Impact of ATP4 guidelines on non statin drugs in lipid management

ATP4 which is published in Nov 2013 came up with huge change in lipid guidelines. ATP 4 has focused on atherosclerotic events i.e. MI and stroke rather than surrogates like LDL HDL Triglycerides values. 
Lipid level treatment and atherosclerosis events has notorious story of mismatch across many trials. It is only statin and gemfibrozil in Helsinki Heart Study (HHS) and Veterans Administration High Density Lipoprotein Intervention Trial (VA-HIT), which have shown benefit of reduction in CV events but other drugs like Niacin in HPS-2 THRIVE trial, CETP inhibitors in dal-OUTCOMES have failed to show clinical benefit although these drugs had pro lipid change. 
Apart from gemfibrozil other fibrates i.e. fenofibrate in FIELD and also ACCORD trial fail to show clinical benefit although it had some positive impact on lipid profile . Gemfibrozil’s benefit cannot be explained totally by pro lipid changes. It is quite possible that Gemfibrozil might have cardio protective action which is not present in other fibrates.
Pleiotropic effects of statin are well-known to all. These pleiotropic properties might be protecting from atherosclerotic events beyond pro lipid actions.
As ATP 4 recommends statins mainly, this leads to serious setback on present non statin drugs. This will also have huge implications on further research of newer class of non statin drugs  i will explain this down below. Fortunately or unfortunately ADA 2013 still continues to recommend targets in treating lipids, and this gives some good scope for usage of present non statin drugs thus allows their survival.
The fate of ezetimibe in terms on benefits will be known somewhere in middle of this year i.e. 2014.
Another new class of drugs PCSK9 inhibitors which are mostly in phase 3 trials for evaluating clinical benefits may take another one or two years to appear in field. These drugs have shown to reduce LDL very significantly over and above statins; apart from LDL they also have pro triglycerides and HDL effects. They are found to be safe in phase 2 trials. We have keep our finger crossed till phase 3 results show reduction in clinical events.

There is another class of drug Saroglitazar with predominate affinity for PPAR alpha and moderate affinity towards PPAR gamma, reduces triglycerides and increase HDL cholesterol with reduction of HbA1c levels in diabetes. This drug is tested in phase three trial with reduction of surrogates only, but about clinical events reduction of MI or stroke there are no studies

My opinion on further research on non statin drugs:-

Present ATP 4 Guidelines advise mainly statins.  This recommendation is in fact compromise.  We all know lower LDL is better by across many, trials the people with lower LDL did better than the higher LDL. Apart from statins other available non–statin drugs have lot of side effects and their benefits in terms clinical end points is questioned. Side effects increase further if combined with statins.  So I think guidelines makers had little choice apart telling us give moderate intensity or high intensity statins for particular group of patients and forget about targets anyway it is difficult to achieve it.


From above assumption I think our present ATP4 Guidelines are demanding more and more active research in field of lipid treatment, newer molecules with newer mode action are more in need then ever before. Present non-statin drugs may not have good future.

Author: Dr Umesh Bilagi

MBBS, MD, DM (cardiology). I am Interventional cardiologist. Blogging is my passion. Associate professor of cardiology KIMS Hubli. Director and consultant at Tatwadarsha Hospital Hubli. Owner of Jeevan Jyoti Hospital Hubli. Mobile +91 9343403620.

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