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Cardiol- lipids

Primary Care Corner with Geoffrey Modest MD: Nature vs nurture: studies on lipids and NAFLD

6 Jun, 17 | by gmodest

by Dr Geoffrey Modest

2 recent articles found significant genetic associations with 2 common clinical conditions: hyperlipidemia and non-alcoholic fatty liver disease (NAFLD). I bring these up to make the point that, though there is often a genetic association with disease, usually this is not determinant and there is an important role for a healthy lifestyle both in preventing the disease from happening and treating it if it does happen.

***Whole genome sequencing of two populations on the island Crete found some genetic variants which were either completely new, or rare in other populations, including one associated with increased HDL levels, and  another with decreased triglycerides and VLDL levels (see DOI: 10.1038/ncomms15606)

 

Details:

–945 patients from Crete, and specifically from Mylopotamos and Pomak villages, had genome-wide association studies done to look for common-frequency variants with small-to-modest effect sizes, evaluating 29 million single nucleotides variants in the Pomak and Mylopotamos cohorts. These results were imputed and validated for the larger populations in the areas

–there were 17 genome-wide significant independent signals found, including 2 novel cardiometabolic associations:

— chr16:70790626 for increased high-density lipoprotein levels (explaining 3.24% of the phenotypic variance in the Mylopotamos cohort)

— rs145556679, associated with decreased triglycerides and VLDL, so far only found in the Mylopotamos cohort and no other worldwide cohort.

— rs13382259, associated with decreased diastolic blood pressure in the Pomak population

Commentary:          

–one advantage of looking at an isolated population is that low-frequency alleles will be amplified by the more limited gene pool

–though not commented on in the article, people from Crete are among the longest-livers in the world: Mylopotamos is called “Village of Long Life”. Of note, there is a similar genetic variant in isolated Amish populations in the United States. Interestingly, the people from Mylopotamos do eat a largely Mediterranean diet though their diet is high in animal fat, but with less atherosclerotic disease than would be predicted by their diet

***5-8% of lean people have evidence of NAFLD, despite the strong association with obesity. This study looked at 3 groups of patients stratified by BMI (see DOI: 10.1038/ajg.2016.318).  This is an Austrian study limited to Caucasian people; the prevalence of lean patients with NAFLD has been well-documented to be higher in Asian people but Caucasians had not been assessed previously. I am not sure about lean African Americans, though their overall prevalence of NAFLD is lower than either Latinos or white patients. This study was a subsample of the 2500 people in the Salzburg Colon Cancer Prevention Initiative study.

Details:

–187 nondiabetic patients were assessed by BMI groupings and had ultrasound evaluation:

–lean healthy: BMI <25, no steatosis, n=71

–age 56, 25male/46 female, bmi 22.7, whr 87 cm (waist-to-hip ratio), ALT 17, diabetes 0, impaired fasting glucose 13%, HDL 67/LDL 120/TG 86, A1c 5.4, adiponectin 13.8 [adiponectin has many functions but higher levels are associated with more insulin sensitivity], FIB4 score 1.2 [a noninvasive measure of hepatic fibrosis]

–lean NAFLD: BMI <25, steatosis, n=55

–age 61, 26male/29 female, bmi 23.6, whr 91 cm, ALT 21, diabetes 31%, impaired fasting glucose 20%, HDL 58/LDL 136/TG 117, A1c 5.5, adiponectin 10.4, FIB4 score 1.3

–obese NAFLD: BMI>30, steatosis, n=61

–age 63, 29male/32 female, bmi 32.7, whr 113 cm, ALT 28, diabetes 36%, impaired fasting glucose 32%, HDL 45/LDL 139/TG 169, A1c 5.8, adiponectin 8.9, FIB4 score 1.1

–all had oral glucose tolerance test,  serum metabolome, and genotyping for single-nucleotide polymorphisms (SNPs) associated with NAFLD

Results:

–lean NAFLD patients had fasting insulin levels similar to lean healthy ones, but did have markedly impaired glucose tolerance

–lean NAFLD patients  had a higher rate of the mutant PNPLA3 CG/GG variant vs lean healthy, 59% vs 35%.

–serum adiponectin levels were decreased in both NAFLD groups vs lean healthy (p<0.001 for both groups)

–metabolomics study showed variations in lysophosphatidylcholines, phosphatidylcholines, lysine, tyrosine and valine (several of these may have anti-inflammatory effects and increase insulin secretion, which could explain some of the differences in glucose tolerance between the groups)

–clinically no difference in lifestyle habits between the 2 lean groups, though the obese group did have more people consuming fast food at least once a week and had lower physical activity

Commentary:

–NAFLD is certainly much more prominent in those with obesity than in lean patients, though this does raise the question as to whether the prognosis is the same in these 2 BMI groups.  They did not do transient elastography (Fibroscans) or get liver histology in this study, though the lean NAFLD group did have the highest FIB4 score (suggesting more hepatic fibrosis, with a score of 1.3 being the cutpoint, suggesting that NAFLD is likely to be deleterious in this group)

–lean NAFLD patients were in between lean healthy and obese NAFLD in terms of metabolic derangements, though they did have much more impaired glucose tolerance than the lean healthy ones, and about 30% did have diabetes as defined by either fasting plasma glucose, impaired glucose tolerance, or A1c levels. The lower adiponectin levels in the two NAFLD groups further confirm their relative insulin resistance.

–the rate of the PNPLA3 allele were similarly high in both NAFLD groups, and much higher than in the lean healthy ones  (p=0.007). This does suggest that this genetic variant does seem to be associated with NAFLD independent of BMI (though not determinant, since 35% of the non-NAFLD people also had this allele). Unfortunately, there were no granular data presented to see if it were just this SNP which was responsible for the NAFLD, or if this subgroup happened to have a less healthy lifestyle. Would also be interesting to know if there were differences in their microbiomes as well, which is also affected by diet and exercise. See the multitude of prior blogs on NAFLD in the http://blogs.bmj.com/ebm/category/gi-liver/ category, or just type NAFLD in the search window.

The reason I am evaluating these articles is to raise the general points that:

–clinically, we should still be suspicious of these underlying medical issues in patients who do not seem to fit the phenotype: a younger thin and athletic person who has a bad lipid profile, a thin person with an increase in their ALT levels on liver function testing, or evidence of fatty liver disease or glucose intolerance.  All of these people may have underlying medical problems (respectively, atherosclerotic disease, NAFLD) which might well affect their longer term morbidity/mortality

–and some anecdotes to fill this in, reinforcing the genetic components:

–one of my residents a few decades ago was curious about the strikingly high incidence of ASCVD/MIs in thin, athletic men in their 40’s in his Indian community near Boston. These men had surprisingly low HDL levels

–and lots of people who are morbidly obese with A1c in the mid 4 range, yet many who are much less obese (and some normal weight) who are either pre-diabetic or diabetic; I have found glucose intolerance in several thin patients with family history of diabetes

–as another example showing that risk factors may be discordant from the clinical picture: though obesity is the dominant risk factor for obstructive sleep apnea, it is found in about 11% of men with normal weight and about 3% of women (overall it is 2-3 times more common in men)

–so, we should think about risk factors when we see patients, but not be swayed too heavily and keep open mind to these diagnoses. Genes may be the dominant player in some patients.

 

On the other hand, there is usually some interplay between nature and nurture. Helping patients develop healthy lifestyles may well counteract the potentially deleterious effect of the genes, or potentially lead to more aggressive preventative approaches (eg, earlier uses of statins to prevent cardiac disease, etc)

–one interesting and I think poignant example of the nature/nurture interplay is that of the US Pima Indians in Arizona, who reportedly have the highest rates of diabetes and obesity in the US (see Schulz. Diabetes Care 2006; 29: 1866). In 1890 their water supply was taken over by white settlers, making it impossible to continue their agrarian lives. The US government subsidized  the food supply with sugar and white flour, and the previously lean population developed obesity and diabetes. It turns out that a group of Pimas, speaking the same language and from the same genetic stock, live in remote areas of rural Mexico and continue to practice their traditional agriculture. These Mexican Pimas have similar lower levels of obesity as other non-Pimas living in the same remote areas (around 7% in men and 20% in women), and have rates of diabetes close to the other non-Pima Mexicans (6.9% vs 2.6%). But the US Pimas have diabetes rate of 38% —  more than 5-fold higher!!! (and 68% in men older than 45, 70% of women older than 45 and 82%of women older than 55), which tracks with prevalent obesity (mean BMI=34), as well as their dramatically lower levels of physical activity there. A pretty clear example of a strong genetic predisposition to diabetes which manifests itself in the setting of a nonhealthy lifestyle/obesity….

so, I think all of this points to the fact that there are often important genetic factors leading to disease,and we as clinicians dealing with individual patients should still be attuned to patients who do not exhibit the typical profile (eg, those with high predisposition to heart disease or have abnormal LFTs from NAFLD but appear to be young and fit, or those who have OSA but are also of normal weight). And healthy lifestyles may not just help with these targeted diseases but are generally beneficial (collateral benefit… see blogs showing likely benefit from cancer, Alzheimers etc etc)

See here  for projected decreased cancer risk from exercise

See here for projected cardiovascular benefit from cardiovascular fitness

See here  for dietary influences on Alzheimers

Or, a slew of blogs on the benefits of Mediterranean diets

Primary Care Corner with Geoffrey Modest MD: Statins in the elderly?

26 May, 17 | by gmodest

by Dr Geoffrey Modest

​A post-hoc secondary analysis of data from the ALLHAT-LLT trial assessed the value of pravastatin, 40 mg per day, versus placebo in older patients, finding no benefit (see doi:10.1001/jamainternmed.2017.1442)

Details:

— the ALLHAT-LLT study, a community-based study which included 10,355 patients who had a fasting LDL level of 120 to 189 mg/dL and fasting triglycerides level < 350 mg/dL. 4546 were excluded for being younger than 65 and an additional 2942 because of baseline atherosclerotic disease, resulting in 1467 people in the pravastatin group and 1400 in usual care (UC)

— The intervention was open label pravastatin 40 mg per day versus UC. Mean follow-up 4.6 years

— mean age 71, 51% female, 40% white/31% Latino, 25% on aspirin/90% on anti-hypertensives/10% of women on estrogens, 22% current smokers, 51% diabetics, BMI 30, mean blood pressure 147/83

— baseline LDL was 148 mg/dL, decreasing to 109 mg/dL in those on pravastatin and 129 mg/dL in UC. The proportion taking statins was 78% versus 29%, respectively, by year 6 [ie, pretty large cross-over of patients]; this was more pronounced for participants 65 to 74 years old, where 32% of the UC group were taking a statin, though in those >75 yo, 15% were.

Results:

— all-cause mortality in pravastatin vs UC was non-significantly different for all adults 65 and older (HR 1.18, p=0.09), including nonsignificant HR of 1.08 those age 65 to 74, and 1.34 for those 75 years old or greater [ie nonsignificant trend to worse prognosis in group on pravastatin]

— coronary heart disease event rates were also not significantly different among the groups. No change with multivariable regression. No significant interaction between the treatment group and age.

Commentary:

— it is true that there are not rigorous data on older people and statin use, especially for adults greater than 75 years old, with much of the existing data being post-hoc analyses.

— One concern with the ALLHAT trial is that it was not a truly randomized controlled trial, with the control group being usual care. As a result, the 29% taking statins in the UC group might have been a very high risk group and thereby dilute the difference with the pravastatin group; and conversely 22% of those assigned to pravastatin did not take it (were they self-selected as healthier and less likely to have an atherosclerotic event??).  So ultimately, there was only a 20 mg/dL difference between the groups (and, pravastatin is one of the weaker statins). Another issue which may have disadvantaged the pravastatin group: among people 75 years and older, the mean systolic blood pressure was 150.6 mmHg in the pravastatin group and 147.5 mmHg in the UC group (p=0.01). Their finding of nonsignificant increases in overall mortality as well as in cardiovascular and stroke mortality, and heart failure event rates (all of which are strikingly contrary to the statin studies in younger people which show marked benefit of statins) suggest to me that intrinsic biases of the current ALLHAT study may have played an important role (though coronary heart disease rates were nonsignificantly lower in the pravastatin group)

–other issues: this was an open label study (with its attendant potential biases), did not include nonpharmacologic therapies of diet/exercise (and did those on statins stop doing these healthful behaviors because perhaps they found out from their clinicians that their lipids were better and they thought they didn’t need to continue the lifestyle changes, as was found in another statin study??), and those already on a statin were excluded from the study (those likely at higher cardiovascular risk, leaving the actual cohort at lower risk).

— There is reasonable theoretical benefit for using statins in the elderly: in people older than 65, about one half of all deaths are from atherosclerotic disease. And, statins reveal their effectiveness pretty quickly, within 6 months to a year.

— In general, although the relative risk of hyperlipidemia causing atherosclerotic disease in the elderly is lower than in younger people, the absolute risk in fact increases a lot with age.

— See blog , which reviews some of the data showing benefit of statins in the elderly, including a relatively recent meta-analysis of 8 trials, finding for example a 39% relative risk reduction for MI in those on statins, with number needed to treat of 24 for one year to prevent one MI. Relatively similar numbers for stroke prevention. Though these are mostly post-hoc subgroup analyses of bigger studies.

 

So, there really should be high quality randomized controlled studies of statin use in the elderly. The pathophysiology of atherosclerosis and the mechanics of statin use would suggest significant benefit for the elderly, even within 6 months of initiating statin therapy, and with minimal likely adverse effects. However, the current information is basically from post-hoc secondary analyses. Given our aging population and their high mortality rates from atherosclerotic disease, it really makes sense to have large rigorous studies. In the meantime, I will continue to treat the elderly with statins on an individual basis, having had (I think) good success: several elderly patients with severe CAD who have lived for decades on statins, dying in their mid 90s, and only one patient with an adverse effect/intolerance.

Also, as I mentioned in a recent blog, I am really concerned that the wrong message is getting out to clinicians: Physician’s First Watch and NEJM Journal Watch stated “Pravastatin Doesn’t Improve Clinical Outcomes in Seniors” . I think these sound-bite type analyses do in fact dumb-down the process of critical analysis of potentially important clinical articles, reinforcing (by omission) that the results of this study sound pretty definitive and thereby perhaps convincing some clinicians to stop prescribing statins. This approach is ahistorical (ie, omits the wealth of prior data suggesting benefit), and tends to reinforce the conception that the newest study trumps (perhaps bad term) all of the older studies (ironically, in this case, this study was based on a post-hoc analysis of a really old study, though I do think that in general newer studies tend to be accepted by us disproportionately, and inappropriately in some cases)

 

Primary Care Corner with Geoffrey Modest MD: Statin myopathy and vitamin D deficiency

1 May, 17 | by gmodest

by Dr Geoffrey Modest

A recent editorial provided reasonably convincing evidence that there is a relationship between low vitamin D levels and statin associated muscle symptoms, SAMS (see Glueck CJ. Atherosclerosis. 2017; 256: 125). See article for the references.

 

Details/summary of data:

— one study showed an inverse relationship between CK levels and vitamin D levels in patients on simvastatin, independent of symptoms

— a non-blinded study with high-dose vitamin D to normalize serum levels found that up to 95% of 134 patients with SAMS were free of muscle symptoms on reinstating statins, and this continued for up to 24 months later (the last time point measured)

— another trial of 150 patients with SAMS with a median vitamin D of 21ng/ml and given vitamin D supplements found that 87% were successfully able to restart their statins and remain symptom-free for 24 months

— a meta-analysis of 2420 patients documented that vitamin D levels tend to be lower in patients with SAMS; several other studies have confirmed that in patients with SAMS and low vitamin D levels, repleting the vitamin D levels leads to about 90% being able to tolerate rechallenge with statins

 

Commentary:

— SAMS is quite frequent, varies somewhat depending on the statin use/dose, but is reported in about 10% of patients.

— Myopathy is also a reasonably common symptom of vitamin D deficiency

— there are studies which suggest that even those with intolerable muscle symptoms from 3 or more statins, only 43% had muscle symptoms on rechallenge (and 27% had muscle symptoms only on placebo, 17% had symptoms to neither drug). ie, there is likely a pretty big placebo effect. Though the 90+% success rates with vitamin D noted above are a bit eye-popping.

— so, a provocative editorial. Clearly, especially in light of the potentially large placebo effect, and in light of the importance of statins in preventing clinical cardiovascular outcomes, there should be a well-designed randomized control trial to assess the true benefit of vitamin D repletion in those with SAMS who are vitamin D deficient. It is notable in several of the uncontrolled studies, increasing vitamin D even in patients with levels in the low 20 ng/ml range was effective, which is actually above what the Endocrine Society defines as deficient, <20 ng/ml. so, it makes sense in future RCTs to look at those patients who have SAMS and with 25-OH vitamin D levels <30 ng/ml or so to see if vitamin D supplementation helps, or perhaps in all-comers to see if there is a 25-OH vitamin D threshold.  The meta-analysis mentioned above found that the difference in vitamin D levels in those with and without SAMS was 28 vs 35 ng/ml.

 

Bottom line: statins are important for many patients, SAMS is common as is vitamin D deficiency, there are likely other benefits from vitamin D sufficiency anyway, vitamin D supplementation is pretty benign and inexpensive, so to me it seems reasonable at this point to try vitamin D supplementation in patients who are intolerant of statins because of SAMS, even if there baseline levels seem pretty good.

 

see here for an array of blogs on vitamin d.

 

Primary Care Corner with Geoffrey Modest MD: Treating LDL to target?? More evidence

3 Apr, 17 | by gmodest

By Dr. Geoffrey Modest

 

A recent Korean multicenter observational study found that patients with coronary artery disease who achieved an LDL <70 mg/dl had very significantly decreased atherosclerotic plaque progression than those with higher LDL, further supporting the concept of treating-to-target to specific LDL levels (see doi.org/10.1016/j.jcmg.2016.04.013).

 

Details:

–147 patients with visible plaques on coronary CT angiography (CTA) who had another CTA at least 2 years later (median 3.2 years), as well as lab values within 1 month of both the baseline and followup CTAs

–mean age 62, 57% male, BMI 25, hypertension 65%, diabetes 33%, active smoker 20%, NCEP ATPIII risk score <10 in 55%/10-20 in 32%/>20 in 13%, Framingham risk score <10 in 63%/10-20 in 29%/>20 in 9%. Of note, those who achieved an LDL<70 were sicker: 1.95 vs 1.54 cardiac risk factors, 54% vs 26% with diabetes. though overall not a high risk group.

–initially, 57% asymptomatic, 8% noncardiac chest pain, 29% atypical chest pain, 3% typical chest pain and 3% shortness of breath

–labs:

–prior to initial CTA: cholesterol 183 mg/dl, HDL 48, LDL 114, TG 154, and 40% were on a statin

–prior to followup CTA: cholesterol 162, HDL 48, LDL 92, TG 122, and 73% on statin

–mean LDL initially in those who had followup LDL<70: 106 mg/dl (vs 116 mg/dl in those with LDL>70) [so, those who achieved a lower LDL started with a lower LDL]

–mean follow-up LDL in those who had  LDL<70: 57 mg/dl (vs 104 in those with LDL>70). All patients who achieved LDL<70 were on a statin.

 

Results:

–univariate associations for annual plaque volume change: BMI (p=0.045), hypertension (p=0.040),follow-up LDL<70 (p=0.018)

–multivariate association: only the achieved LDL on followup CTA exam was associated with less plaque volume change (p=0.021)

–in the subgroup on statins: comparing those achieving LDL <70 (n=37) vs >70 (n=70):

–change in plaque volume: 12.7 vs 41.8 mm3, p=0.009

–annual change in plaque volume: 4.6 vs 14.5 mm3, p=0.015

 

Commentary:

–There are some limitations to this study, including its retrospective/observational design (eg, there could be missing unknown biases which influenced the aggressiveness of patient treatment), lack of information on the particular statins and doses used, and lack of data on consistency of statin use (data only for the month before the CTAs)

–However, the conclusions of this study are impressive in terms of differences in plaque progression, and add to the already pretty abundant literature finding that achieved LDL is an important target to therapy in those with coronary artery disease. And, I might add that even the 2013 AHA/ACC guidelines, which call for statin intensity determined by demographic or comorbidity criteria and not “treating-to-target” (ie, not using patient-level achieved LDL levels) do implicitly incorporate a treat-to-target approach in that they support more aggressive LDL reduction in some patients over others. But, they argued that since there were no clear RCTs stratifying patients to specific LDL goals, they should therefore not recommend using  LDL targets. This reasoning was suspect to me (as per prior blogs), since pretty much all of the other AHA recommendations were based on even​ less rigorous data​

–There are several older studies which supported treating LDL to target instead of prescribing high- vs moderate-intensity statins based on categories of risk.

–studies have shown pretty unambiguously that the achieved LDL determines the risk of cardiac events (there is a summary of the evidence in the ezetimibe blog referenced below)

–older studies using IV ultrasounds have also shown decreased plaque progression with statins. Coronary CTA, as in the above study, has been shown to be reproducible, correlates well with IVUS measurements, is noninvasive (other than radiation…)​, and supports the prior more-invasive IVUS studies

–several new studies have reinforced the utility of trying to decrease LDL to a lower target:

–IMPROVE-IT trial found that adding ezetimibe to simvastatin in 18,144 patients led to a 24% reduction in LDL levels (down to 53.7 mg/dl), associated with a 6% decrease in a composite of cardiovascular outcomes.   See here  for a critique of that study, along with more detailed arguments for targeting-to-treat LDL levels, plus an argument for adding HDL into the treatment decision model.

–FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) study, just released of 27,564 patients followed over 2.2 years (see DOI: 10.1056/NEJMoa1615664) found that adding PCSK9 inhibition, vs statin therapy alone (70% on high-intensity, 30% on moderate-intensity) led to a mean LDL of 30 mg/dl from a baseline of 92 mg/dl, and an associated 15% reduction in the combined primary endpoint (MI, stroke, hospitalization for chest pain, stent placement, death), a reduction from 11.3% to 9.8% of patients. [this was less of a reduction than the anticipated 20% reduction, which, by the way, led to a significant reduction in the value of the company in the stock market…]. In terms of secondary outcomes: 20% reduction of the combination of cardiovascular death, MI, or stroke; 27% decrease in risk of MI;  21% decrease in stroke, and 22% decrease in coronary revascularization, with clinical benefit evident within 6 months and increasing thereafter. There was no significant reduction in cardiovascular deaths or hospitalizations for unstable angina. I personally am not pushing these very expensive injectable drugs at this point (and have never prescribed them), but bring up this study as further evidence that targeting a low LDL seems to be beneficial.

–I suspect that some of the rationale for pushing the statin intensity argument, as opposed to the treat-to-target, is that if there is not a really simple guideline, many patients will not be treated at all with statins.  And I do respect that argument. The rationale for starting statins when patients are in the hospital with an atherosclerotic cardiovascular event is that otherwise they might never get the statin….

–but, there is large inter-patient variability in what the achieved LDL will be on different doses of statins, some of which depend on the initial pretreatment LDL and some on just individual variation (eg, some of my very high risk patients on atorvastatin 10mg achieve LDLs of 40 or so. Do they need more aggressive treatment? with the attendant increase in adverse reactions?)

–and, on the other hand, I certainly have several patients who did not achieve their LDL goal even with the “high-intensity” atorvastatin 40 or even 80mg, but who did when switched to rosuvastatin 40mg.

–so one consequence of not using a target LDL is that we may be undertreating some high-risk patients, even without needing to go to the newer agents. and the other is that we may be overtreating others by starting off with too high a dose of statins.

–and, i think it makes reasonable sense to target the LDL levels on a per-patient and per-statin basis (ie, not on a community scale, where the dose is determined by age, comorbidities, etc).  it’s a bit like treating hypothyroidism by the T4 level, where normal is a bell-shaped curve based on community data, vs TSH, which reflects the individual’s response to their own ambient T4 level​

 

–my major concern with statins really is the finding that many patients stop doing general lifestyle changes (and perhaps many clinicians do not continue to focus on them) because of the pretty dramatic lipid improvement with statins.  But the data are pretty consistent that a healthy lifestyle has a multitude of positive physical and psych effects beyond just the cardiovascular ones, and it is important to me that we continue to help motivate patients to improve their diet and exercise in particular.

 

–so, my sense is that there really are consistent data from an array of different types of studies suggesting that lower LDL levels lead to less accumulation of atherosclerotic plaque (as in the above study) as well as fewer atherosclerotic events (per both older statin studies as well as the newer studies with the newer agents), that titrating statin dose to the individual patient seems reasonable based on this, that we can pretty often achieve LDL levels <70 through that titration (likely to the benefit of the individual patient, especially important in secondary prevention),  but that we should be vigilant in reinforcing healthy lifestyle changes.

 

Primary Care Corner with Geoffrey Modest MD: Cardiac Drug Interactions with Statins

16 Nov, 16 | by EBM

By Dr. Geoffrey Modest

The American Heart Association just published their recommendations for managing drug-drug interactions between statins and other drugs used for cardiovascular disease (see DOI: 10.1161/CIR.0000000000000456 ). I bring this up because statins are such an important drug that we use all the time, drug-drug interactions overall are common (leading to about 3% of hospital admissions, and the result of many annoying flags in electronic medical records) and because this review goes into detail on the mechanisms of these interactions (whether through the cytochrome P-450, CYP450, system of oxidative enzymes, or those interactions involving permeability glycoprotein P-gp, a superfamily of membrane-associated ATP-binding cassette-transporters, also called multidrug resistance-1; this article gives a good review of these systems, the latter of which was pretty much unknown to me prior to seeing this article….), and the article comments on the likely clinical importance of these interactions. Of note, I did not include recommendations for fluvastatin or pitavastatin, since these seem to be used rarely. Here is a brief review of the important/relatively common drugs used in primary care:

  • Amlodipine: minor interaction with lovastatin and simvastatin (for the latter, 1.8-fold increase in simvastatin level, with recommendation to limit simvastatin dose to 20mg)
  • Colchicine: variable interaction with all of the statins, though combination “may be considered”. Monitor muscle toxicity closely. Of note, colchicine itself can cause myopathy, so can be hard to differentiate from statin-induced. Colchicine does not seem to impair CYP450 system though does seem to compete for P-gp-mediated efflux. Not much clinical data on the interaction with statins, but likely that best tolerated (based on the effect on P-gp) would be rosuvastatin, lovastatin, or pravastatin. And probably best to use lower doses of colchicine: 0.6-1.2 mg loading dose and 0.3-0.6 mg/d maintenance
  • Digoxin: not dependant on the CYP450 system. atorvastatin increases digoxin level 1.2-fold. Combo is reasonable with any statin without dose adjustment. But best to monitor digoxin levels in those on atorvastatin, esp if on higher doses.
  • Diltiazem: minor interaction with atorvastatin, but moderate with lovastatin and simvastatin (about 4-fold increase in statin levels). Limit lovastatin dose to 20mg and simvastatin to 10mg
  • Fenofibrate: insignificant interaction with all (though no data on lovastatin)
  • Gemfibrozil: minor interaction with atorvastatin and rosuvastatin. Avoid combo with lovastatin, pravastatin, and simvastatin
  • Verapamil: moderate interaction with lovastatin and simvastatin. Limit dose of lovastatin to 20mg and simvastatin to 10mg
  • Warfarin: 30% increase in INR with simvastatin, variable effects with lovastatin, rosuvastatin. But monitor INR with initiation or change in dose of any statin [which i think is reasonable with almost any new drug…]

A brief comment on cardiac and other drugs used less frequently in primary care:

  • Amiodarone: metabolized by both CYP34A and CYP2C8, as well as substrates of P-gp efflux transporter. Not use simvastatin (and definitely not more than 20mg) or lovastatin (not more than 40mg). rest are okay
  • Dronedarone: similar to amiodarone, but recommended to use simvastatin and lovastatin at even lower doses (e.g. not more than 10mg)
  • Ranolazine: best to use rosuvatatin, atorvastatin, pravastatin. FDA recommendation to limit dose of simvastatin to 20mg
  • Ticagrelor: can use atorvastatin; if use simvastatin or lovastatin, then no more than 40mg/d; no reported interactions with other statins
  • Conivaptan (a vasopressin receptor antagonist): not use lovastatin/simvastatin; best to use atorvastatin, pravastatin, or rosuvastatin. Tolvaptan can be used with any statin
  • Immunosuppressants: avoid combos of lovastatin or simvastatin with cyclosporine, everolimus, tacrolimus; best to use rosuvastatin up to 5mg, atorvastatin up to 10mg, pravastatin up to 20mg
  • Sacubitril/valsartan: limited data, minimal metabolism by CYP450 system, some increase in atorvastatin levels but no reported adverse clinical effects
  • Ivabradine: limited data, but extensively metabolized by CYP34A system (so, I would avoid simvastatin/lovastatin)

Commentary:

  • This review was helpful to me for a few drug-drug interactions in particular
    • Gemfibrozil: my prior held belief (and the 2013 American Heart Association guidelines statement) was that we should not use the combo of gemfibrozil with any statin, because of significant risk of myositis with the combo  (also some increased risk of hepatotoxicity). This created a bit of a problem, since studies do suggest that fenofibrate seems to be much less effective in lowering triglyceride levels and does not seem to have the same cardiovascular benefits of gemfibrozil (e.g., comparing the FIELD trial of fenofibrate and the VA-HIT or Helsinki trials with gemfibrozil; also a meta-analysis confirmed that fenofibrate is a poor cousin to gemfibrozil). These new guidelines still prefer using fenofibrate, since large studies with the statin/fenofibrate combo do not show an increased toxicity; and they suggest using atorvastatin or rosuvastatin at a lower dose (FDA suggests max rosuvastatin of 10mg/d) if use gemfibrozil. But at least the combo of gemfibrozil and atorvastatin or rosuvastatin is now acceptable.
    • It really is okay to use simvastatin with amlodipine, despite my electronic record and pharmacist yelling at me when I have tried to do so. Though, that being said, it does seem that atorvastatin is overall better tolerated in terms of drug-drug interactions (rosuvastatin and pravastatin are also quite good). The reason is that simvastatin and lovastatin are metabolized in the CYP3A4 system, the most common enzyme system in drug metabolism, and atorvastatin is metabolized by this system less so. Rosuvastatin is metabolized in the less commonly used CYP2C9 system. Pravastatin is not metabolized through the CYP450 system at all, but is by the OATP enzymes (organic anion-transporting polyprotein)
  • So, overall this guideline does present a more detailed (and complex) characterization of the drug-drug interactions between statins and other cardiac meds, and is pretty helpful with some very specific guidance. Unfortunately, it does not deal with non-cardiac meds (and, it turns out, that we in primary care do sometimes prescribe non-cardiac meds…)

Primary Care Corner with Geoffrey Modest MD: Statin Use Lowers Cirrhosis Risk in Hep B

26 Aug, 16 | by EBM

By Dr. Geoffrey Modest

A new study looked at a large number of patients with chronic hepatitis B (CHB) who were on a statin, finding improved hep B outcomes (see Huang Y. Am J Gasstroenterol 2016). This blog follows a recent one I sent out: see http://blogs.bmj.com/ebm/2016/05/16/primary-care-corner-with-geoffrey-modest-md-use-of-statins-in-patients-with-hepatitis-looks-like-a-yes/ , which reviewed a recent study showing statin benefit in those with hepatitis c, also comments on the benefit of statins in NAFLD, and mentions that the data on hep B is more mixed. Details of the current study from Taiwan, where 15-20% of the population has CHB, half of which is by perinatal transmission:

  • Population-based cohort study in Taiwan, with 298,761 patients with chronic hepatitis B (but without concomitant hep C, biliary cirrhosis, or alcoholic liver disease) and 6,543 on statins
  • Mean age 50, 53% male, 5 year follow-up on cirrhosis and same for decompensated cirrhosis, more comorbidities in the non-statin group (including more cardiovascular and pulmonary diseases)
  • Compared on 1:1 ratio with non-statin taking patients, with propensity scoring (to mathematically attempt to eliminate confounders). Also controlled for “inception point” of when statins started, to make sure that the comparisons between patients happened at the same approx time (to decrease likelihood that they were treated differently because of treatment changes over time)

Results:

  • Those on statins had:
    • 57% lower risk of developing cirrhosis [RR=0.43 (0.34-0.52, p<0.001)]: in 30,000 person-years of follow-up, 173 of those on statins developed cirrhosis (incidence rate 0.561/100 person-years), vs 400 not on statins (1.338/100 person-years)
    • 53% lower risk of developing decompensated cirrhosis [RR=0.47 (0.34-0.64, p<0.001)]: in 30,000 person-years of follow-up, 59 on those of statins developed decompensated cirrhosis (incidence rate 0.190/100 person-years), vs 126 not on statins (0.411/100 person-years)
    • Adjusted for age, gender, comorbidity index (which includes MI, CHF, PVD, rheumatic disease, chronic pulmonary disease, dementia, renal disease, cancers, HIV), hypertension, diabetes, hyperlipidemia, hepatocellullar carcinoma, obesity, NAFLD, aspirin use, diabetes medication, CHB treatment, non-statin lipid meds, and triglyceride meds: those on statins had
      • 49% lower risk  of developing cirrhosis [RR=0.51 (0.41-0.63, p<0.001)]
      • 47% lower risk of developing decompensated cirrhosis [RR=0.53 (0.43-0.66, p<0.001)]
    • In looking at the length of time taking statins, there was a dose response for the adjusted hazard ratios:
      • Cirrhosis
        • 15% lower if statin use 28-90 days (nonsignificant)
        • 53% lower if 91-365 days (p<0.001)
        • 80% lower if >365 days (p<0.001)
      • Decompensated cirrhosis
        • 7% lower if statin use 28-90 days (nonsignificant)
        • 39% lower if 91-365 days (borderline significant  at p=0.053)
        • 77% lower if >365 days (p=0.001)
      • The Kaplan-Meyer curves for both of the above showed widening curves over 12 years, with the major divergence in the first 6 years of follow-up
    • Also, overall mortality over 12 years of follow-up was lower in those on statins (13% vs 17%, with p<0.001)

Commentary:

  • The reason I bring up this article is that I still hear clinicians who feel that it is dangerous to prescribe statins in those with underlying chronic liver disease. As mentioned in the prior blog noted above, there are some reassuring data for NAFLD and Hep C. This huge trial, I think, pretty clearly adds Hep B to the mix. Although these are mostly retrospective/observational studies, and therefore not rock-solid RCTs, they pretty much show that statins at least are not harmful to an already-inflamed liver, and may well be beneficial. Of course, with observational studies, there always is the issue of unequal treatment in the different groups (were those on statins perceived to be less sick with their CHB and therefore getting more aggressive cardiovascular treatment??), but the use of propensity-matched scoring for lots of potential confounders and making sure that people were compared during the same time-frame (to minimize differences in overall treatment during differing time periods) do strengthen the conclusions.
  • There is reasonable biologic plausibility: studies have shown that simvastatin lowers portal pressure in patients with cirrhosis, and improves portal hypertension and sinusoidal endothelial dysfunction in rats (presumably by increasing nitric oxide and decreasing hepatic vascular resistance). And reduction in portal pressure correlates with protection from complications from cirrhosis. Also statins seem to inhibit fibrosis through several mechanisms (e.g. decreasing procollagen I and a-smooth muscle actin, connective tissue growth factor, etc.) and may directly decrease hepatitis B viral replication
  • The dose-response curve (the longer on statins, the more protective) also strengthens the likely conclusion that statins are protective against disease progression
  • And statins may be particularly useful in those with chronic inflammatory conditions such as hepatitis, since these patients are more predisposed to cardiovascular disease
  • So, it seems to me, that for the major international causes of chronic liver disease (hep B, hep C, NAFLD), we should not hold off using statins for fear of increasing the liver problems. That being said, I do check and follow liver function tests a bit more closely, though I have never found any problems in these patient groups.

Primary Care Corner with Geoffrey Modest MD: Statins Adverse Effects, Again

30 Jun, 16 | by EBM

By Dr. Geoffrey Modest

There are several significant adverse effects associated with statins noted in the literature and in our clinical practice. A blog a few years ago noted that there does not seem to be much difference in the incidence of myalgias between those on statins and controls, there is a 9% increased likelihood of diabetes, and there is a pretty high incidence of mild transaminase elevations (see http://blogs.bmj.com/ebm/2013/11/25/primary-care-corner-with-dr-geoffrey-modest-adverse-statin-effects )

  1. A recent blog looked at statins and myalgias, perhaps the most common patient complaint with statins, showing that a majority of people who think they are intolerant of even 3 different statins because of myalgias really do not have a true statin myopathy (a placebo-controlled study found that either they did not have more of a problem with atorvastatin vs placebo, or only had myalgias with the placebo!). See http://blogs.bmj.com/ebm/2016/04/29/primary-care-corner-with-geoffrey-modest-md-nonstatin-lipid-lowering-drugs-and-statin-myopathy/.

I should note that there is a relatively new entity found, an autoimmune myositis associated with statins: developing antibody against HMG-CoA reductase, and persistent symptoms after statin withdrawal. This needs aggressive therapy with prednisone or immunosuppressants — see Mammen AL. N Engl J Med 2016; 374: 664.

 

  1. Another oft-cited issue is statin-induced diabetes. This also is a tad murky, since:
  • There are studies suggesting that it is actually the low LDL itself and not the statin per se which is related to the diabetes (see blog http://blogs.bmj.com/ebm/2015/10/15/primary-care-corner-with-geoffrey-modest-md-low-ldl-and-diabetes-risk/ )
  • It is hard to find really granular data in the relevant studies on the association between statins and diabetes, bringing up a few issues:
    • The studies typically define the development of diabetes as we all do: arbitrarily as a HgbA1c of 6.5 (which is based actually on the approximate point where the incidence of diabetic retinopathy starts to increase), or by increased fasting glucose etc.
    • 70-80% of diabetics die from atherosclerotic cardiovasc disease (ASCVD), and even those with glucose intolerance (sub-6.5 A1c) have about a 2-fold increased risk of ASCVD. And statins work well in them in preventing ASCVD, as shown in several studies (same relative risk reduction as nondiabetics, higher absolute risk reduction)
    • This all makes it hard to determine the real clinical significance of “developing diabetes”. Are there really small changes in A1c levels (e.g., going from 6.4 to 6.5) causing us to lump these patients as “new diabetics”? Do these types of small differences really matter, since there seems to be a continuous relationship between A1c and ASCVD even in the pre-diabetic range? Similar argument for small changes in fasting glucose etc. A much more clinically significant outcome would be if there were more dramatic changes in A1c, both in the nondiabetic range (e.g. going from 5.0 to 6.4) or the diabetic range (e.g. 7.0 to 9.8), but we don’t know based on the data presented. For one review of the studies, see Preiss D. JAMA 2011: 305(24): 2556, which looked at older studies, mostly using fasting plasma glucose to diagnose diabetes, though the issue is the same.

 

  1. There have been a few reports suggesting that statins are associated with dementia. A recent large retrospective analysis did find an increase in reports of acute memory impairment in the first 30 days after initiating treatment, though this was found with all lipid lowering drugs (LLDs). The researchers utilized The Health Improvement Network, a database of anonymized patient records extracted from the general practitioners’ (GPs’) offices in the UK (see Strom BL. JAMA Intern Med 2015; 75: 1399). Prior studies have found mixed results; some finding improved memory [e.g. Jick H. Lancet 2000; 356(9242: 1627)] and others with no difference.

Details:

  • From 1987 through 2013, 482543 new statin users were compared to 482543 matched nonusers and 26484 users of nonstatin LLDs (bile-acid sequestrants, fibrates, niacin). Patients with a history of dementia /cognitive dysfunction or meds used for dementia were excluded, as well as those with traumatic brain injury or schizophrenia. A new statin user was defined as a person not on a statin for at least 1 year previously; similarly for nonstatin LLDs.
  • A case-crossover review of 68028 patients with incident acute memory loss looked at statin exposure in the period immediately before this diagnosis and the 3 earlier periods, to assess a statin association especially in patients who might have been intermittent statin users to see if they used statins more often in the immediate 30 days vs up to 300 days before.
  • The primary outcome: acute, reversible memory impairment.

Results:

  • Not so surprisingly, those on statins were older (63.4% >60yo vs 57.3% in nonusers), had more medical diagnoses with medical indications for LLDs/higher prevalence of comorbidities and meds. And (perhaps more surprisingly) those on nonstatin LLDs had more diabetes, hypercholesterolemia and cardiovascular disease than statin users, as well as more depression/anxiety. So the analyses were adjusted by propensity-score matching based on sex, age, and duration of enrollment.
  • First exposure to statins vs no LLD therapy: strong relationship with incident acute memory loss, with fully-adjusted OR 4.40 (3.01-6.41). This elevated risk decreased dramatically after the first 30-day period (they also looked at the 60-day reporting to see if there were some delay: again noting only an early association, decreasing monotonically thereafter).
  • Both atorvastatin and simvastatin showed the increase in the first 30 days, but there were fewer users of other statins in the studies (simvastatin being by far the most prescribed)
  • Overall, the association was strongest with the most lipophilic statins, and there was a clear dose-response curve, with the highest incidence of dementia with the highest doses of statins
  • But no statistically-significant difference between using statins vs nonstatin LLDs. Again, with nonstatin LLDs there was a notable increased association in the first 30 days [OR 3.60 (1.34-9.70)], decreasing monotonically thereafter.
  • The case-crossover analysis showed little association. 18.9% of patients with an episode of acute memory loss had received a statin in the prior 30 days. This was only slightly more when compared to other time periods up to 300 days prior.
  • There was a validation study of 100 patients with acute memory loss, done by direct outreach to the GPs. Most confirmed the acute memory loss, but only 38% had confirmed resolution of the memory loss. 43% had slowly progressive memory loss.
  • A rechallenge analysis found very few positive cases of memory loss (see table 10 in the supplement)

Commentary:

  • It would not be surprising if any LLD caused a change in neurologic functioning, since cholesterol is such an important component of neuronal membranes and changes could conceivably affect depolarization/neural transmission.
  • Several earlier studies (pre-statin) did find small increases in violence/suicides/accidents in those on LLDs. Monkey experiments did show more aggression with lipid lowering. But subsequent lipid-lowering studies in humans did not confirm this finding.
  • But, on the other hand, b-amyloid plaques incorporate cholesterol, and statins could conceivably interrupt this process. And there might be some additional benefit from their anti-oxidant and anti-inflammatory effects.
  • A few caveats of this study:
    • It was a really large, but still retrospective study. There was not a systematic approach to assessing acute memory change, but instead they relied on patient report and physician documentation. (Though the validation study found 76 of 86 patients had confirmed diagnosis, the actual incidence of reversible acute dementia was validated in only 38% of them)
    • There are likely biases: confounding by indication (patients on LLDs had many different baseline characteristics, and there may be unknown confounders there), detection bias (patients on LLDs probably saw their GPs more often, so more chances of reporting the memory change)
    • There was no systematic attempt to look at LLDs and chronic/slowly progressive memory changes.
  • It is at least a little reassuring that the acute effects on memory were short-term (within the first 30 days) with no evidence that they persist/happen later
  • So, a few issues going forward, assuming that there may be some adverse effect of statins on memory in some individuals:
    • We do not have a clear idea of what the goal LDL should be, and the new ACC/AHA guidelines of 2013 dismiss this issue (as those of you who have followed these blogs for a bit know, I do not agree with several of the recommendations of their guideline, including their dismissal of LDL goal)
    • For example, if I have a patient who has an indication for a statin (perhaps known atherosclerotic disease) but has an LDL of 96, should I really put them on a “high-intensity” statin and lower their LDL to 38? Or should I/the patient be happy with a lower intensity statin getting their LDL down to 60? Is there any cardiovascular benefit to such a low LDL? And, are there more adverse effects which could be associated with such a low LDL, such as diabetes, or memory issues etc. (at least there seems to be dose-response for the adverse effects)?
    • Are there differences between different statins – and, specifically between those most lipophilic (e.g. lovastatin, simvastatin or atorvastatin), which presumably cross the blood-brain barrier more readily, vs the more hydrophilic ones (e.g. pravastatin, and to a lesser degree, rosuvastatin). We do know clinically that the lipophilic ones are more associated with some CNS effects, such as insomnia or nightmares.

 

But, to me, perhaps the most important of the common statin adverse effects is that patients on statins are really happy with their lipid improvement (as are we), but a large % stop doing the lifestyle changes that they may have started after they hear their lipids are good (i.e., stopping the diet, exercise, wt loss). I think it is really important that we keep pushing on the lifestyle changes, since so many more bad health outcomes are related to lifestyle issues that are not addressed by statins (including diabetes, cognitive impairment, arthritis, cancer…….)

Primary Care Corner with Geoffrey Modest MD: Fasting Lipids? Not so Fast

19 May, 16 | by EBM

By Dr. Geoffrey Modest

There was a recent review summarizing the data and strongly suggesting that we use nonfasting lipid testing (see Mora S. JAMA Internal Medicine; published online April 27, 2016).

Details for these recommendations:

  • There was a recent consensus statement from the European Atherosclerosis Society comparing nonfasting with fasting lipids, finding that there was not more than an 8 mg/dl difference in total cholesterol, calculated LDL, non-HDL cholesterol, and up to a 26 mg/dl difference for triglycerides, with no difference in HDL, apo A or B (see Nordestgaard BG. Eur Heart J in press with doi:10.1093/eurheartj/ehw152). They go on to suggest we “consider” a fasting sample if the non-fasting triglycerides are >440 mg/dl.
  • Several studies have found pretty consistently that nonfasting lipids are appropriate for general cardiovascular screening, including the impressive large study by Mora from 2008 mentioned in last blog below. Also there was a meta-analysis of 68 studies which found no diminution of the association between lipids and CVD when using nonfasting measurements
  • Studies that have specifically included both fasting and nonfasting lipid determinations have found similar and sometimes stronger cardiovascular disease associations with nonfasting vs fasting determinations (including LDL and triglycerides)
  • Although many intervention studies have used fasting lipids, 3 large clinical trials with 43000 patients used nonfasting lipid determinations
  • Current recommendations are quite mixed: NCEP suggests fasting lipids, USPSTF recommendations are for either fasting or non-fasting cholesterol and HDL (which is the same as the 2015 NICE recommendations). Even the 2013 ACC/AHA cholesterol guidelines, which suggested that initial screening be with fasting lipids, does allow for nonfasting total and HDL cholesterol (in order to calculate the chol/HDL ratio, or the non-HDL levels)

A few comments:

  • I personally have been only using nonfasting lipid measurements for the past 20+ years after I saw a study from the Boston VA hospital which showed very small differences (<10%) between fasting and nonfasting values, with the huge benefit of ordering nonfasting blood work being that I could get the lab test when I was seeing the patient (i.e., the patient did not have to return in a fasting state, the test would get done more reliably, and with diabetics it seemed a mixed message to say that one needs to regularize their eating patterns as much as possible but come in tomorrow am before breakfast to get your blood test…). Since then, there have been a variety of studies confirming the utility and some suggesting the superiority of nonfasting levels.
  • Even the data on triglycerides, which have the most variation with eating, find that nonfasting triglycerides are a better predictor of cardiovascular events than fasting (there were several articles in a single issue of JAMA in 2007 finding this, including Bansal S. JAMA 2007; 298: 309). Perhaps this should not be surprising, since we do seem to eat pretty regularly/perhaps too often and our bodies are more exposed to nonfasting than fasting lipids. And there are even studies showing that the role of triglycerides is even more important in those with larger areas under the curve after eating: given the same meal, some people have more profound and longer lasting increases in triglycerides, which seems to correlate with more clinical disease).
  • Since I have written about this before, I will add a blog from 8/4/14, which also refers to the blog from 11/14/12, and also refers to the study by Samia Mora from 2008, who wrote the article above.

Blog from 8/4/14:

Over the years, I have sent out several blogs on the utility of checking nonfasting cholesterol (see blog appended below). There was a recent article in Circulation assessing the prognostic value of fasting vs nonfasting LDL levels in the Natl Health and Nutrition Survey III (see DOI: 10.1161/CIRCULATIONAHA.114.010001). This study reviewed the cross-sectional NHANES-3 database from 1988-1994 and stratified people by fasting status (fasting = at least 8 hours), followed a mean of 14 years and looked at outcomes, using propensity-matched scoring to adjust the subgroups to make them more apparently equivalent (by choosing the fasting and nonfasting cohorts with similar baseline characteristics).
Results:

  • 4299 pairs of fasting and nonfasting people assessed (62% of the whole group had fasting samples).
  • Primary outcome (all-cause mortality): no difference between groups
  • Secondary outcome (cardiovascular mortality): no difference between groups.
  • For both outcomes (not shockingly) there was an equivalent increase as LDL levels increased.
  • They also looked at fasting vs nonfasting triglycerides (which can vary by 20-30% by fasting status) and similarly found no difference in either of the outcomes by fasting status

So, further evidence that nonfasting lipid samples are fine. See my comments in the blog below. Many of the major therapeutic intervention trials for lipid reduction used fasting lipids (reasons not particularly clear why that was chosen, but just for reference, several studies did not – e.g. Heart Protection Study, Anglo-Scandanavian Cardiac Outcomes Trial).

Blog from 11/14/12:

Recent article (see doi:10.1001/archinternmed.2012.3708) which reinforces legitimacy of checking nonfasting lipids. I stopped checking fasting lipids 15+ years ago, when I saw a small study from the VA hospital in Boston showing that there was only a small difference in total and hdl cholesterol in fasting vs nonfasting, and only a 10% or so difference in calculated LDL (added note: there was another larger study in 2012 confirming a <10% variance — see Sidhu D, Naugler C. Arch of Intern Med 2012; 172: 1707-10).  So, I did it mostly because it was much easier for patients and more likely to actually get done. This new study, which is pretty huge, found essentially the same thing. In brief:

  • All blood tests in Calgary,Canada in a 6-month period in 2011 have had the time since last meal recorded. They looked at 200K pts, 99% outpatient blood tests. Controlled for age and sex.
  • Variance for total cholesterol and HDL was less than 2% (some recommendations suggest only testing chol and HDL, and these are the lipids input into the Framingham model)
  • Variance for calculated LDL was <10%
  • Variance for triglycerides was <20%
  • This article did not look at clinical outcomes

There have been a litany of articles in the past several years, several on triglycerides, showing nonfasting is superior to fasting in prediction of stroke, for example. (Triglycerides vary the most by fasting status, and one of the historic issues is that there is no standardized meal prior to checking non-fasting triglycerides, so how reproducible is it????). But these studies were pretty impressive. One of the physiologic reasons may be that high triglycerides after a meal may reflect decreased clearance associated with hyperinsulinemia/metabolic syndrome. So, either the metabolic syndrome is to blame, or perhaps the increased tissue exposure to high triglycerides and low HDL (they go together here) over time (i.e., increased area under the curve). There are also other articles which look at clinical events in fasting and nonfasting measurements. A large study by Mora at the Brigham have found that nonfasting chol and HDL as well as triglycerides were at least as predictive of events as fasting (see DOI: 10.1161/CIRCULATIONAHA.108.777334). More recently there has been more disparity in the recommendations from different medical societies, with some suggesting fasting and others nonfasting samples, which I think reflects the above list

Primary Care Corner with Geoffrey Modest MD: Use of Statins in Patients with Hepatitis? Looks Like a “Yes”

16 May, 16 | by EBM

By Dr. Geoffrey Modest

One question that comes up a lot in patient care is whether it is safe to use statins in patients with ongoing hepatic inflammation. A new retrospective VA study of hepatitis C (HCV) patients found an actual benefit for statins, as has been found in some other studies (see DOI 10.1002/hep.28506).

Details:

  • From the Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES) database, they looked at subjects initiated on anti-HCV therapy from 2001 to 2014, as well as all incident cases of cirrhosis and hepatocellular carcinoma (HCC). Those coinfected with HIV or hepatitis B were excluded, as well as those with baseline cirrhosis
  • Mean age 53, 65% white/18% black/6% Hispanic, 95% male, ALT 75, AST 53, FIB-4 score 1.7 (see below), median length of follow-up was 7-8 years. More statin users were diabetic (24% vs 9%), on metformin, other lipid-lowering agents, ACE-I, and they had a higher baseline LDL , triglycerides, and lower HDL). 90% were treated with PEG/RBV, 10% with PEG/RBV/telaprevir (i.e., the old drugs)
  • 9135 eligible people, of whom 1,649 developed cirrhosis, and 239 developed incident HCC [cirrhosis was defined by a FIB-4 score of >3.5, where the FIB-4 score is a mathematical calculation based on age, AST, platelet count, ALT]

Results:

  • Statin use was associated with
    • Higher likelihood of sustained viral response (55.1% vs 47.5%, p<0.0001)
    • A 36% reduction in development of cirrhosis, adjusted HR: 0.64 (0.53-0.68), p<0.0001.
    • Lower fibrosis progression, with a dose-response curve revealing progressively decreasing risk
  • Of the statins used, the highest decrease in FIB-4 score was with atorvastatin and fluvastatin (though only 34 patients were on fluvastatin): those without statin had FIB-4 increase of 0.26, those on simvastatin had increase of 0.11, but those on atorvastatin had decrease (-0.17), p=0.04,after adjustment for baseline FIB-4 score and established predictors of cirrhosis.
  • Statin use was also associated with a 49% reduction in incident HCC (adjusted HR: 0.51; 95% CI: 0.36, 0.72). A similar dose-response relationship was observed. [Interestingly, the decrease in HCC was independent of changes in the FIB-4 score. Though with hep C, the progression to HCC is tied in with presence of fibrosis].

So, does this make sense?

  • There are several mechanisms by which statins could decrease progression of liver fibrosis:
    • They have lots of “pleiotrophic” (non-lipid) effects: anti-inflammatory, antiproliferative, anitangiogenic, pro-apoptotic, immunomodulatory. And there are data suggesting they can inhibit cell growth, decrease proteolysis, block tumor spread, and may be chemoprotective against such malignancies as HCC.
    • Hepatitis C virus depends on cholesterol to replicate, so interference by statins might well help control hep C (statins do inhibit hep C in vitro; and people with hep C have lower LDL levels, which increase after the virus is cleared)
    • Statins also decrease components of the metabolic syndrome, and there are several studies suggesting that the combination of hep C infection and metabolic syndrome, present in about 20-25% of people with hep C, leads to a higher incidence of HCC
    • Humans studies (including another one from the above VA database: Butt AA. Hepatology 2015; 62: 365) have found decreased risk of hepatic fibrosis progression and development of cirrhosis by 43%; a Taiwanese study found that just using statins in patient with hep C infection found a reduced risk of cirrhosis in a dose-dependent fashion, also found in the HALT-C study. Another VA study of patients with compensated cirrhosis found a 45% decreased risk of decompensation and a similar mortality benefit
  • For patients currently on DAAs (direct-acting antiretrovirals) for hepatitis C, I found the following drug-drug interactions:
    • Ledipasvir/sofosbuvir possibly increases the levels of the statins (I checked atorvastatin, pravastatin, rosuvastatin, and simvastatin), though the warning for atorvastatin seems the most benign
    • Elbasvir/grazoprevir increases atorvastatin dose by 94%, rosuvastatin by 126%, simvastatin has likely interaction but not studied, no interaction with pravastatin
    • Daclatasvir expected increases in levels of atorvastatin, pravastatin, simvastatin — not studied, and 58% increase in rosuvastatin
    • Ombitasvir/paritaprevir/ritonavir increases levels of rosuvastatin 1-2 fold and pravastatin by about 33%. do not use with atorvastatin or simvastatin
    • And, none of the statins seemed to affect the levels of the DAAs

Effects of statins on other hepatitides:

  • NAFLD: statins have been shown also to decrease liver inflammation in those with NAFLD
  • One of my favorite studies, because of its name, was the GREASE study, which in fact was a study of Greek people with high lipids!! (Athyros VG. Lancet 2010; 376: 1916). They looked at 437 patients with baseline elevated ALT (but < 3x the upper limit of normal), 90% with metabolic syndrome, and all with LDL>100 and documented CAD, finding that atorvastatin for 3 years led to 1/3 the rate of recurrent CAD events (30% in placebo and 10% with atorvastatin), but 89% had normalization of their LFTs on the statin (although a simultaneous increase in ALT in those on placebo)
  • Hepatitis B: data on hepatitis B is somewhat mixed:
    • There are case reports of asymptomatic hepatitis B reactivation in a patient on atorvastatin, which resolved with discontinuation of the atorvastatin (see Wu DC. Intl J Infect Dis; 2013:e1069). Though, I should add that I had a patient with chronic hepatitis B, who was asymptomatic but developed a dramatic increase in his ALT to 450 on routine check after being on atorvastatin for 8 years, and the hepatic inflammation spontaneously resolved within weeks even while continuing the atorvastatin. So, it seems that even if statins did cause the hep B reactivation, there are not necessarily bad outcomes (perhaps my patient had HBV reactivation related to the statin, but then enough of an immunologic response to contain it).
    • On the other hand, a recent 2-year Chinese study (Hsiang JC. J Hepatol 2015; 63: 1190) in patients with chronic HBV infection found a 32% decreased risk of HCC in those on statins, and on subgroup analysis, those on a statin and nucleos(t)ide analog had a 59% risk reduction compared to those on a nucleos(t)ide analog alone (i.e., the combo might even be better: which may be really significant for HBV, since unlike hep c, the development of HCC is not so dependent on having baseline cirrhosis)
    • In general, it is pretty well accepted that there is no significant relationship between statin use and liver disease. In most large trials, there is no increase in statin-induced liver disease. As a result, the FDA changed their recommendations in 2012: check LFTs prior to starting statins, then only if clinically indicated

So, what does this all mean in the era of the potent new hepatitis C drugs?

  • My guess is that it is very unlikely that a statin will improved the efficacy of these new hep C drugs, since they are so powerful on their own
  • The issue of statin effect on decreasing the progression of fibrosis/cirrhosis is interesting, as well as the decreased likelihood of developing HCC. Unclear exactly why: it may well be that the effect of statins is not a direct effect on the development of these conditions, but simply its anti-inflammatory effect (though that is still welcome, and still could have long-term effects in preventing cirrhosis). And this could also be different in the current era of hep C treatment
  • If someone is on a statin prior to starting hep C DAA therapy, it makes sense to check the most up to date drug interactions (e.g. at http://www.hep-druginteractions.org/checker ) and likely decrease the dose of the statin, stop or change the statin, as indicated
  • For someone with hepatitis C who is not currently on treatment, it looks to me like there are good reasons to use a statin, probably best for atorvastatin (in part for its role in preventing CAD in those with this chronic inflammatory state — though it would be important to have confirmatory RCTs; and in part based on the above studies of its anti-hep C potential)
  • And, overall, it seems very likely than statins may be useful for those more generally with inflammatory liver disease, with reasonably impressive data for NAFLD and probably as well for hepatitis B. It would be really great to have more long-term data, preferably based on RCTs, which looked at real clinical outcomes and not just changes in ALT as with the NAFLD data (though I should add that the dramatic decrease in CAD events seems to justify the use of statins independent of their hepatic effects. And there are some data suggesting that simvastatin is less effective in decreasing biopsy-proved hepatic inflammation than atorvastatin). So, I have been using atorvastatin in particular in my patients with NAFLD and both hepatitis B and C, but following their LFTs more regularly, even in asymptomatic patients.

Primary Care Corner with Geoffrey Modest MD: Nonstatin Lipid Lowering Drugs, and Statin Myopathy

29 Apr, 16 | by EBM

By Dr. Geoffrey Modest

The ACC/AHA has just released a therapy guideline for patients who are on a statin but do not achieve the goal LDL (see http://content.onlinejacc.org/article.aspx?articleID=2510936#tab1 for full guideline). The context here is that recent guidelines have suggested that we do not add meds on top of statins, but there are a couple of studies which led them to change these recommendations). Main points:

  • If a patient is on a high-intensity statin but not achieving the goal LDL (which in the former guidelines was >50% decrease in LDL, though they are noting that one “may consider LDL <100” as a target)
    • Address statin adherence and intensify lifestyle changes (consider phytosterols)
    • Increase to high-intensity statin if not already on one [as pointed out in prior blogs, there are really pretty broad differences in statin intensity within their groupings: rosuvastatin 40 gets more LDL reduction than atorvastatin 40, so I definitely move within the high-intensity group as my first med change. As a side-issue, I do see many patients who have a really low LDL, in the 40-50 range, even on “low-intensity” statins, and I do not move to more intense ones — see my many prior blogs on this: I am still pretty convinced of the data on treating to a goal LDL and still do so. And I think their “consider LDL<100” suggests that they are moving more in that direction as well]
    • Consider adding non-statin meds:
      • Consider ezetimibe first, or consider adding or replacing with PCSK9 inhibitor second
    • Especially in patients with clinical CAD, and especially in diabetics, it is better to look at non-HDL levels (i.e., total cholesterol minus HDL), which has more predictive value than LDL levels [there are a few studies I have seen on this. In general, for those just on statins, the non-HDL is a better predictor of further clinical events (see JAMA 2012; 307:1302), and the target is non-HDL <100. as per above, they do include as a “may consider” the LDL goal of <70 or non-HDL goal of <100]
    • In high risk patients on a statin who do not achieve the goal, consider adding ezetimibe [though they acknowledge there is an evidence gap there, which is a euphemism for the fact that this has not been studied], or a bile-acid sequestrant if triglycerides <300 as second line [also no clinical outcome data on this….]. And in those with really high risk (documented CAD plus baseline LDL>190 and not achieve >50% LDL reduction or LDL<70), consider adding PCKS9 inhibitor even as a first step
    • They even consider PCKS9 inhibitors in patients without clinical CAD but baseline LDL>190 and not achieve >50% reduction in LDL on high-intensity statin. But no clear role for them for primary prevention or LDL <190, with or without diabetes
    • Can consider a nonstatin add-on in adults 40-75 yo without clinical ASCVD or diabetes, LDL 70-189 and estimated 10-year risk of >7.5% and on a statin for primary prevention but who do not achieve a >=30% reduction in LDL. consider ezetimibe or bile-acid sequestrant
  • They are not so clear on what to do if the patient is statin-intolerant. They do suggest that there may be less problem with lower statin dose [and the data are pretty clear that the majority of LDL reduction is with 5-10mg of a statin] or less frequent dosing [I have seen some data long ago suggesting similar lipid effects if take atorvastatin only a few times a week as with every day.]

Interestingly, at about the same time as the AHA came out with their guidelines for using non-statin lipid lowering therapy, JAMA published the GAUSS-3 RCT which found that the commonly-reported statin myopathy is very often not really true, and also found that evolocumab (a PCSK9 inhibitor) is much more effective than ezetimibe (see doi:10.1001/jama.2016.3608).

Details (in pretty brief):

  • 511 patients with uncontrolled high LDL levels and a history of intolerance to 2 or more statins (e.g. atorvastatin 10mg or any dose of other statins)
  • 2 phases of the study:
    • Phase A: a 24-week crossover trial with atorvastatin 20mg vs placebo, on each drug for 10 weeks
      • 491 patients (mean age 61, 50% women, 35% with CAD, mean LDL of 212. BMI 28, 95% white, 35% with CAD, 10% smokers, 13% diabetic, 63% high risk with 10-yr risk Framingham risk score of >20%. more than 80% were intolerant to 3 or more statins)
      • Results: “intolerable” muscle symptoms in 43% (209 of the 491) in those put on atorvastatin but not on placebo; 130 (27%) had muscle symptoms only on placebo; 48 (10%) had symptoms on both placebo and atorvastatin; and 85 (17%) had symptoms to neither drug
    • Phase B: those with muscle symptoms only on atorvastatin were randomized to ezetimibe 10mg/d vs evolocumab 420 mg subcutaneously per month.
      • Results: mean LDL 220 initially, decreasing to:
        • Ezetimibe: 183 mg/dL, absolute decrease of 31.0 [-16.7% (-20.5 to -12.9%)]; 0% achieved LDL <70 at 24 weeks
        • Evolocumab: 103.6 mg/dL, absolute decrease of 106.8 [-52.8% (-55.8 to -49.8%)]; 27% achieved LDL <70 at 24 weeks
      • Muscle symptoms reported in 28.8% on ezetimibe and 20.7% on evolocumab.

So, several issues:

  • In this last study, the presence of “intolerable” muscle symptoms actually from statins was confirmed in a minority of patients who had failed >= 3 statins in 80% of them. And a large retrospective study looked at people who had discontinued a statin due to adverse effects but were then rechallenged, finding a 92% success in restoring therapy, although not necessarily with the same statin or dose. This brings up the “nocebo” effect, where placebo gives patients either a perceived adverse effect (e.g., myalgias, in the above study) or even a profound measurable physiologic effect (e.g. hypotension in a patient who “overdosed” on placebo) — see prior blog: http://blogs.bmj.com/ebm/2013/11/25/primary-care-corner-with-dr-geoffrey-modest-nocebo/ . And, for better or worse, patients are more focused on adverse effects of meds than before (?? why: related to TV advertising, more distrust of meds given publicity of drug company malfeasance, deterioration in clinician/patient relationship….). But, in my experience, the bottom line is that if a patient is convinced that a med has a bad adverse effect, there is a pretty low probability that changing to another of the same class of drug will work.
  • Unfortunately the new guidelines do not really answer a pretty common question: what do I do with patients who are unable to take statins, even after trying several different ones at low doses?  The ACC/AHA guidelines punt on this one, with some vague recommendation that these patients “should be evaluated for statin intolerance and considered for referral to a lipid specialist”. The reality is that there really are limited possibilities, as follows:
    • Ezetimibe: the reason for including ezetimibe as an “add-on” drug in the ACC/AHA guidelines above is based on the IMPROVE-IT trial (see http://blogs.bmj.com/ebm/2015/06/23/primary-care-corner-with-geoffrey-modest-md-improve-it-trial-ezetimibe/for the blog on the IMPROVE-IT trial of simvastatin plus ezetimibe vs just simvastatin on patients with acute coronary syndrome, finding small but significant benefit with the addition of ezetimibe, though this drug-company sponsored trial and, per the blog, raises many questions about how useful ezetimibe really is as an adjuvant (e.g., it might be more useful to raise the statin dose maximally first). There are no studies on other cardiac conditions (primary prevention, those with stable CAD, etc.). And the data on ezetimibe is pretty clear: those with genetic mutations which presumably create the same situation as by ezetimibe (inhibiting the Niemann-Pick C1 like 1 protein) have lower ASCVD risk, ezetimibe lowers LDL cholesterol by about 17% alone, and provides an additional 14% reduction beyond that of simvastatin, but the trials of using ezetimibe are pretty bad (other than IMPROVE-IT): a 14-month trial of people with CAD on a statin were randomized to ezetimibe or 2 g of niacin, finding an increase in carotid intima-media thickness (CIMT) with ezetimibe, vs decrease with niacin. a 2 year study (ENHANCE trial) in patients with familial hypercholesterolemia put on simvastatin 80mg with or without ezetimibe found that ezetimibe lowered LDL a lot, but there was again an increase in CIMT with the addition of ezetimibe and a nonsignificant trend to more cardiac events with ezetimibe. bottom line: I am not so excited about this drug, and in general would not prescribe it alone (without a statin) and would first really push the statin to the maximally effective one (eg rosuvastatin 40) before considering it as an add-on
    • PCSK9-inhibitors: pretty powerful LDL lowering (though in the above study, the 52.8% is on a par with the high-intensity statins). The only clinical study to date is the pretty short 11 month OSLER study (N Engl J Med 2015; 372:1500), which found that evolocumab plus standard therapy (mostly statin, some on just ezetimibe) had a 61% decrease in LDL, and 0.95% cardiovascular events (vs 2.18% in the standard-therapy group). So, really expensive drug, reasonable at this point in patients at very high risk of a clinical event with suboptimal LDL lowering on a maximal statin, bigger studies are ongoing, and no clinical data yet on monotherapy.
    • And the old standbys, with some reasonable clinical data:
      • Cholestyramine: lipid research trial: lowered LDL 10-20%, 2% decrease in ASCVD events for each 1% lowering of LDL. No mortality benefit but study was not powered to achieve than endpoint. I have been using more colesevalam as my preferred bile acid sequestrant, since it is a little stronger in terms of LDL reduction and has additional benefit on LDL when added to a statin, though there are no studies showing it specifically has clinical benefit (and there are some studies showing improved glycemic control in diabetics)
      • Gemfibrozil: Helsinki study: 1% decrease in cholesterol was associated with 4% decrease in ASCVD events. Also underpowered for mortality benefit; VA-HIT trial: 22% decrease in ASCVD in those with mean LDL 111 but low HDL of 32.
      • Niacin (which I have not used for years) at high doses in the Coronary Drug Project was associated with 27% decrease in ASCVD over 6 years, with decreased mortality 9 years after the study stopped

So, bottom line: statins are pretty great overall, with significant reduction in lipids and improvement in clinical events within 6 months or so. And the 2 studies looking at long-term effectiveness have confirmed benefit up to 20 years later. One of my major concerns with statins is the recent observation that those on statins revert to stopping their lifestyle changes (“after all, my cholesterol is so good…..”). And probably we get some blame as well (“your cholesterol is so good”, and then move on to other issues). Lifestyle changes (exercise, healthy diet, losing weight, decreasing stress, stopping smoking, etc. etc.) are so important for many other things besides lipids (diabetes prevention, improved cognition, decreasing ASCVD beyond the effect of decreasing lipids, increasing longevity…) that we as clinicians should make sure to reinforce these issues. And I have had a couple of patients do so well with lifestyle changes that they have come off statins. And these lifestyle changes take on an even more significant role in those who are intolerant of statins

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