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

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 https://stg-blogs.bmj.com/bmjebmspotlight/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 https://stg-blogs.bmj.com/bmjebmspotlight/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.

 

2. 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 https://stg-blogs.bmj.com/bmjebmspotlight/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.

 

3. 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…….)