How to Tackle Statin Induced New Onset Diabetes (Type-2)

CME INDIA Presentation by Dr. N. K. Singh, MD, FICP, Director – Diabetes and Heart Research Centre, Dhanbad, Jharkhand, India. Editor, www.cmeindia.in.

(Based on the presentation at LAICON 2022 (Lipid Association of India International, New Delhi) on 14th August 2022. Author is thankful to Dr. Raman Puri, New Delhi and Dr. G. B. Sattur, Hubli for this Presentation.)

Statin is viewed as New Nectar

• Statins (HMG CoA-reductase inhibitors) are universally accepted as first-line treatment for medical prevention of atherosclerotic cardiovascular disease (ASCVD) events.
• Statins are used with or without established cardiovascular 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).

Statins has been broadly categorized as:

• Hydrophilic (pravastatin, rosuvastatin).
• Lipophilic (Atorvastatin, Fulvastatin, Lovastatin, Simvastatin, Pitavastatin).

Defining NODM (New onset diabetes mellitus)  

• If a non-diabetic patient develops diabetes at least 180 days (lag period) after the index date (As many studies took this cut-off period.
• Recent studies have used serum HbA1c levels≥5.7% at any point before and within 180 days after enrollment. It has increased the reliability of the causal relationship between statins and NODM.

Is it a causal relationship or an On-Target effect?

• The association has been consistently shown in large cohort studies.
• In meta-analyses of randomized clinical trials of statin versus placebo, this association emerged.
• Even in a Mendelian randomization study of genetic variants of the HMG CoA-reductase gene, it was found that genetically reduced HMG CoA-reductase activity was associates with increased risk.

How the Story started?

• Two trials in 2004 and 2006 first talked about possibility (1,2).
• The JUPITER trial (2008) was one of the first to acknowledge the increased incidence of physician-reported diabetes in individuals randomized to the rosuvastatin arm.
• However, diabetes was not an adjudicated end point in the JUPITER trial.
• No further explanation for the finding was explained by the JUPITER investigators.
• Later studies started to emerge that tried to elucidate the potential link between NODM and statins.

Message from Meta-analyses of randomized statin-dosing trials

• Higher-intensity treatment (whether by higher doses or with higher-efficacy agents) associates with increased new onset T2DM risk.
• Statin treatment to LDL-C goals of <100 or <70 mg/dL has been associated with adjusted 16% or 33% increases in new onset T2DM risk, respectively.

Who develops NODM after Statin?

• Approximately 10–20 per 10,000 patients treated per year develop NODM after statin.
• It is similar to the risk of developing a significant myopathy.
• The risk is proportional to the dose used. It appears soon after starting therapy.
• If the patient has risk factors for cardiovascular disease (Elevated body mass index, impaired fasting glucose or high HbA1c) chances of developing diabetes is more.
• We must remember that cardiovascular event rate reduction with statins far outweighed the risk of incident diabetes even for patients at highest risk for diabetes.
• In true sense the absolute risk increase is small (In a study over 5 years of follow-up, 1.2% of participants on placebo developed diabetes while 1.5% on rosuvastatin developed diabetes).
• As per a meta-analysis of 13 randomized statin trials showed an odds ratio of 1.09 for a new diagnosis of diabetes. It means that (on average) treatment of 255 patients with statins for 4 years results in one additional case of diabetes while simultaneously prevents 5.4 vascular events among those 255 patients.
• In nut-shell, Individuals on statins have an increased risk of developing NODM compared to individuals who did not receive statins.

How Statins induce NODM?

Credit: Int. J. Mol. Sci. 2020, 21(13), 4725; https://doi.org/10.3390/ijms21134725

Increased Insulin Resistance appears most likely to induce NODM

• New data from Abbasi et al (2022) shows that increased Insulin resistance can now be considered likely the primary means by which statins cause NOD2.
• The effects of statins on insulin secretion are less consistent.
• Abbasi et al found a 9% increase in insulin secretion initially. It appeared compensatory to the increase in Insulin resistance.
• Initially insulin secretion increases to compensate for the increased Insulin resistance.
• Its insulin resistance is sustained over time, compensatory increase may later start to decline. Eventually it fails to match insulin requirements leading to NODM.

Things to Ponder. Any way out?

• The risk-benefit ratio remains strongly in favor of statin therapy as first-line ASCVD prevention.
• Should we simply accept the increased of NOD2 risk in patients with metabolic syndrome and other risk factors, or should we actively reduce that risk by employing mitigation measures.
• We need to advise our patient s to follow diet and lifestyle recommendations. If these measures are insufficient medical prevention should next be considered.
• Pioglitazone should generally be first choice since it is very effective in NODM prevention, improves the lipid profile, and reduces CVD risk.    
• If we add metformin to pioglitazone may enhance NODM prevention, Metformin alone may also reduce NODM.
• Two uncommonly used statins, pravastatin, or especially pitavastatin may be favored.
• As these have apparently lower tendency to cause diabetes.

Is it the time to question the ardent and widespread advocacy for maximally tolerated statin?

• It is well known that Statin is effective for ASCVD prevention and it is strongly related to LDL-lowering when comparing lower- versus higher-intensity statin regimens. This is the rationale for the preference for higher-intensity statin treatment.
• Now whether in 2022 there could be less urgency for high-intensity statins as advances in statin adjuncts. We have a greater number of available agents with well documented efficacy for LDL-lowering and ASCVD prevention, as well as safety.
• It is clear that higher-intensity statin therapy does help further prevent ASCVD, but also increases the risk of statin-induced NODM.
• Statin adjuncts are already universally endorsed when maximally tolerated statin therapy fails to adequately lower LDL-C. But now should we consider statin adjuncts preemptively as statin-sparing agents?
• Suppose you double a statin dose; it will provide only an additional 6% or so of LDL-C lowering. So, initiating a statin at moderate- or even low-intensity along with a statin adjunct is appealing when asymptomatic to avoid risk of NODM.
• As this concept is not in vogue, monitoring for progression of Insulin resistance towards NODM could be done.
• We not forget that lower-intensity statins plus statin adjuncts clearly can match or exceed the LDL-lowering available with statin monotherapy.
• Addition of ezetimibe or PCSK9 (proprotein convertase subtilisin/kexin type 9)-inhibitor mAbs decrease ASCVD is now attractive option without raising NODM risk.
• “Less is more” regarding statin intensity (plus statin adjuncts, as needed) for most patients at elevated NODM should be followed.

Which statin is safer if we consider NODM?

Why Pitavastatin performed better?

• It has been found in an in vitro study that reduction in the rate of insulin secretion in pancreatic islet β-cells treated with pitavastatin was less than that of those treated with atorvastatin or rosuvastatin. Also, cell viability was better than that with other statins.
• The reduction in coenzyme Q10 levels caused by statin treatment affects insulin secretion and abnormal glucose metabolism.
• There is evidence that pitavastatin has minimal effects on coenzyme Q10 through its unique pharmacological mechanism.
• The glucose uptake rate of human skeletal muscle after treatment with pitavastatin has been found better than that with atorvastatin or rosuvastatin.
• Pitavastatin significantly increases adiponectin levels, while atorvastatin has neural effects on adiponectin levels and rosuvastatin has harmful effects.

Network research focusing on NODM risk related to statins by head-to-head comparison using real-world clinical CDM data (2022) Seo et al. Cardiovascular Diabetology (2022) 21:82

• Pitavastatin has been found to reduce the HR of NODM by 28% compared with atorvastatin+rosuvastatin.
• Pitavastatin has been shown to have significantly lower risk of NODM in comparison with atorvastatin or rosuvastatin. (This effect was prominent in the comparison between pitavastatin and moderate intensity atorvastatin or rosuvastatin. There was no statistically significant difference in the comparison between pitavastatin and high-intensity atorvastatin or rosuvastatin).

Quick Take-Aways

References:

1. Sabatine MS, Wiviott SD, Morrow DA, McCabe CH, Canon CP. High dose atorvastatin associated with worse glycemic control: a PROVE-IT TIMI 22 substudy. Circulation 2004;110:Suppl:S834-S834
2. Sasaki J, Iwashita M, Kono S. Statins: beneficial or adverse for glucose metabolism. J Atheroscler Thromb 2006;13:123-129
3. Int. J. Mol. Sci. 2020, 21(13), 4725; https://doi.org/10.3390/ijms21134725
4. https://doi.org/10.1161/ATVBAHA.121.316893Arteriosclerosis, Thrombosis, and Vascular Biology. 2021;41:2798–2801
5. Seo et al. Cardiovascular Diabetology (2022) 21:82 https://doi.org/10.1186/s12933-022-01524-6
6. doi.org/10.1161/CIRCULATIONAHA.112.122135Circulation. 2012;126:e282–e284

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