Are all statins the same: does pitavastatin improve diabetic control?
EAS 2011, Gothenburg, Sweden –
Does pitavastatin have a potential benefit on diabetic control? This was the question suggested by subgroup analyses in 1200 patients presented from the LIVES (Livalo Effectiveness and Safety) study, in which diabetic control (as assessed by HbA1c) did not worsen during long-term treatment. According to the session co-Chair Professor Philip Barter, Director of the Heart Research Institute, Sydney, Australia: ‘The suggested effect on diabetic control is especially interesting and is in line with studies showing improvement in glucose homeostasis associated with HDL cholesterol raising in our laboratory. If this could be substantiated in further prospective clinical studies, this may help the clinician to differentiate between statins.’ The data were presented during the Education Symposium ‘Novel strategies for raising HDL-C: pitavastatin in clinical practice’ on Tuesday 28th June.
These data are especially pertinent with a recent meta-analysis of statins reporting a significant increase in the risk of diabetes mellitus associated with statin use in high doses.1 The analysis of 32,752 patients without diabetes at baseline enrolled in five trials (PROVE-IT, A to Z, TNT, IDEAL, and SEARCH) compared the effects of high-dose versus conventional doses of statin therapy. Of these patients, 1,000 participants had been followed-up for more than 1 year. High-dose statin therapy was associated with a 12% (95% CI 4-22%) increase in risk of new-onset diabetes versus conventional dose-therapy.
Further analyses also highlighted the pitavastatin effect on HDL cholesterol. While the overall increase in HDL cholesterol was 5.7%, there was greater improvement (28.9%) among patients with low baseline levels (<40 mg/dL). Time course analysis of the HDL cholesterol response in this group showed that HDL cholesterol was increased by 14% at 12 weeks and 24.9% at 2 years. Subgroup analyses also showed significant benefit in terms of elevation in HDL cholesterol, among patients switching from other statins. Treatment was also associated with decreases in LDL cholesterol (~30%) and triglycerides, in line with the effects of other statins. The HDL raising effect of pitavastatin is relevant in the context of reducing cardiovascular risk. Previous data from the TNT study clearly showed that even among patients who achieve low HDL cholesterol levels, those with low HDL cholesterol levels (<40 mg/dL) are at substantially increased cardiovascular risk (by 40-60%).2 Indeed, the recently published ESC/EAS guidelines for dyslipidemia management highlight the relevance of HDL cholesterol as a cardiovascular risk factor by incorporating SCORE risk tables taking into account different levels of HDL cholesterol.3,4
In the LIVES extension study, there was a 59% decrease in cardiovascular risk when individuals with low baseline HDL cholesterol (<40 mg/dL) were compared with those with normal baseline levels. These data highlight the relevance of both lowering LDL cholesterol as well as raising HDL cholesterol to reduce cardiovascular risk. Indeed, a recent EAS Consensus Panel paper has drawn attention to the high cardiovascular risk in patients associated with elevated triglycerides and/or low HDL cholesterol, even if LDL cholesterol levels are adequately controlled.5
This raises questions about the mechanistic basis for this incremental and progressive increase in HDL cholesterol. Previously, it has been reported that pitavastatin stimulates apoA-I production in vitro, which may potentially translate to effective raising of levels of lipid-poor apoA-I particles in vivo.6 Professor M. John Chapman, EAS President suggested that this effect may be relevant in driving the HDL particle cascade and flux of apo-AI, cholesterol and phospholipid through the HDL pathway, favouring the production of HDL particles that are more able to accept free cholesterol in cholesterol efflux. Thus progressive elevation in HDL cholesterol may be attributed to mobilisation of cholesterol pools in adipose tissue with slow turnover. This is likely to have potential benefits in high-risk patients with defective HDL particle function. In the Japan ACS study, treatment of patients with acute coronary syndromes induced almost 20% decrease in plaque volume, implying stabilisation of the unstable plaque. ‘Evidence shows that to effectively treat patients at high cardiometabolic risk we must both lower levels of apoB particles such as VLDL and LDL and raise apoA-I in HDL. These findings with pitavastatin are provocative and warrant further study,’ said Professor Chapman.
References
1. Preiss D, Seshasai SR, Welsh P et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA 2011;305:2556-64.
2. Barter P, Gotto AM, LaRosa JC et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med 2007;357:1301-10.
3. Reiner Z, Catapano A, de Backer G et al. ESC/EAS guidelines for the management of dyslipidaemias. The Task Force on the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011; doi:10.1093/eurheartj/ehr158 [Epub ahead of print].
4. Catapano A, Reiner Z, de Backer G et al. ESC/EAS guidelines for the management of dyslipidaemias. The Task Force on the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Atherosclerosis 2011; doi:10.1016/j.atherosclerosis.2011.06.012 [Epub ahead of print].
5. Chapman MJ, Ginsberg HN, Amarenco P et al; European Atherosclerosis Society Consensus Panel. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J 2011; 32: 1345-61, doi:10.1093/eurheartj/ehr112.
6. Yamashita S, Tsubakio-Yamamoto K, Ohama T, Nakagawa-Toyama Y, Nishida M. Molecular mechanisms of HDL-cholesterol elevation by statins and its effects on HDL functions. J Atheroscler Thromb 2010;436-51.