March 6th, 2012

Another Round in the Debate on Diabetes and Statins

Let me start by saying that I am proud to have Eric Topol as a friend and a trusted advisor over the past 20 years. His work has been an inspiration to cardiovascular health professionals for several decades. His new book, The Creative Destruction of Medicine: How the Digital Revolution Will Create Better Health Care, should be required reading by all physicians and in all medical schools. It is simply that good.

Eric is a strong believer that we need to have more personalized medicine. I agree. I predict that he and his research group will lead the way to help us understand why certain people benefit more from certain medications and others may not. So far, the only ways we have to decide which asymptomatic persons would benefit from statin therapy are the traditional risk factors which make up the Framingham risk score, hsCRP, and coronary calcium measurements. Both of the latter two tests have been given a class IIa indication from the AHA for use in intermediate risk adults (Framingham score of 10-20% risk of an MI over the next decade.)

Eric is concerned about the apparent increased risk of diabetes with statin use. A 2010 meta-analysis in the Lancet found about a 10% increased risk in statin users. Eric rightly points out that the relative risk was higher with the more potent rosuvastatin in JUPITER. Yet, that is where we saw a  significant decrease in total mortality and the largest relative risk reduction in CVD events.

Dr. Topol is one of the country’s leading geneticists and thought-leaders. He may be an invited guest to Stockholm in the next decade to accept a great award. If that is the case, I would like to be on his invitation list.

No one is right all the time – just ask my wife. We know that chlorthalidone reduces clinical events and reduces mortality in persons with a systolic blood pressure greater than 160 but it also raises blood sugar. We also know that niacin raised blood sugar in the Coronary Drug Project, but it reduced events and mortality as a single agent.

We don’t know why certain adults go from a glucose of 115-125 and then go over that magic 125 threshold more frequently. Though this has not been published, I have been told by several statin investigators that the vast majority of the persons who crossed the 125 line were clearly insulin resistant with glucoses between 115-125. We are not talking about going from a glucose of 90 to 140!

Before we throw out the NCEP guidelines on primary prevention, I think that we need to be more skeptical of the diabetes fear from statins. The benefit is very clear in high risk primary prevention patients. Please refer to Professor C. Michael Minder’s latest paper on the American Journal of Medicine website. It is a masterpiece. Just like William Shakespeare’s Much Ado About Nothing. My favorite line from that play was “Let every eye negotiate for itself and trust no agent.”

All of us await the ATP guidelines and how to make sense of the benefits and possible risks of the hyperglycemia seen with the more potent statins. In the meantime, please read Dr. Topol’s book. It is fabulous and thought-provoking. And by the way if your statin patient’s glucose goes above 125, simply remind them of the importance of dropping a few pounds and exercising more. Eat Less, eat smarter and move more. A lot more.

I look forward to teeing it up with my friend, and trusted mentor Eric Topol at Torrey Pines and Congressional sometime in 2012!  Dr.Topol may prove to be correct on this topic but my view of statins is much more optimistic in high risk primary prevention patients.

12 Responses to “Another Round in the Debate on Diabetes and Statins”

  1. Steven Greer, MD says:

    As a business analyst, I see far too often how clinical research becomes junk science. I doubt the very integrity of the few statin trials that were conducted all over the world in enrollment sites with no oversight, and even then barely showed any benefit to statins in primary prevention. Most cardiology research really is worthless and does not help clinicians. It is made for marketing.

    I discussed this problem of large trials conducted outside the US with the head of the FDA’s drug divisions

  2. Alain Efstratiou, MD says:

    Dr Blumenthal, I agree completely with your assesment. Cardiovascular outcomes constantly improve and most of our patients are on statins. At least for the duration of the studies published, there is overall benefit with statin treatment irrespective of the 1% more diabetics. If someone shows that 15, 20 years later we increase harm, then we should reconsider.
    I respect Dr Topol’s contributions but I think he jumped the gun on this one.

  3. Quantitative thinking is at the core of this question. The consequences of high cardiovascular risk are known–the challenge is precise identification of those with high lifetime risk early enough.

    The numbers speak in favor of statin use in the population at guideline cutoffs, which may change. But in addition, the natural history of the syndrome of statin-induced insulin resistance qualifying for the diagnosis of diabetes (or statin-induced intensification-of-preexisting insulin resistance) is yet to be characterized.

    Richard Kones MD

  4. I side with Dr. Topol. The statin studies have been of short duration and have demonstrated on average a 21% reduction in MI and little measurable benefit with mortality. The onset of diabetes would not increase mortality in a study lasting 2 to 4 years as is the limit for most statin studies.

    While I have found statin use helpful as part of the whole in coronary prevention, I am bothered by the inflated status that statins seem to enjoy from most clinicians and the public at large. “What was I thinking, but now I am on Lipitor”.

    Aside from the stain debate, I am surprised that HS-CRP has II-A indication from the AHA. Did we not notice that it had no value in ASCOTT-LLA in either predicting risk or monitoring response to therapy.

    In addition, in MESA, the baseline HS-CRP did not correlate with MI risk until the DATA was contorted to provide a minimal benefit but nothing compared to the value of coronary calcium imaging. With the Jupiter like substudy from MESA, of those with “normal lipids” but elevated HS-CRP, coronary calcium determined the 50% with 0 calcium scores and such low risk that statin use could only increase risk.

    It is past time for personalized medicine and the use of serial calcium imaging provides the best measure of risk and the best measure of response to therapy.

  5. I forgot some conflicts of interest.

  6. Statins are the master drugs for both primarty & secondary prevention of CHD/CVD & supported by voluminous data of RCTs. What is reliability of those data claiming statin use &risk of diabetes? It it replicated? Even if such small risk persist which cleary out-weighted by the benefit.

  7. Correction:- Statins are the master drugs of prevention & treatment of CHD & CVD. Their beneficial effect clearly outweighs any small risk like diabetes. About impairment of cognition no good quality data support it. On the contrary by preventing recurrent stroke it helps presevation of cognition.

  8. Ankush Gupta, MBBS, MD Internal Medicine says:

    statins are the wonder drug that has proved itself in many large RCT and in our own practice and its beneficial effect outweight the small risk of diabetes. my large number of patients are on statins for primary and secondary prevention of CHD and CVD. i have observed marked reduction in hospitalization due to acute vascular events in patients on statins especially high dose of statin irrespective of there lipid profile status.

  9. Steven Greer, MD says:

    What if, just what if, statins have been over-prescribed and the efficacy data were bogus. How badly an foolish would well intentioned doctors feel? Then what would human nature and psychology do next? Yep, we are in anger and denial stages folks.

  10. While the mortality statistics over short-term studies using statins in primary prevention are not overwhelming, this is simply because within a large, young sample, cardiovascular events are rare. Would a huge definitive study, as suggested by Fuster et al recently, ever take place? The expense and duration would be immense barriers, since they would require sufficient power and meticulous design. In addition, the objection of multinational variation in quality of execution would again arise.

    Clinicopathological correlation between events in children, compared to the same participants as young adults, eg, as in the Bogalusa study, as well as evidence from other sources, enables a logical inference regarding the natural history of CV events, since they may be tracked over longer periods of time.

    As cardiovascular risk rises secondary to dual epidemics of obesity and diabetes, the blurring of primary and secondary prevention also increases. When a high risk patient is seen in the AM, s/he may not qualify for statin drugs. But that same PM, after a CAC is done, that very same patient may be eligible for statins for secondary prevention. Data also suggest that for many patients who are overweight, diabetics, or who have metabolic syndrome, an LDL-P will also “convert” many patients from “primary” to “secondary” prevention. The disease that existed in the AM is the same as the disease in the PM, only re-viewed.

    The numbers comparing benefit to risk regarding statins and diabetes are about 9 to 1.

    Assume those patients with significant 2+ risk factors (a huge number nowadays)–do not qualify for primary prevention statin therapy, and do nothing to improve their risk factors through lifestyle. What do you think will happen to them? Their subclinical CV disease will progress until a major event occurs, or they will succumb to a competing cause of death. Lifetime risk data from Lloyd-Jones et al and current causes of death so indicate now, without an expensive 20-year study.

    Re: CRP. Not perfect, but a considerable portion of residual risk, a large problem limiting outcomes, may be attributable to unaddressed inflammatory processes. A lot of the bricklayers that put the calcium imaged in arteries have CRP as their last name, with cousins called TLRs. Please see the recent editorial by Braunwald E. Creating controversy where none exists: the important role of C-reactive protein in the CARE, AFCAPS/TexCAPS, PROVE IT, REVERSAL, A to Z, JUPITER, HEART PROTECTION, and ASCOT trials. Eur Heart J.2012; 33(4):430-432.

    Richard Kones MD

  11. Neville Wilson, M.B., Ch.B., D.Fam. Med., M.Sc., D.Obs (COG) SA., B.A. says:

    Dr. Blumenthal invites us to be “sceptical of the diabetes scare”, thereby disagreeing with the contrary concerns of Dr. Topol, arising from data which includes the meta-analysis of 13 trials showing a 9% risk increase for new onset diabetes among statin users.
    While it is true that meta-analysis cannot establish causation, given the liklihood of confounders, flaws and data gaps, the strong association over a relatively short time-span provide enough reason for concern about the long term use of statins, in most cases given for the wrong reasons !
    A credible mechanism of causation may be upstream at pancreatic level, where endogenous cholesterol in beta cells plays a critical role in regulating insulin secretion, with impaired B cell secretion resulting from cholesterol inhibition.
    Fuzhen et al have shown that chronic inhibition of cholesterol biosynthesis leads to a profound interference in beta cell structure and function.
    The long term consequences of this mechanism may be a greater incidence of new onset diabetes than the 9% observed over 4 years.
    I agree with Dr. Blanchet’s view that the short duration of statin trials do not present a realistic assessment of morbidity or mortality linked to new onset diabetes.
    I fail to understand how statins can be called “master drugs” (Dr. Sur)given these observations, and I share the doubts expressed by Steven Greer regarding the integrity of many statin trials, having scrutinised much of the available data, rather than just the abstracts !
    I go with Dr. Topol on this one.

  12. Lisa Martin, AB, MD says:

    The randomized trials show a 9% increase in diabetes occurrence, in a meta-analysis of trials. However, diabetics have a high incidence of cardiovascular disease, so should be on a statin in any case. Some of these patients may have crossed over by definition, from metabolic syndrome to diabetes by a small elevation in glucose. The pathophysiology as to how any significant rise in glucose would occur is unclear. The JUPITER trial had a 27% increase in diabetes in patients on statins, but this group of patients had elevated CRP, in most cases due to metabolic syndrome or obesity, I would imagine. It would not be hard to cross the line over to a diagnosis of diabetes. In the recent WHI publication in the Archives of Internal Medicine, there was a 70% greater chance of diabetes if you were taking a statin, but this study was observational, and no causal relationship can be made. Additionally, there was no correction for lipid levels, asa thsi data was not available.