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Cardiol- lipids

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)


  • 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 , 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)


  • 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)


  • 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 )

  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

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 )
  • 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.


  • 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.


  • 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)


  • 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).

  • 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).


  • 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]


  • 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 ) 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 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: . 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 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

Primary Care Corner with Geoffrey Modest MD: Statin Primary Prevention in Intermediate Risk Patients

15 Apr, 16 | by EBM

By Dr. Geoffrey Modest

2 articles were in the NEJM this week from the HOPE-3 study presented at the Am Heart Assn meetings, looking at lipid and blood pressure lowering in people at “intermediate-risk” (see DOI: 10.1056/NEJMoa1600176 ). This blog will review the cholesterol one (the hypertension one will be reviewed Tuesday). Study funded by Canadian Institute of Health Research and a drug company. Details for the lipid arm of the study (this was a 2×2 factorial design with the hypertension arm):

  • 12,705 people in 21 countries/6 continents (eligibility criteria: men ≥​ 55 yo/women ≥​ 65, with at least one of: elevated waist-to-hip ratio, history of low HDL, current or recent smoking, dysglycemia, family history of premature CVD, mild renal dysfunction; also women ≥​​60 yo with 2 or more of these criteria), all without baseline cardiovascular disease (CVD) and at intermediate CVD risk (defined at annual risk of approx 1% per the INTERHEART risk score, a score from 0-49, where the low-risk group had a score ≤ 9), then randomized to rosuvastatin 10 vs placebo.
  • Median age 66, 87% with elevated waist-to-hip ratio, mean BMI 27, 27% current/recent smokers, 6% diabetes,mean HDL 44.7 mg/dl, LDL 127.8, triglycerides 128.8, hs-CRP 2.0, INTERHEART risk score of 14.5, 29% Chinese/27% Hispanic/20% White/15% South Asian/2% Black
  • Initial 4 week run-in period where people got both rosuvastatin and the BP med (candasartan/HCTZ) to make sure they were tolerated. the most common adverse effect was hypotension in 2%
  • First coprimary outcome: composite of death from cardiovascular causes, nonfatal MI, or nonfatal stroke; second coprimary outcome: the first one plus revascularization, heart failure, and resuscitated cardiac arrest
  • Followup 5.6 years
  • Results:
    • Rosuvastatin lowered LDL by 26.5% (35 mg/dl), triglyceride by 21.2 mg/dl, and hs-CRP by 0.19 mg/L. overall med adherence was 77.3% by the end of the study (74.8% in the placebo group)
    • Rosuvastatin (vs placebo) resulted in:
      • First coprimary outcome: in 235 people (3.7%) vs 304 (4.8%), a 24% reduction [HR 0.76 (0.64-0.91, p=0.002)], NNT (number-needed-to-treat) to prevent a first coprimary outcome was 91
      • Second coprimary outcome: in 277 people (4.4%) vs 363 (5.7%), a 25% reduction [HR 0.75 (0.64-0.88, p<0.001)]​, NNT was 73 for the second coprimary outcome​
      • In terms of the actual outcomes: statistically significant decrease in MI (35%), stroke (30%), revascularization (32%), hospitalizations for cardiovasc reasons (25%)
    • The above results were consistent in subgroups of baseline cardiovascular risk, lipid level, C-reactive protein level, blood pressure, race/ethnicity (though, interestingly, the subgroups doing better included those the lowest cardiac risk score, the lowest initial LDL of <112.3/mean of 89.1, the lowest SBP of ≤​131.5/mean of 122.2; and men and those of European descent)
    • The curves began to separate after 1 year and continued to splay apart for both outcomes. Also, there was pretty much no difference in the group on just rosuvastatin and those on double therapy with candesartan/HCTZ)
    • No excess diabetes or cancer with rosuvastatin, but increased cataract surgery (3.8% vs 3.1%, p=0.02) and myalgias with CK rise >10 ULN (5.8% vs 4.7%, p=0.005) — though no difference in number of people who discontinued the rosuvastatin from myalgias. And fewer people on rosuvastatin had a DVT or PE (14 vs 31, p=0.01) [FYI, this has been found in many of the statin trials]. Overall the rate of med discontinuation for adverse events was somewhat higher in the placebo group….

So, this trial addresses primary prevention in a less high-risk group than previous studies, which had been largely done in North American and Europe in white people. A few points:

  • Internationally, CVD is associated with 18 million deaths/yr and an equal number of nonfatal cardiovasc events. 80% of the global burden is in low- and middle-income countries
  • High LDL levels provide a population-attributable risk of about 50%, and this risk is graded with no documented threshold
  • There was no attempt to achieve a target lipid level, though of note, most people had “normal” LDLs
  • The degree of CVD reduction was consistent with the degree of LDL reduction found in previous statin trials (approx 25% decrease in CVD per 1 mmol/L, or about 40 mg/dl, decrease in LDL)
  • The low level of adverse events supports the approach of just giving the med and not doing lots of blood tests afterward (which makes this approach even more useful in resource-poor countries). And cheaper generic statins are readily available in most areas
  • This trial does extend the results for statin treatment in primary CVD prevention to include even those at intermediate CVD risk as well as to those from an array of different ethnic backgrounds. [The placebo group had a 5.0% incidence of CVD events over 5.6 years, confirming this was a truly intermediate group]

So, how should this affect our practice?? There are several points that would support a more aggressive approach to lipid control, despite the fact that over 5.6 years, the absolute benefit was not so dramatic (73 people treated to prevent only one event):

  • These were relatively low risk patients, with the placebo group having only having CVD events at a rate of about 1%/yr, so not so surprising that one would need a longer trial to see more potential clinical efficacy
  • ​On subgroup analysis, those who seemed to benefit the most were those at even lower risk: those with the lowest LDL, the lowest blood pressure, the lowest INTERHEART risk score; so, one might project the most benefit in those with an even lower than 1%/yr CVD risk, requiring an even longer study
  • And, overall the curves, to me, look like they are showing increasing benefit of statins over time, especially in the last 1-2 years of the study (and this is despite decreasing medication adherence and increasing LDL levels)
  • From my perspective, I think this really reinforces the importance of the primary role of lifestyle changes:
    • Overall these participants were overweight
    • Mean LDL was 128 (which maybe really isn’t “normal”, since in non-Western populations without significant heart disease, they have much lower LDLs, with total cholesterol levels of about 130)
    • Mean blood pressures was 138/82 (more on this in the next blog) and this is not “normal” (in fact, the majority of blood-pressure-attributable-mortality occurs in this range, mostly because this is actually elevated and is much more common/disproportionately represented in the population overall)
    • 27% were current or recent smokers
  • Therefore, I strongly feel that our primary role in health care is prevention; these risk factors should be addressed aggressively by us in primary care and there should be broad-based public health initiatives to promote a healthy lifestyle. And that we not be complacent about mild elevations in the LDL or blood pressure, even though our guidelines suggest “no treatment”. This is reinforced by our sense of the “new normal” when we see so many patients with really high blood pressures and cholesterol levels. And, I certainly include myself in this category. It is hard for me to get excited about someone with a blood pressure of 135/85 or an LDL of 125 when I see so many patients with 190/120 and 220, respectively. But this study reinforces how important it is to focus on this very large group with somewhat high risk.
  • But, that being said, I think this study also reinforces that we should really be somewhat more aggressive medically in treating people at intermediate risk

Primary Care Corner with Geoffrey Modest MD: New DM Management Algorithm

25 Jan, 16 | by EBM

By Dr. Geoffrey Modest

The Am Assn of Clinical Endocrinologists and the Am College of Endocrinology just came out with their 2016 updated diabetes management algorithms (see ). Note: this is different from the annual Am Diabetes Assn diabetes care summary, which I cannot access now (website down) but will review at some point.

  • Lifestyle optimization is the cornerstone of diabetes therapy:
    • Optimal weight, regular activity (at least 150 min/week of moderate-intensity activity such as brisk walking plus strength training), sufficient amount of sleep (6-9 hours/night is associated with improved cardiometabolic risk factors), tobacco avoidance, behavioral support including groups for emotional support, motivation, and specific support around issues such as weight loss and exercise.
    • They also support the 8 FDA-approved drugs for weight loss in overweight or obese patients, and bariatric surgery if BMI>35.
  • The importance to individualize A1C targets: though an A1c<=6.5 is optimal “if it can be achieved in a safe and affordable manner”. But “minimizing both severe and non-severe hypoglycemia is a priority”.
  • Glycemic control targets include fasting and postprandial blood sugars, as per self-monitoring of blood glucose (SMBG)
  • Minimizing weight gain is a priority
  • The choice of meds should be individualized, looking at the array of risk/benefits (see MEDS below)
  • The drug algorithm stratifies drug choices by initial A1C levels
  • Comprehensive therapy includes lipid and blood pressure therapy [though I would add smoking cessation, and decreasing alcohol when applicable]
  • Until patient is stable, then should be seen at least every 3 months to review SMBG, check A1c, check comorbidites (g. blood pressure, lipids), psychosocial issues [again, would add smoking, alcohol]. When stable, can have less frequent monitoring
  • Prediabetes: primary goal is weight loss when indicated, and they emphasize [appropriately] that these patients have a higher atherosclerotic risk and should have more aggressive risk factor management. There may also be a role for metformin, acarbose, TZDs, and GLP-1 agonists (espliraglutide3mg) in preventing diabetes, as shown in clinical trials


  • Low risk of hypoglycemia, promotes weight loss, “has good antihyperglycemic efficacy at doses of 2,000 to 2,500 mg/d”, and has “robust cardiovascular safety relative to sulfonylureas”. They do upgrade the creatinine/GFR limitations, commenting that some authorities recommend stopping metformin only when the GFR<30 (see blog: And they comment on vitamin b12 deficiency in up to 16% of users, and advocating monitoring levels and treating [see below on my comments on metformin dosing]
  • GLP-1 agonists. Low risk of hypoglycemia, robust A1C lowering, reduce blood sugar fluctuations in both fasting and postprandial states. Do not use exenatide if creat clearance <30, hx of pancreatitis (though no studies showing it can cause pancreatitis), and theycan cause delayed gastric emptying [which may be part of the weight loss, but can be a problem in patients with gastroparesis]
  • Sodium glucose cotransporter 2 (SGLT-2) inhibitors: cause glycosuria, decrease A1c, decrease weight. They recommend, despite the increased risk of mycotic genital infections, severe DKA though infrequent, increases in bone fractures in some studies. limited efficacy if GFR <45
  • Dipeptidyl peptidase 4 (DPP-4) inhibitors: enhances GLP-1 by blocking its breakdown, modest A1C effect, weight neutral, low risk of hypoglycemia,
  • Thiazolidinediones (TZD): directly reduce insulin resistance, relatively potent A1C effects, low risk of hypoglycemia. And pioglitazone may confer cardiovasc disease benefit. Adverse effects include weight gain, increased bone fracture risk, and increased risk of edema/heart failure. Decreased adverse effects if use <=30mg/d of pioglitazone. [Appropriately, they do not even mention rosiglitazone]
  • Alpha-glucosidase inhibitors (AGIs): modest A1C lowering, low risk of hypoglycemia, and some data finding lower cardiovasc Adverse effects of bloating, flatulence, diarrhea.
  • Sulfonylureas (SFUs): relatively potent hypoglycemic effect (though lower durability than others), risk of weight gain and hypoglycemia. Glinides have lower effect on A1C, have shorter half-life, and lower risk of hypoglycemia
  • Colesevelam: bile-acid sequestrant which lowers A1C modestly, no hypoglycemia, decreases LDL levels, though 10% have GI intolerance.  can also increase triglycerides
  • Bromocriptine: slight A1C lowering, no hypoglycemia, and may be associated with decreased cardiovascular events
  • Insulin: most potent glucose-lowering agent. Consider especially in patient on 2 oral agents and A1C>8%. Usually start with single daily dose of basal insulin. Dosage can be adjusted by the patient, with clear instructions, based on SMBG readings. If on basal insulin and inadequate control, consider adding GLP-1, SGLT-2 or DPP-4 active drugs [I personally advocate the GLP-1 ones, as below]. May need to decrease insulin dose when adding these drugs. Can also add mealtime rapid insulin bolus to cover the meals. Problems with insulin include weight gain (1-3 kg more than those on other agents) and hypoglycemia (7-15% have at least 1 episode/yr). [I also have some concern about potential cardiovascular effects of the commonly associated hyperinsulinemia, as per prior blogs]
  • In new onset diabetics with A1C<7.5, lifestyle plus metformin. But can use pretty much anything (GLP-1, SGLT-2 inhib, DPP-4 inhib, TZDs, AGIs, SFUs or glinides)
  • If A1C>7.5, use metformin withanother drug. [See below. I think this is too aggressive and potentially dangerous]
  • A1C>9 who are symptomatic might benefit from insulin. Asymptomatic, can use insulin or “may initiate therapy with maximum doses of 2 other medications” [See below. I think this is too aggressive and potentially dangerous]


  • Blood pressure: target <130/80 [lower than JNC-8 suggests]. Less stringent in elderly [and I would add my usual caveats: check orthostatics regularly anyway, since I have seen many patients with systolics of 150 range which fall rapidly to 110 on standing; and even 130+ may be associated with cognitive decline]. In younger patients, a goal of <120/80 is reasonable if achieved safely, which seems to have a protective effect against strokes in a few studies. Lifestyle therapy is also important here (weight loss, Na restriction, alcohol restriction [though they comment on the benefits of moderate drinking, which I have challenged in several recent blogs, such as], and exercise. They also suggest starting with 2 agents if BP>150/100 [which I still think is too aggressive/potentially dangerous, and has appropriately been abandoned by JNC-8]
  • Lipids: all diabetic patients should be classified as high or very high ASCVD risk, even those <40 yo. They recommend treating-to-goal (unlike the AHA recommendations) with LDL targets of <100 or <70 depending on their ASCVD risk. Lifestyle changes as above. They do bring up using ezetimibe to achieve further LDL reduction [though I am hesitant to endorse this; see ] and the PCSK9 inhibitors. They also mention colesevelam and fibrates as potential add-ons, and even high-dose niacin. Also, high dose of fish or omega-3 fish oil. In those with triglycerides>500, consider low-fat and low carbohydrate diet, fibrates, omega-3-fatty acid and/or niacin (though these combos are unproven in clinical trials)


  • They do acknowledge the importance of life style optimization. In my experience, treating diabetes is the hardest issue in primary care, since achieving optimal (or even marginal) control is contingent on motivating the patient to optimize their lifestyle issues: exercise is often difficult for patients (g., for medical reasons such as knee arthritis or underlying depression/other psych issues, etc; or for practical reasons such as unsafe neighborhoods to walk around for personal safety issues or specific neighborhood issues such as poorly maintained sidewalks, unsafe crosswalks, etc), and diet is often difficult for a variety of reasons (lack of access to healthy foods, traditional diets high in carbs, psych issues, just trouble  breaking the habit of eating unhealthy and very tasty foods for a long time, etc). and if someone does not eat a reasonably consistent diabetic die, blood sugars may range from 45-450 mg/dl, and simply cranking up the diabetic meds is potentially dangerous no matter what their A1C is (ie, lowering the 45 even further).
  • As noted in many of my blogs on diabetes meds, there are precious few studies looking at important clinical outcomes. The FDA many years ago allowed drug companies to use the A1C as a surrogate marker for advances in diabetic meds. I will certainly grant that there are enough older studies that have shown consistently that lowering the A1C does lower the risk for microvascular disease, and I do not want to understate the importance of that. BUT, diabetic patients, by far, die from macrovascular disease (heart disease, strokes…), on the order of 80% of their deaths. And, though studies suggest that lowering the A1c can be beneficial for that outcome, it really depends on the drug (g., rosaglitazone was pretty effective in lowering A1C levels, but was associated in several studies with increased cardiac outcomes). The DPP-4 drugs have also been associated with adverse cardiovascular events in some studies (see And there are other significant adverse outcomes which may override the benefits of lowering the A1C: the FDA just supplemented their warning on SGLT-2 inhibitors, which are also pretty good for lowering A1c, but are associated with severe urosepsis and ketoacidosis (for prior blog, see​ )
  • So, my general approach to drugs (again, always continuing to work on the lifestyle issues) is:​
    • Metformin is generally very well-tolerated. I have seen dramatic effects of low dose metformin, with my typical starting dose of 500mg once a day, and only raise the dose as needed. There is decreased marginal effectiveness with increasing doses, similar to statins, where the majority of effectiveness is with the lowest dose. Also, metformin is better tolerated from a GI perspective when taken with meals. I think metformin is the single most useful agent for diabetic control. also, see the curious/interesting blog on metformin and the intestinal microbiome, suggesting that much of its effect may be from positive changes in the microbiome (see: I am concerned with the above recommendations which advocate using pretty much any drug as a single agent, as opposed to other guidelines which make metformin #1, then adding others.
    • I really disagree with their aggressive approach to patients with new onset diabetes. Many have A1C in the 13-19 range. I think this is mostly due to slowly progressive increases over time, which in part is from glucotoxicity (that is: as the sugar increases, the endogenous insulin works less well with documented decreases in insulin-mediated glucose uptake, leading to higher blood sugars), and this progresses until the patient becomes very symptomatic. Physiologically, my approach, as with very high but not hypertension emergency, is to see the increased sugar or blood pressure typically as a slowly progressive, with some physiologic adaptation by the body, and that it is safer to lower the blood sugar or pressure more slowly with frequent follow-up (I have seen too many patients treated aggressively, leading to electrolyte disturbances in diabetics and strokes in hypertensives).  In terms of new onset diabetes with initial A1C >15%: my experience with at least 25 newly diagnosed diabetics, 100% do very well and for a long time with just metformin (which often is initially augmented with insulin, which can be tapered off over weeks to months). And this is typically with just 500-1000 mg metformin/day.
    • Lately, I have been using more GLP-1 agonists if metformin needs a boost. They work really well, are mostly very well tolerated, do not cause hyperglycemia, to me seem to be pretty targeted and physiologic agents (they restore the “incretin effect”, which is blunted in diabetics). I also prescribe older drugs with more of a track record and known adverse effects (g., insulin, sulfonylureas). Though I often do add them to metformin, there is not much support for their macrovascular efficacy. Pioglitazone, especially in the 15-30mg range, works well and seems to be cardioprotective, per the PROACTIVE study (Lancet2005; 366: 1279)
    • ​For the newer drugs, I really focus on those with the best efficacy/adverse effect ratio, and also those that have the least ubiquitous effects (g., the DPP4 inhibitors poison a prevalent enzyme system in the body, so I am hesitant to use them because their efficacy is not so great in lowering A1C levels, and their potential for longterm adverse events is high given the abundance of potential non-diabetic effects). These issues have become more concerning as the FDA is pushing through approvals more quickly, often with the intention of requiring post-marketing surveillance which the drug companies mostly do not do (see blogs below). And, of note, 19 of the 20 members of the committee developing these recommendations have drug company ties….

See: which critques the study on the SGLT2 inhibitor empaglifozin which purportedly shows cardiac benefit, though the FDA came out with an advisory about it causing severe urosepsis and ketoacidosis

But, as noted in prior blog , <20% of required postmarketing studies for medical devices were done within 3 years of the FDA requiring them, and no fines have been issued for noncompliance with the FDA mandates. which goes through some of the drug company malfeasance in nonreporting of severe drug adverse effects, lack of follow-up on postmarketing studies, and the poor enforcement by the FDA.​ promoting fructose restriction in diabetes management which questions advocating alcohol for diabetics with FDA warning about DPP-4 inhibitors and joint pain


Primary Care Corner with Geoffrey Modest MD: Prescribing Alcohol to Diabetics?

13 Nov, 15 | by EBM

By Dr. Geoffrey Modest

An Israeli study was just published in which adults with type 2 diabetes were randomized to drinking wine vs water, and an array of cardiometabolic  parameters were assessed (see Ann Intern Med. 2015;163:569-579​) — the CASCADE trial: CArdiovaSCulAr Diabetes & Ethanol trial, which just goes to show you that you can develop an acronym pretty easily for just about anything.



  • 224 patients (baseline: mean age 60, 69% men, BMI 30.0, HDL 1.12 mmol/L or 43.5 mg/dL, LDL 2.41 mmol/L or 93.0 mg/dL, cholesterol/HDL ratio 4.1, fasting plasma glucose 150.4 mg/dL or 8.3 mmol/L, HgbA1C=6.9%, BP 137/78, waist circumference 105 cm, and mean positive metabolic syndrome criteria was 3.1 of 5) were randomly assigned to 150ml of mineral water, white wine or red wine with dinner daily for 2 years. Previously, these subjects had drunk no more than 1 drink of alcohol/week (mean 2.3 g/d)
  • All followed a Mediterranean diet without calorie restriction
  • They also looked at alcohol metabolism/ ADH1B polymorphism, where 36% were CC, 38% were CT and 26% were TT (the TT polymorphism of ADH1B is also called ADH1B*2 rs1229984, and is associated with much faster hepatic clearance of alcohol); and assessed the homeostatic model assessment of insulin resistance score (HOMA-IR, a measure of insulin resistance), which was 5.0 at baseline


  • Those on red wine vs water had: increased HDL [0.05 mmol/L (0.04=0.06), or 2.0 mg/dl (1.6-2.2), p<0.001] and apolipoprotein A1 [0.03 g/L (0.01-0.06),p=0.05], and decreased total cholesterol/HDL ratio by 0.27 [(-0.52 to -0.01), p=0.039]. Those drinking white wine were not significantly different from water in terms of lipid changes (except that, interestingly, both the red and white wine drinkers did have decreases in triglycerides by .09 mmol/L or 7.9 mg/dL with white wine and -0.1 mmol/L and 12.0 mg/dL with red wine). White wine, but not red wine, was associated with significant decreases in fasting plasma glucose levels (decreased 1.0 mmol/L, or 17.2 mg/dL) and HOMA-IR scores.
  • Only when looking at the slow alcohol metabolizers (ADH1B*1 carriers), both red and white wine had better fasting plasma glucose, HOMA-IR​, and hemoglobin A1C levels similarly
  • ​And, sleep quality improved in those drinking wine (p=0.040)
  • But no difference in blood pressure, adiposity, liver function, drug therapy, symptoms, or quality of life
  • Overall, red wine led to decrease in number of components of the metabolic syndrome by 0.34 [(-0.68 to -0.001), p=0.049], not with white wine

So, there are a few issues here

  • There have been many studies and meta-analyses from observational trials suggesting that moderate amounts of alcohol ingestion are cardioprotective, largely attributed to the alcohol content itself. For more discussion of this, see for blogs on alcohol, and​ which argues that the attributable benefits from even small amounts of alcohol consumption are likely related to inherent biases in the observational data collection.
  • This study is the first I’ve seen where there is an actual intervention done. Of course, the intervention is not really through a randomized controlled trial since I suspect that those drinking wine were in fact aware that it was not mineral water. And, one wonders if there might have been other changes in the diet related to drinking wine with the meal, though all were instructed in Mediterranean diet guidelines – i.e., they did not monitor the actual dietary composition, and the glass of wine could have altered the choices or quantities of foods consumed.
  • As noted in prior blogs, not all HDL is the same, and there are nonfunctional and even pro-inflammatory variants (see , and will append an older blog on pro-inflammatory HDL at the bottom). So, looking at HDL numbers may not necessarily translate to cardioprotection.
  • If the findings of the study are indeed valid, they suggest that the effect of wine on diabetic markers is basically through the alcohol itself (since both red and white wine improve the diabetes markers especially in the slow metabolizers who have more sustained blood alcohol levels), while the lipid effects were more evident with red wine, suggesting that its particular components may be protective (perhaps the phenolic compounds: resveratrol and quercetin), perhaps through their antioxidant, endothelial or antiplatelet actions (though in general it is felt that the quantity of these in red wine is insufficient to achieve therapeutic effects)
  • So, interesting study, though I don’t think it provides definitive answers to the question. I.e., I’m not ready to suggest alcohol to patients yet… (and, per the 5/14/12 blog, the real answer will come from looking at real clinical events and not the surrogate markers of changes in cholesterol, since alcohol also increases the proinflammatory variant).

Here is blog from 5/14/12

Although the vast majority of epidemiologic studies have found HDL to be cardioprotective, there have always been some concerns. HDL is comprised of a diverse group of lipoproteins with significant metabolic heterogeneity. There were a few older studies finding a “pro-inflammatory HDL”, which predisposed people to heart disease. The clinical trial of Torcetrapib, a cholesterol ester transfer protein inhibitor, dramatically increased HDL but was not cardioprotective. The researchers suggested that the HDL was somehow deformed. (This large torcetrapib trial overwhelmed a meta-analysis last year in BMJ, suggesting no benefit to raising HDL). In any event, there is a likely very illuminating article from Harvard school public health (see doi:10.1161/JAHA.111.000232). They had found before that there was occasionally a small apolipoprotein (apo C-III) on some lipoproteins causing a pro-inflammatory and atherogenic response. On LDL particles, this apo C-III caused increased coronary atherosclerosis independent of the LDL itself. They looked at the data from 2 large epidemiologic studies — Nurses health study (NHS, 121K female nurses) and the health professionals follow-up study (HPFS, 52K males), looked at stored serum and assessed the HDL C-III relation to cardiac events.


  • 14% of women in NHS had HDL with apo C-III; 11% of men in HPFS had apo C-III
  • Overall, each standard deviation increase in HDL was assoc with a 21% dec in cardiac events; but for patients without apo C-III, there was a 34% decrease in events and for those with apo C-III there was a statistically significant 18%
  • Looking at the effect of apo C-III in multivariate analysis of other risk factors (all of below statistic signif):
    • Compared to pts with normal wt, overweight and obesity were associated with 7% and 12% lower levels of HDL without apo C-III – i.e., overwt/obesity with lower of the good HDL.
    • Alcohol was assoc with 3% higher levels of both HDL types
    • Smokers had 1% higher levels of HDL with apo C-III (the bad one)
    • Premenopausal women had 9% higher levels of HDL without apo C-III, as did postmenop women on estrogen replacement therapy, vs other postmenop women
    • Per SD increase in triglycerides, 8% lower HDL without apo C-III and 15% increase in HDL with apo C-III
    • Per SD increase in A1C, 4% increase in HDL with apo C-III

(i.e., several of these risk factors which change HDL also lead to more HDL with apo C-III)


Primary Care Corner with Geoffrey Modest MD: Comparison of the 2013 ACC/AHA lipid guidelines to ATPIII

5 Aug, 15 | by EBM

By: Dr. Geoffrey Modest 

A recent study assessed the accuracy of the 2013 ACC/AHA guidelines in identifying patients in the Framingham Study who either developed cardiovascular disease (CVD) and/or coronary artery calcification (CAC), comparing the results to that of the prior 2004 ATPIII guidelines. (see JAMA. 2015;314(2):134-141​).


–2435 statin-naive participants (mean age 51.3, 56% female, mean Framingham Risk Score — FRS — of 6.7%, mean LDL 121 mg/dL, mean CAC score of 95 with 42% having CAC score >0, overwhelmingly white population) were enrolled from the longitudinal offspring and third-generation cohorts of the Framingham Study. median followup 9.4 years.


–39% of patients were deemed statin-eligible by the 2013 guidelines vs 14% by ATPIII.

–There were 74 (3.0%) incident CVD events (40 nonfatal MIs, 31 nonfatal strokes, 3 fatal coronary artery disease/ CAD events).

–Those statin-eligible by 2013 guidelines had increased HR for incident CVD vs those eligible by ATP III: HR 6.8 (3.8-11.9) vs 3.1 (1.9-5.0), with p<0.001

–by the ATP III guidelines 6.9% of those statin-eligible vs 2.4% statin-ineligible had incident CVD event. by the 2013 guidelines, 6.3% of statin-eligible had CVD and 1.0% of those statin-ineligible

–for women, the numbers were smaller than for men (2.0% vs 4.4% had incident CVD). There was a nonsignificant difference between statin-eligible and statin-ineligible by the ATPIII guidelines, though there was a significant (p<0.001) difference in those groups by the 2013 guidelines

–there were similar results in those at intermediate Framingham Risk Score (FRS), 38% of the total population (3.9% developing CVD), but the CAC score was significantly higher in people with intermediate FRS who developed incident CVD. 80% of this intermediate group were statin-eligible by the 2013 guidelines vs 27% by ATP III [note: the definition of intermediate FRS is somewhat complex and depended on the LDL level and number of CAD risk factors]

–those with CAC scores>0 were more likely to be statin-eligible by 2013 guidelines than ATP III (all with p<0.001):

–CAC score >0 (n=1015) 63% vs 23%

–CAC score >100 (n=376) 80% vs 32%

–CAC score >300 (n=186) 85% vs 34%

–CAC score of 0 was associated with very low CVD risk in stain-eligible people by the 2013 new guidelines, comprising 33% of the cohort, and with a CVD rate of only 1.6%

–if all of the patients with CAC score of 0 were considered to be statin-ineligible (ie, this was a strong negative risk factor for starting statins), there was no difference in the % of incident CVD in the statin-ineligible groups by either the ATP III or 2013 guidelines, and a much higher % incident CVD in the statin-eligible group [which suggests that those with CAC=0 really would not benefit from statins, leaving even greater benefit for those with CAC>0 who were statin-eligible by either guideline]

Several points:

–FRS did not fare well in differentiating likely statin benefit as compared to the 2013 guidelines. One suggestion from the data is that perhaps a large part of the reason is that the 2013 guidelines captured more people with CAC scores>0.

–the 2013 guidelines cast a much wider net in terms of those who would be statin-eligible, which I think include a lot of people at very low risk of cardiovascular disease (see prior blogs: here , here, and here)​ For example, using the 2013 guideline risk calculator, a 60 year old white male nonsmoker with systolic BP on 130 on meds and an LDL of 70 and an HDL of 70 should get a moderate intensity statin. Same for a 45 year old African-American with the same clinical picture. So, it is not surprising that adding an additional 12.8 million adults who would get statins by the 2013 guidelines over the ATP III guidelines would lead to less heart disease, but would also treat lots of patients at very low risk

–CAC is the one CAD marker which is felt to be the most useful of the non-traditional ones (ie, better than C-Reactive Protein — CRP, etc) by the American Heart Assn.  Many studies have shown that low CAC scores nearly exclude clinically important CAD (as in the current JAMA study, with other studies finding similarly about a 1% risk in 10 years). And those with extensive CAC have 10-fold increased risk after multivariate adjustment. This really is not so surprising: the existence of any atherosclerotic disease (eg peripheral artery disease) is associated with a significantly increased risk of CAD, so showing calcification of the coronaries themselves is at least as likely to predict risk of CAD…

— the Multi-Ethnic Study of Atherosclerosis looked at the relative risks of CRP vs CAC (see Lancet 2011; 378: 684–92), following 950 people for 5.8 years, finding no association of clinical events with CRP levels, but

–47% had initial CAC scores of 0 and had CAD event rate of 0.8/1000 person-years

–74% of all of the CAD events were in the 25% with CAC scores >100, at a rate of 20.2 events/1000 person-years

–for CAD, the 5-year NNT for CAC=0 score was 549, but was 94 for scores 1-100, and 24 for scores >100

–for CVD, the 5-year NNT for CAC=0 score was 124, but was 54 for scores 1-100, and 19 for scores >100

So, this new JAMA study by itself does not add much, other than that by really spraying statins relatively indiscriminately all over the place, there are fewer atherosclerotic events (this would likely happen by just lowering the threshold for treatment with the old ATP III guidelines). As a person who does prescribe lots of statins (always reinforcing lifestyle changes as well) to many more patients than those qualifying by ATPIII criteria (including those with PAD or any evidence of atherosclerotic disease, and often those with metabolic syndrome or glucose intolerance — as noted in prior blogs), and as someone who is pretty strongly anti-radiation exposure (eg, see here), I am leaning toward including CAC as part of my CAD risk assessment (i haven’t done so yet, but am thinking pretty strongly about doing so, if covered by insurance), since:

–CAC pretty directly correlates with coronary atherosclerosis and ultimately with cardiac events (and a score of 0, present in a good proportion of patients even at intermediate CAD risk, seems to render CVD incidence miniscule)

–the actual radiation exposure is only 0.89 mSv in the MESA study, well below both the overall background radiation (3 mSv/year) and the average dose in the now-accepted low dose lung CT scans for smokers (1.5 mSv and this is annually, though really the average annual dose is 8 mSv given the number of false positives leading to more intensive radiologic investigation: see here). And the cost in 2011 was about $100 for the CAC scan.

–and there really are harms to prescribing statins to those who do not need them: occasional really bad adverse events (I’ve seen a couple who have had bad rhabdo, renal failure, and prolonged dialysis), more frequent less bad events (diabetes, maybe cognitive decline), troublesome events (myalgias, bad dreams…), cost of meds, cost of followup exams and labs, and increasing the medicalization of the patients.

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