Statin-Related New-Onset Diabetes Appears Driven by Increased Insulin Resistance: Are There Clinical Implications?
See accompanying article on page 2786
Statins (HMG CoA-reductase inhibitors) are universally acknowledged as first-line treatment for medical prevention of atherosclerotic cardiovascular disease (ASCVD) events in essentially all patients either with or without established disease. Statins are generally safe and well-tolerated but have been repeatedly associated with increased insulin resistance (IR) and increased incidence of new-onset diabetes type 2 (NOD2). This association has been consistently shown in large cohort studies1–5 and more importantly, in meta-analyses of randomized clinical trials of statin versus placebo.6–9 Furthermore, a Mendelian randomization study of genetic variants of the HMG CoA-reductase gene showed that genetically reduced HMG CoA-reductase activity associates with increased NOD2.10 Finally, meta-analyses of randomized statin-dosing trials have shown that higher-intensity treatment (whether by higher doses or with higher-efficacy agents) associates with increased NOD2 risk,11 while statin treatment to LDL-C (low-density lipoprotein-cholesterol) goals of <100 or <70 mg/dL was associated with adjusted 16% or 33% increases in NOD2, respectively.12 Together, these data establish that an increase in NOD2 risk is causally related to statin use, likely as an on-target effect.
Given the convincing evidence that statins can cause NOD2, Abbasi et al13 explored the mechanisms of this adverse effect in a study published in this issue of ATVB. Using detailed, gold-standard methods, they measured IR (or its reciprocal, insulin sensitivity) as well as insulin secretion in the largest subject group ever to be tested in such a definitive way. Their cohort of 71 subjects was recruited for an absence of prevalent diabetes type 2, although they were over-recruited for elevated plasma triglycerides, associated with both increased IR and with increased NOD2 risk with statin use. At baseline, all subjects were off statins for at least 4 weeks and underwent 3 advanced studies of insulin and glucose metabolism: (1) a standard 75 g oral glucose tolerance test, (2) a graded glucose infusion test, and (3) a modified insulin suppression test. All tests were repeated after 12 weeks of high-intensity statin treatment, atorvastatin 40 mg daily, with each subject serving as his/her own control. The primary result was a modest, but convincing, 8% increase in IR (P=0.002).
Most other published studies have also shown an increase in IR with statin treatment, although using somewhat less precise methods. These include a retrospective cohort of 27 155 subjects on atorvastatin versus nonstatin treatment,14 a cohort of 938 subjects after taking various statins for 30 days or longer15 and a prospective cohort of 8749 subjects treated with various doses of simvastatin and atorvastatin for nearly 6 years.16 Importantly, both this third cohort and also a trial of 213 subjects randomized to atorvastatin, 10 through 80 mg/d versus placebo for 2 months, showed dose-dependent increases in IR at all doses (P=0.008).17 Given these prior publications and the new data from Abbasi et al,13 increased IR can now be considered likely the primary means by which statins cause NOD2 (Figure [A through D]).
Meanwhile, the effects of statins on insulin secretion are less consistent in the scientific literature. Abbasi et al13 found a 9% increase in insulin secretion, which appeared compensatory to the increase in IR. An additional published study found increased insulin secretion with statin treatment,18 but several others have reported a decrease.14–16 This apparent variability in the effects of statins on insulin secretion may be due, in part, to the variability in insulin secretion response during sustained IR (Figure [B through D]). That is, initially insulin secretion increases to compensate for the increased IR (Figure [B]) but if IR is sustained over time that compensatory increase may later start to decline (Figure [C]) and eventually may fail to match insulin requirements, causing NOD2 (Figure [D]). The published variability in statin effects on insulin secretion may also be due to differences in study populations or perhaps in methods used for its measurement or calculation. Importantly, this tendency towards decreased insulin secretion in most in vivo studies of statins concurs with data from in vitro studies of statin exposure to beta cells (see Carmena and Betteridge19 for a review). Additional research is needed to further validate this schema regarding the sequence of the evolution of NOD2 with statins, as well as to refine its predictors and treatments to prevent it.
What are the clinical implications of this tendency of statins to nudge most patients towards NOD2, to the point of causing frank diabetes in many patients with preexisting risk factors?20,21 First of all, as correctly stated by Abbasi et al,13 and others, the overall risk-benefit ratio remains strongly in favor of statin therapy as first-line ASCVD prevention, even in patients who later develop NOD2 because of that treatment. The optimal approach to statin use, however, is not simply to accept increased NOD2 risk in patients with metabolic syndrome and other risk factors,20,21 but instead to actively reduce that risk by employing mitigation measures. As noted by Abbasi et al,13 diet and lifestyle recommendations are clearly warranted. If, however, these measures are insufficient, as is often the case, medical prevention should next be considered. Pioglitazone should generally be first choice since it is very effective in NOD2 prevention,22 improves the lipid profile,23,24 and reduces CVD risk.25 Furthermore, pioglitazone is inexpensive, well-tolerated, and generally safe, although it is contraindicated in patients with moderately to severely symptomatic (New York Heart Association stage 3–4) congestive heart failure.26 Adding metformin to pioglitazone may enhance NOD2 prevention,27 and metformin alone may also reduce NOD2.28 In addition, 2 uncommonly used statins, pravastatin,29 or especially pitavastatin30,31 may be favored over other statins in patients at elevated risk of NOD2, due to their apparently lower tendency to cause diabetes (see Carmena and Betteridge19 and Laakso and Kuusisto29 for reviews).
Finally, it seems appropriate at this time to question the ardent and widespread advocacy for maximally tolerated statin intensity, since such softening could provide another means to reduce the risk of statin-induced NOD2. Statin efficacy for ASCVD prevention is strongly related to LDL-lowering when comparing lower- versus higher-intensity statin regimens,32 which is the rationale for the preference for higher-intensity statin treatment and the concept of maximally tolerated statin therapy. The latter has been widely encouraged for ASCVD prevention in high-risk patients since the 2013 American College of Cardiology/American Heart Association Cholesterol guidelines,33 which favored maximization of statin intensity over achievement of any particular on-treatment LDL-C level. Unfortunately, in any patient not tolerant of maximal statin intensity, pursuit of a maximally tolerated regimen by definition may induce statin intolerance. This pursuit can be time-consuming at best for both patient and prescriber and may result in abandonment of statin treatment unless a somewhat cumbersome rechallenge is performed.34,35 Fortunately, since 2013, there can be less urgency for high-intensity statins due to advances in statin adjuncts, both in number of available agents and in documentation of their efficacy for LDL-lowering and ASCVD prevention, as well as safety. For this reason, cholesterol treatment recommendations since 2013 have reverted to (or continued) less emphasis on maximal statin intensity and more focus on levels of on-treatment LDL-C, either as a goal of treatment or a threshold for treatment intensification.36–38
Meanwhile, although higher-intensity statin therapy does help further prevent ASCVD, it also increases the risk of statin-induced NOD2, as detailed above.11,12,17,39 Unfortunately, patients who develop compensated IR (Figure [B]), late-stage metabolic syndrome (Figure [C]) or even NOD2 (Figure [D]) on a statin, may have few or no symptoms and thus would not ordinarily be considered statin-intolerant. In such cases, statin back-titration to a “tolerable” dose seems unlikely. Statin adjuncts are already universally endorsed when maximally tolerated statin therapy fails to adequately lower LDL-C, but why not consider statin adjuncts preemptively as statin-sparing agents? Since doubling a statin dose provides only an additional 6% or so of LDL-C lowering,40 initiating a statin at moderate- or even low-intensity along with a statin adjunct is appealing when asymptomatic IR or NOD2 threaten, even if high-intensity statins might otherwise be well-tolerated. Alternatively, monitoring for progression of IR towards NOD2 could be done,41 triggering back-titration of the statin regimen with addition of a statin adjunct as needed. Lower-intensity statins plus statin adjuncts clearly can match or exceed the LDL-lowering available with statin monotherapy.42–44 More importantly, addition of ezetimibe or PCSK9 (proprotein convertase subtilisin/kexin type 9)-inhibitor mAbs decrease ASCVD as much as does statin uptitration, without raising NOD2 risk.45–47 A trial directly comparing ASCVD and NOD2 outcomes of high-intensity versus lower-intensity statin therapy plus nondiabetogenic adjuncts is needed to prove this novel strategy superior to the conventional one but would be costly and impractical to conduct. It currently seems likely, however, that “less is more” regarding statin intensity (plus statin adjuncts, as needed) for most patients at elevated NOD2 risk, as an alternative to one-size-fits-all maximally tolerated statin regimens.
In summary, confirmation of the IR-raising effect of statins enhances our knowledge about statin-induced NOD2 in susceptible patients. Greater attention to diabetes prevention during statin treatment in these patients is warranted, by traditional diet and lifestyle measures, use of inexpensive medications effective in diabetes prevention, choice of less-commonly used statins and/or softening the widely endorsed paradigm of maximally tolerated statin intensity in favor of lower-intensity statins plus greater use of nondiabetogenic statin-sparing adjuncts.
E. Brinton is a speaker and consultant for Amgen, Esperion, Kowa, and Medicure, has received research support from Kowa and Regeneron, and served as an expert witness for Robins Cloud.
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