Thread by @cardiomet_CE

Join us tomorrow for the launch of a new #accredited #tweetorial on the primary care management of #hyperlipidemia covering the relationship between #LDL_C & major #CV events, CV risk categories, recommended LDL-C treatment goals, & oral therapeutic options for lipid-lowering

1) Welcome to a new #tweetorial on the primary care management of #hyperlipidemia. Our returning @cardiomet_CE expert author is dedicated #SoMe education advocate Kevin Fernando, FRCGP FRCP Edin, FAcadMEd MSc Diabetes @drkevinfernando

2a) This is the next instalment of @cardiomet_CE's 10-part #tweetorial foundational series on #lipid management! It is accredited for #CME/CE and intended for #physicians #physicianassociates #nurses #nursepractitioners #pharmacists.
#FOAMed @MedTweetorials #cardiotwitter

2b) This series is supported by an educational grant from Esperion Therapeutics. See Accreditation Statement & faculty disclosures at cardiometabolic-ce.com/disclosures/.

3) Let’s start with a poll exploring the impact of intensive lowering of #LDL_C levels with statin therapy and the risk of major cardiovascular (#CV) events.
For every 1mmol/L reduction in LDL-C, there is an annual reduction in coronary death of:

4) It's D--2⃣0⃣ % !! Do you give #LDL_C enough respect?

Figure from 🔓pubmed.ncbi.nlm.nih.gov/21067804/

5) #Cholesterol has many key functions in the human body; it is an essential component of cell membranes and is required to produce steroid-based hormones such as #testosterone & #VitaminD

6) #LDL_C is the primary transport molecule for cholesterol in the blood and excess levels of LDL-C are a proven direct cause of atherosclerotic cardiovascular disease (#ASCVD). Moreover, overall #mortality risk ☠️increases with LDL-C level

7) There is a clear & established relationship between LDL-C and the risk of major CV events. Regardless of how it is achieved, lower LDL-C levels correlate with a lower CV risk!
See 🔓pubmed.ncbi.nlm.nih.gov/29020411/

8) An expanding evidence base has driven down recommended #target LDL-C levels over the last 20 years, particularly for our very high-risk patients

So, which of our patients are at very high risk of CVD? Here are the @escardio / #EAS CV risk categories:

9) Perhaps we are underestimating the #CV risk of some of our patients in #primarycare?

10a) Let’s pause for a case study. You see a 66-year-old functionally independent ♀️ living with #T2D & #CKD. Recent #eGFR is 55ml/min, urinary #ACR is 22mg/mmol. #BP is well controlled (122/74mmHg) and HbA1c is satisfactory (53mmol/mol (7%)).

10b) Lipid profile reveals an #LDL_C of 3.0mmol/L (116mg/dL). She is on #atorvastatin 40mg (in addition to several other medications) which she assures us she is taking regularly

Poll – what is your target LDL-C for this patient?

11) Did you answer D? Remember--how LOW can you GO?? As outlined above, this patient is at very high risk of CVD due to her #T2D with target organ damage (clinically significant #microalbuminuria)

12) Updated 2019 ESC/EAS guidelines for the management of #dyslipidaemias now recommend a #LDL_C goal for very-high risk individuals of <1.4mmol/L (55mg/dL) and a >50% reduction from baseline LDL-C level

13) Furthermore, for individuals with #ASCVD suffering a 2nd vascular event within 2y whilst taking maximally tolerated statin & ezetimibe therapy, an #LDL_C goal of <1.0mmol/L (<40mg/dL) is now recommended!
🔓pubmed.ncbi.nlm.nih.gov/27567407/
🔓pubmed.ncbi.nlm.nih.gov/31504418/

14) As you can see, we are now in an era of much lower #LDL_C goals.
Unsurprisingly, around 80% of individuals living with #ASCVD on moderate-high intensity #statins failed to achieve their LDL-C goal of <1.8mmol/L
🔓pubmed.ncbi.nlm.nih.gov/29273856/

15a) This treatment gap was further explored in the #DA_VINCI study, led by @cardiomet_CE author @ProfKausikRay (🔓pubmed.ncbi.nlm.nih.gov/33580789/), finding that a mismatch persists between clinical guidelines & clinical lipid management across Europe.

15b) The authors concluded that even those on optimised doses of #statins will require additional non-statin lipid-lowering therapies #LLT to achieve these tighter LDL-C goals

16a) We are well accustomed in #primarycare to using combination therapy for #diabetes & #hypertension. Now this is the direction of travel for lipid management too. Statins alone are unlikely to achieve these tighter LDL-C goals!

16b) So, how are we going to get our 70♀️ down to her #LDL_C target of <1.4mmol/L?
Let’s have another poll. What would you do next for her lipid-lowering regimen?
a. Double her atorvastatin to 80mg
b. Switch to rosuvastatin 20mg
c. Add ezetimibe 10mg
d. Add bempedoic acid 180mg

17) Ponder that, mark your best response, and RETURN TOMORROW for guidance on this vexing clinical question, more education, and your🆓CE/#CME credit!
👏@GoggleDocs @PaulDThompsonMD @cpcannon #MedTwitter @WilmotEmma @Amandaepps123 @kamleshkhunti @hvanspall @DrMarthaGulati

18) WELCOME BACK! I am @drkevinfernando & we are talking about management of #hyperlipidemia in #primarycarewhilst YOU earn 🆓0.5h CE/#CME!
We left you with a quiz (16b). There may be more than 1⃣ tx approach in this setting, but data ➡️ C--add ezetimibe. Let's explore this.

19a) For those of you who chose to double her #atorvastatin dose, are you aware of the “rule of 6” with #statins? The dose required to reduce #LDL_C levels to a similar degree varies substantially among different statins
The response to dose increases is also not proportional

19b) As a rule of thumb, doubling the dose of statin above the minimal effective dose, further reduces #LDL_C levels by just an additional 6⃣%
The maximal reduction in LDL-C levels seen with statin treatment ranges from 24–60%.

20) So, what about the value of adding #ezetimibe then for further #LDL_C reduction?

In 🇬🇧 #NICE has recommended the use of ezetimibe since 2007.

21) In the #IMPROVE_IT CV outcomes study, led by @cardiomet_CE author @cpcannon (🔓pubmed.ncbi.nlm.nih.gov/26039521/), #ezetimibe ⬇️ LDL-C by a further 24% when added to #statins ➡️absolute risk ⬇️ of 2% in the primary composite endpoint of #CV mortality, major CV event or non-fatal stroke

22) Number-needed-to-treat (#NNT) over 6 years to prevent 1 primary outcome was 50. Benefits were particularly apparent in older individuals over 75 years and those living with #T2D in pre-specified subgroup analyses. Learn more and earn more 🆓at cardiometabolic-ce.com/lipids5/

23) I appreciate this is only a modest treatment benefit given the large sample size (circa 18k participants) and long follow-up period (6 years), but #ezetimibe does do exactly what it says on the tin and significantly ⬇️#LDL_C levels

24a) As an aside, do not forget about secondary causes of #hyperlipidaemia in new or established individuals found to have hyperlipidaemia.
Key secondary causes of hyperlipidaemia should be excluded prior to treatment with any lipid-lowering therapy

24b) These include:

🫀 Type 2 diabetes #T2D
🫀 Chronic kidney disease #CKD
🫀 #Hypothyroidism
🫀 Medications including steroids, betablockers, diuretics, antipsychotics & retinoids
🫀 Obesity
🫀 Excessive alcohol consumption 🍸

25) Returning to our case study and the poll in 16b ⤴️, what on earth is #bempedoic_acid?!
Oh my, perhaps you missed @PaulDThompsonMD 's epic tweetorial in this series, still available for credit at cardiometabolic-ce.com/lipids3/ ? Either way, we're covering it here too!

26) #Bempedoic_acid is a new lipid-lowering option in our primary care toolbox to reduce #LDL_C levels.

Bempedoic acid lowers LDL-C by inhibiting cholesterol synthesis in the liver but via inhibition of a different enzyme to that of statins.

27) Bempedoic acid is a pro-drug that is activated in the liver so there are no active metabolites found in skeletal muscle 💪. Therefore, one of the 🔑advantages of bempedoic acid is that it is not associated with the muscle symptoms commonly encountered with #statins

28a) So, does bempedoic acid do exactly what it says on the tin?

#Bempedoic_acid has been extensively studied in the phase 3 #CLEAR trial programme which explored its efficacy at lowering #LDL_C as well as its safety profile

28b) Bempedoic acid ⬇️ LDL-C levels by 17-28% from baseline after 12 weeks (compared to placebo), depending on risk factors & concomitant medication. See
🔓pubmed.ncbi.nlm.nih.gov/31714986/
🔓pubmed.ncbi.nlm.nih.gov/30865796/
🔓pubmed.ncbi.nlm.nih.gov/30922146/
🔓pubmed.ncbi.nlm.nih.gov/29910030/

28c) A combination of bempedoic acid and ezetimibe resulted in a 38% reduction in LDL-C from baseline at 12 weeks (on top of maximally tolerated statin (35% were not on a statin)).
See 🔓pubmed.ncbi.nlm.nih.gov/31357887/

What about clinical outcomes?

29) There are no published CV outcomes for bempedoic acid, but the #CLEAR_Outcomes #CVOT is underway and due to report by the end of this year. One could postulate that this study will achieve a positive result given the levels of #LDL ⬇️ seen with #bempedoic_acid.

30) With regards to safety, most adverse effects with bempedoic acid were mild or moderate in intensity. The most commonly reported adverse effects were hyperuricaemia (#gout in 1.4% of patients on bempedoic acid vs 0.4% treated with placebo), pain in extremities, & anaemia.

31) It would seem prudent to use bempedoic acid with caution in those with a history of gout however I do not routinely check serum urate prior to starting bempedoic acid in those without a history of gout

So, what would I do for our patient? (Back to that poll in tweet 16b!)

32) I would add in #ezetimibe 10mg and recheck #LDL_C levels after 2-3 months. If still above target, I would add in #bempedoic_acid 180mg (it is available as a combination product with ezetimibe which can help reduce pill burden)

33a) So . . . some key take-home messages to conclude:
🔑There is irrefutable evidence that lower #LDL_C levels correlate w/ lower #CV risk
🗝️We are in an era of tighter LDL-C goals for our higher risk patients: <2.6mmol/L (100mg/dL) even for our moderate CV risk patients
(cont)

33b)
🔑To achieve these tighter targets, we need to use combination #LLT rather than statins alone
🗝️Consider using more ezetimibe (this has been a big change in practice for me over the past year) – it does exactly what is says on the tin & significantly ⬇️LDL-C levels
(cont)

33c)
🔑#Bempedoic_acid is a new oral lipid-lowering therapy which appears more efficacious at lowering LDL-C than ezetimbe and does so in a mostly favourable manner. It is also not associated with the 💪side-effects that seem to plague #statins

34) And that's it! You just earned 0.5h 🆓CE/#CME 🇺🇸🇬🇧🇨🇦🇪🇺! Go claim your certificate at cardiometabolic-ce.com/lipids7/ and FOLLOW US here at @cardiomet_CE for more expert-led #accredited education! I am @drkevinfernando. Thanks for joining us!
#FOAMed #Cardiotwitter #MedTwitter