tell me what you had to eat yesterday.” And I would give them a rundown, and they’d just look at me, usually like I was lying. I can read people pretty good, and I’m like, “You think I’m lying?” When I said, “I don’t drink,” and you’d have doctors turn and be like, “Uh-huh.” And you’re like, “Okay, dude, I don’t drink.”

Dr. Harini Shah: What I took away from our conversation with Erin was the importance of believing our patients when the history doesn’t fit the numbers. If someone gives you a careful dietary history, insists that they don’t drink alcohol, and their triglycerides are persistently hundreds or thousands, that disconnect is itself a clue that there may be an underlying genetic disorder going on.

Dr. Shreya Trivedi: Yeah, so I guess when we do suspect FCS, what should we be doing reaching for?

Dr. Roger Blumenthal: Olezarsen was specifically mentioned in our guideline, and then plozasiran was subsequently approved in this country, and I think both are going to get much more use in the coming years because there are quite a number of patients with this severe hypertriglyceridemia. We usually think about familial chylomicronemia being triglycerides that are persistently 800 or higher, but there are studies going on with both plozasiran and olezarsen looking at individuals whose triglycerides are 500 or higher. So those are things that are typically, if you have a patient where they’re having those persistently high triglycerides, probably a smart idea to send them to a lipid specialist.

Dr. Shreya Trivedi: And as of June 2026, the indication of olezarsin was expanded to adults with severe hypertriglyceridemia to reduce triglycerides and the risk of acute pancreatitis.

Dr. Harini Shah: So to summarize, if triglycerides stay severely elevated, especially around 800 or higher, or if there’s recurrent pancreatitis or a clinical picture that just doesn’t fit the lifestyle story, would refer to a lipid specialist and consider genetic testing at that point.

Dr. Shreya Trivedi: Definitely. And interestingly, when we asked Dr. Watson about genetic testing, she said that it’s actually not something that she does regularly for patients she suspects FCS on.

Dr. Karol Watson: So we rarely do genetic testing in our lipid clinic, and I can tell you most clinicians don’t either. There’s a really characteristic pattern in patients with familial chylomicronemia syndrome. It’s not subtle. And you can often see it. We see this really commonly, especially young women can be fine their whole life, then they have their first period and that surgeon estrogen, they suddenly get recurrent pancreatitis, and we see it.

Dr. Harini Shah: I thought that was a really helpful perspective. Genetic tests are good, but they definitely aren’t perfect and can miss people with atypical presentation. So sounds like a lot of lipidologists really just look at the clinical picture and then treat as FCS if the history fits.

Dr. Shreya Trivedi: Awesome. Yes. And so before we wrap up, why don’t we do some rapid-fire takeaways?

Dr. Harini Shah: If triglycerides are 150 to 499, don’t treat the number; treat the risk. We calculate PREVENT, look for secondary causes, and then optimize LDL-lowering therapy first.

Dr. Shreya Trivedi: And then if triglycerides are elevated and the LDL looks reassuring and you’re still worried about some residual risk, think about ApoB or a non – HDLC.

Dr. Harini Shah: Spend more time counseling on refined carbohydrates, alcohol, and then don’t forget measuring the waist circumference. Also, remember Dr. Watson’s three-day carb control trial, which can quickly target carb-responsive hypertriglyceridemia.

Dr. Shreya Trivedi: And then non-fasting lipid panels are generally appropriate for most patients unless the triglycerides are markedly elevated, you suspect genetic lipid disorder, or the fasting result would change management. And then of course, just make sure we’re comparing apples to apples when you’re trending the triglyceride levels.

Dr. Harini Shah: And then finally, if the triglycerides are 500 or higher, that’s when we start thinking about pancreatitis. If especially there’s recurrent pancreatitis or a history that does not fit the elevated triglycerides, we think of FCS and then consider referring to a lipid specialist.

Dr. Shreya Trivedi: Great. Awesome. And with that, a huge thank you to Dr. karol Watson, Dr. Roger Blumenthal, and Aaron Bowman for sharing their expertise and their experience with us. Thank you to Dr. Nabil Sweis for the graphic. We’ll link the 2026 ACC AHA lipid guidelines and additional resources in our show notes. Thank you so much for listening, and we’ll see you next time on Core IM. Take care.  

References

• Core IM Podcast. The Lipid Panel Reimagined: Mind the Gap Segment. December 2022.
• Klein S, Allison DB, Heymsfield SB, et al. Waist circumference and cardiometabolic risk: a consensus statement from Shaping America’s Health: Association for Weight Management and Obesity Prevention; NAASO, The Obesity Society; the American Society for Nutrition; and the American Diabetes Association. Am J Clin Nutr. 2007;85(5):1197-1202.
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• Khan MS, Chandani DK, Siddiqui E, Khalid M, Waafira A. Olezarsen: FDA approval and clinical impact in familial chylomicronemia syndrome (FCS). Ann Med Surg (Lond). 2025;87(11):7846-7850. Published 2025 Sep 4.
• AJMC. FDA Approves Plozasiran to Reduce Triglycerides in Familial Chylomicronemia Syndrome. November 2025.