Night and Day… join us for part II of our exploration into why we prescribe medications in the morning vs. at night, featuring statins!

Time Stamps

• 03:28 How do statins and cholesterol synthesis work again, anyway?
• 04:00 Power in numbers – what do the meta-analyses say about timing of statins?
• 04:40 The long and short of it – how half-life may dictate when to take your statin.
• 07:35 Effect magnitude – does medication timing actually really impact patient outcomes?
• 10:30 Practical matters – so what should we tell patients?
• 11:05 Review of teaching points

Show Notes

1. Back to blood pressure, remember that patients whose blood pressure does NOT dip at night may be at higher risk of cardiovascular mortality.
2. But how do we identify who those patients are? Most insurance doesn’t cover home blood pressure monitoring for this purpose. We extrapolate which patients are most likely to be non-dippers, such as those with coronary artery disease or diabetes, or those with elevated morning blood pressures.
3. For those higher risk patients, consider changing their beta-blockers and ACEs or ARBs to night-time dosing. Don’t change their diuretics to night-time though; that’s just cruel!
4. On to statins: they work by blocking HMG coA reductase, part of the cholesterol synthesis pathway that is more active at night.
5. But even if production spikes at night, lipid levels don’t actually vary that much during the day.
6. A Cochrane Review from 2016 demonstrated that LDL levels did not improve more in patients who took statins at night vs. day-time.
7. However, a 2017 meta-analysis in the Journal of Clinical Lipidology contradicts this, showing that with short-acting statins in particular, taking them at night leads to a greater drop in LDL.
8. Short acting statins include pravastatin, simvastatin, lovastatin, and fluvastatin with half-lives of 2-5 hours. Long-acting statins include rosuvastatin and atorvastatin with half-lives of 14-19 hours..
9. The effect in the 2017 meta-analysis was unimpressive; day-time dosing of short-acting statins improved LDL by 10 points more only.
10. LDL has been directly correlated with cardiovascular risk, and the latest AHA/ACC guidelines take LDL levels into account, but this is not a very impressive improvement.
11. Also, the direct connection between statin timing, LDL reductions, and cardiovascular mortality is still theoretical; no studies have directly linked statin timing to actual cardiovascular patient outcomes. 
12. Another important consideration: taking medications at night may be associated with lower adherence. Talk to your patients about what is realistic for them!
13. Finally, most patients are now on long-acting statins, where timing does not seem to matter.

Transcript

J: Last time we talked about why it might be better to take blood pressure meds at night. But one thing some listeners noted was that we didn’t really address which medications to switch.

S: Sure. But actually I was kinda hoping you guys wouldn’t notice because I wasn’t really sure, but good on you anyways.

J: So we were chatting with our reviewer Dr Matthew Sparks S: And he had some interesting personal anecdotes to share.  

J: For starters, he brought us back to reality. 

S: Yeah, while the research studies we referenced used ambulatory blood pressure monitors to diagnose blood pressure dips or non-dips at night, nobody does that in the real world.

J: Yeah, some of that has to do with insurance. It turns out , most insurances don’t cover ambulatory BP monitoring unless you’re trying to diagnose white coat hypertension.  

S: Oof  that’s a pretty good gamble on their part. I’m not sure my ego could handle prescribing a test just to see if my patients are secretly afraid of me… 

J: Well Steve, they probably are. But, it’s not really all about you…But in all seriousness, we asked Dr. Sparks what he does in real life, because he can’t just pretend that all patients have white coat HTN to get them ambulatory BP cuffs:

S: That would be insurance fraud.  

J: Exactly… I think. So because it’s too hard to get the blood pressure testing, he thinks about which pts are more likely to be non-dippers or even reverse dippers at night, which as we mentioned correlates with higher cardiovascular mortality.   S And to review from our last episode. They’re typically patients with CAD or diabetes, or even people with elevated BPs only in the morning.  

J: And for those patients specifically, he’ll consider switching their beta-blockers, ACE inhibitors, or ARBs to night-time dosing.   S But  he keeps diuretics as daytime meds, because making people pee all night isn’t very nice.   

J: So thanks, podcast listeners, for the feedback, – we hope that answers some of your questions!   S So let’s move on to today’s episode.  

J: Statins. (angel noise)  

S: Oooohh. So exciting.  

J: Today we’re going to explore: why we should take statins at night, or should we?  

S: And to do that we’ll review #1, the physiology of cholesterol synthesis  

J: We’ll spend some time talking about #2, what data supports giving statins at night.  

S: #3 we’ll discuss does any of that really matter?  

J: Lastly we’ll share some additional thoughts about nighttime dosing of medications in general.  

S:  So tuck yourselves in as we try to put this debate on statins to bed.  

J: And dive a little deeper into the dream.  

S:  Courtesy of Mr Sandman    

🎵INTRO MUSIC 🎵   

J: Hi I’m Janine Knudsen

S: And I’m Steve Liu

J: Welcome to Mind the Gap

S: A CoreIM podcast

J: We’d like to thank Dr. Michael Tanner, Internist at Bellevue Hospital, Associate Professor at NYU, and muralist extraordinaire, for peer-reviewing this episode.

S: Subscribe for our show notes at CoreIMPodcast.com

J: And follow us on insta and twitter.

S: The crux of our discussion today is a little simpler than that whole dipping and non-dipping thing we talked about with hypertension.

J: It’s thought that our bodies rev up cholesterol production at night between midnight and 6AM

Wright DFB, Pavan Kumar VV, Al-Sallami HS, Duffull SB. “The influence of dosing time, variable compliance and circadian low-density lipoprotein production on the effect of simvastatin: simulations from a pharmacokinetic-pharmacodynamic model.” Basic Clin Pharmacol Toxicol. 2011; 109 (6):494-498.

Jones PJ, Schoeller DA. “Evidence for diurnal periodicity in human cholesterol synthesis. J Lipid Res 1990;31 667-673.

S: And that’s because that’s when HMG CoA reductase – The rate limiting step of cholesterol synthesis – Is most active.

J: So just as a reminder, statins block the HMG CoA reductase enzyme 

S: Meaning that if we take a statin at night, its  maximum drug concentration/effect will happen at the same time as maximum cholesterol synthesis.

J: And voila – lower cholesterol levels.

S: Or at least so we think.

J: But some of you clever listeners are probably wondering, that sounds nice but does it really matter? Your body still make some cholesterol during the day, right? 

S: The short answer is yes, we think it might matter.

J: And the long answer?

S: Well that’s complicated…

J: So let’s explain the short answer first.

S: To do that we’ll take a look at some meta-analyses.

J: So in 2016, the guys and gals at Cochrane tried to answer whether taking statins at night was better. They performed a meta-analysis of 7 studies looking at a total of 767 people.  

Izquierdo-Palomares et al. Chronotherapy versus conventional statins therapy for the treatment of hyperlipidaemia. Cochrane Database of Systematic Reviews 2016, Issue 11. Art. No.: CD009462

S: They concluded that there were no difference in total cholesterol, LDL, HDL, or triglyceride levels  when statins were taken at night instead the day.

J: And they were pretty blunt about it, saying quote “Taking statins in the evening does not have an effect on the improvement of lipid levels with respect to morning administration.”

S: And they conclude that there isn’t overwhelming data in either direction and the data that does exist, well it kinda sucks.

 J: And so then what’s the long answer? That seem pretty convincing to me… We just talked about a meta-analysis

S: Well the main reason for not putting this to rest is that not all statins are created equal. And not all meta-analyses are equal. We found another one that actually disagreed with the Cochrane report.

J: Take a look at (gather round) this 2017 meta-analysis from the Journal of Clinical Lipidology.

Awad et al; Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group. Effects of morning vs evening statin administration on lipid profile: A systematic review and meta-analysis. J Clin Lipidol. 2017 Jul – Aug;11(4):972-985.e9.

S: And here they argued that the data favored taking statins at night. They noted that there may be a decrease in total cholesterol and that this was driven by a statistically significant decrease in LDL.

J: So wait, why did they get different results from the Cochrane report?

S: Because they’re a bunch of liars…

J: Ummmm

S: I kid, I kid – Well, for one they actually differentiated between short half-life and long half-life statins.

J: Ah, I see. So statins with shorter half-lives should have more of a peak right after you take them, right? So in taking them at night, you’d really be timing that peak with your body’s spike in cholesterol synthesis.

S: Exactly. So their analysis showed that short half-life statins lowered cholesterol more when they were taken at night. They still saw this phenomenon with long half-life statins, but it wasn’t nearly as strong. 

J: So I can’t remember which statins have short vs. long half-lives. Let’s go over that again. 

S: Right – so short acting statins include pravastatin, simvastatin, lovastatin, and fluvastatin

J: They have half lifes (half lives?) ranging from 2-5 hours

S: Compare that against long acting statins like rosuvastatin and atorvastatin,  

J: Their half lives are 14-19 hours

S: So let’s remind ourselves why half-lives are important.

J: The  old mantra (old man Steve) says that three half-lives are what you need to eliminate a drug. So a drug like pravastatin, with a half-life of 2 hours,  is gone in about 6 hours.

S: Meaning if you take short acting statins in the morning, their effect wears off by night-time when your peak  lipid synthesis happens.

J: So the FDA took this pharmacokinetic logic to heart, (haha) and specifically recommends taking the short acting statins at night. As a reminder that’s lovastatin, simvastatin, pravastatin, fluvastatin

Plakogiannis R, Cohen H. “Optimal low-density lipoprotein cholesterol lowering-morning versus evening statin administration.” Ann Pharmacother. 2007; 41:106-110.

S: The same meta-analysis makes it seem like there is still  some benefit to taking even the long-acting statins at night

J: And this really doesn’t have to do with peak effects of the statin. It’s actually a little more straightforward than that. If you eat a big dinner and then take your statin you probably absorb less of it than you would on an empty stomach in the morning.

S: So we’ve made a somewhat convincing argument about how there may be a difference in night vs. day dosing of statins. 

J: Now let’s talk for a second about how much of a difference  we’re really talking about.

S: So in the 2017 study where they found an effect, they saw that when you look at all statins, long and short half-lifes, taking statin at night leads to an LDLs 3mg/dL lower than if you take them in the morning.

J: Seriously? Did we really just spend all this time talking about night vs. day for an effect that’s practically lab error?

S: Well, yes but there’s a silver lining. That modest decrease was driven by long -half statins where you don’t see much of a difference. But short half-life statins were actually better when taken at night – dropping LDL an additional 10 compared to daytime. 

J: Ok, that’s a little convincing…. Maybe they at least showed that this led to an improvement in patient outcomes?

S: Actually Janine… neither the cochrane review or 2017 article looked at clinical outcomes – they didn’t have the data to do so.

J: Ok, so all we have to guide our clinical practice is a slight drop in LDL levels. I thought that the latest guidelines from the AHA/ACC de-emphasized LDL targets!

 Grundy SM, Stone NJ. 2018 American Heart Association/American College of Cardiology Multisociety Guideline on the Management of Blood Cholesterol: Primary Prevention. JAMA Cardiol. 2019 Apr 10.

S: You are not wrong Janine. They didn’t say LDL levels don’t matter, it was just trying to simplify guidelines for statin use. They still recommend LDL targets for high risk patients.

J: Ok true, without getting too much into those weeds, historical data does suggest that lowering LDL and total cholesterol levels correlates with decreased cardiovascular risk.

S: The 2017 AACE guidelines make this really clear.. That’s the American Association of Clinical Endocrinologists.

Jellinger PS. American Association of Clinical Endocrinologists/American College of Endocrinology Management of Dyslipidemia and Prevention of Cardiovascular Disease Clinical Practice Guidelines. Diabetes Spectr. 2018 Aug;31(3):234-245.

J: Yes, they mention that some data suggests that a 1% decrease in serum cholesterol leads to a 2% reduction in coronary events. And there’s also data from post-marketing studies of statins showing that LDL lowering specifically correlated to a lower rate of cardiac events. 

 The Lipid Research Clinics Coronary Primary Prevention Trial results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA 1984;251 :365-74.

S: So we haven’t really wasted your time yet. In summary, taking short half-life statins at night MAY marginally lower LDL by 10mg/dL, and that MAY be enough of an effect to lower the risk of cardiac events. 

J: Just one caveat Steve

S: What’s that?

J: Well, LDL actually has a pretty long half life itself, more than 3 days!

S: And how is that caveat?

J: So if the studies changed the statins to night-time to better suppress production of cholesterol synthesis, they should’ve waited at least 1-2 weeks to measure a change in LDL levels. 

S: And that also means that even if statins are *slightly* more effective at blocking cholesterol synthesis at night, it’s not like that’s going to lead to a big drop in LDL levels the next morning because LDL hangs around for a really long time. 

J: Well, lets review one final piece of data that suggests night-time dosing may actually be worse. But for a totally different reason than the biochem / pathophys / blahblah that we talked about. 

S: Well, there’s an interesting simulation that looked specifically at simvastatin. It found no difference between daytime and nighttime dosing of simvastatin.

Wright DFB, Pavan Kumar VV, Al-Sallami HS, Duffull SB. “The influence of dosing time, variable compliance and circadian low-density lipoprotein production on the effect of simvastatin: simulations from a pharmacokinetic-pharmacodynamic model.” Basic Clin Pharmacol Toxicol. 2011; 109 (6):494-498.

J: But they also noted that other people have found lower adherence rates to medications at nighttime. When they included this in their simulation, surprise surprise they found that simvastatin was less effective at reducing LDLs and cholesterol at night.

S: But the thing is that while there is some research that suggests nighttime adherence to medications can be lower, there have also been trials showing it may not matter. That’s science for you!

J: Ok, well I guess we’re back at our usual approach, which is to customize your treatment plan to your patient. Which means actually talking to them about what they prefer – night-time or daytime.

S: Such a primary care doctor. And the reality is nowadays most folks are on longer acting statins like atorvastatin and rosuvastatin  anyway. Those were the statins where – according to the 2017 meta-analysis – nighttime dosing probably didn’t lower cholesterol levels that much anyway.

J: So more important that all the pathopahys is just to make sure they take ANY statin rather than worrying about what time is most optimal.

S: But it brings to mind an important idea, to quote Michael Scott, you miss one hundred percent of the shots you don’t take. – Wayne Gretsky.

J: I don’t think that’s what that quote means…

S: 80% of life is showing up?

J: Let’s not quote Woody Allen…

S: Yes, on to your favorite part – our summary. Take it away.

J: Thanks Steve. So we covered 1) how statins work. They block HMG coA reductase, part of the cholesterol synthesis pathway that is more active at night. But cholesterol has a long half-life, so even if production spikes at night, lipid levels don’t actually vary that much during the day.

S: And 2) there’s a cochrane review from 2016 claiming that LDL levels are NOT better if you take statins at night vs. day, but a newer meta-analysis from 2017 contradicting this.

J; That study showed that the greatest improvement in night-time dosing happened with short-acting statins, where the peak effect coincides with the peak of cholesterol synthesis.

S: But 3) even if this effect is real, the magnitude of it is not impressive. For short acting statins LDL was only lowered by 10 pts by taking it at night vs. day. And no studies have directly linked this to better cardiovascular outcomes, which is what we really care about.

J: And our final free-bee 4th point: taking meds at night may be associated with lower adherence, so you should really have a conversation with your patients about what’s realistic for them.

S: And finally 5) most people are now on long-acting statins anyway, that stay in your body for more than 24 hours, so day vs. night timing really shouldn’t matter.

J: Aaaand, we’re back to square one. I for one am no longer going to make a big deal about my patients taking their statins at night! And if I do, maybe I’ll only care about simvastatin since it’s short acting. But even then, I really just want them to take darn medicine, no matter what time of day.

S: Yeah, statins are hard… people don’t usually love taking meds that don’t actually make them feel any different.

References

• Wright DFB, Pavan Kumar VV, Al-Sallami HS, Duffull SB. “The influence of dosing time, variable compliance and circadian low-density lipoprotein production on the effect of simvastatin: simulations from a pharmacokinetic-pharmacodynamic model.” Basic Clin Pharmacol Toxicol. 2011; 109 (6):494-498.
• Jones PJ, Schoeller DA. “Evidence for diurnal periodicity in human cholesterol synthesis. J Lipid Res 1990;31 667-673.
• Izquierdo-Palomares et al. Chronotherapy versus conventional statins therapy for the treatment of hyperlipidaemia. Cochrane Database of Systematic Reviews 2016, Issue 11. Art. No.: CD009462
• Awad et al; Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group. Effects of morning vs evening statin administration on lipid profile: A systematic review and meta-analysis. J Clin Lipidol. 2017 Jul – Aug;11(4):972-985.e9.
• Plakogiannis R, Cohen H. “Optimal low-density lipoprotein cholesterol lowering-morning versus evening statin administration.” Ann Pharmacother. 2007; 41:106-110.
• Grundy SM, Stone NJ. 2018 American Heart Association/American College of Cardiology Multisociety Guideline on the Management of Blood Cholesterol: Primary Prevention. JAMA Cardiol. 2019 Apr 10.
• Jellinger PS. American Association of Clinical Endocrinologists/American College of Endocrinology Management of Dyslipidemia and Prevention of Cardiovascular Disease Clinical Practice Guidelines. Diabetes Spectr. 2018 Aug;31(3):234-245.
• The Lipid Research Clinics Coronary Primary Prevention Trial results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA 1984;251 :365-74.
• Wright DFB, Pavan Kumar VV, Al-Sallami HS, Duffull SB. “The influence of dosing time, variable compliance and circadian low-density lipoprotein production on the effect of simvastatin: simulations from a pharmacokinetic-pharmacodynamic model.” Basic Clin Pharmacol Toxicol. 2011; 109 (6):494-498.
• Kim SH et al. “Efficacy and safety of morning versus evening dose of controlled-release simvastatin tablets in patients with hyperlipidemia: a randomized, double-blind, multicenter phase 3 trial.”

 

---

Tags: cardiology, Clinical Practice, Mind the Gap, primary care