Alternatives to Add-On Therapy for T2D and Hyperlipidemia

Zachary T. Bloomgarden, MD, MACE: There’s a misconception that fibrates, as a class, are associated with adverse muscle reactions to statins. In fact, this is absolutely a finding with gemfibrozil. [However], with fenofibrate, a number of studies have looked at the combination of fenofibrate with statins and have shown that, particularly when fenofibrate is used in individuals who don’t have renal insufficiency, this is not an issue.

Nevertheless, many guidelines discourage the use of fibrates with statins, and this is an area where physician education is important to understand that there are certain cases in which fenofibrate is appropriate for use with statins. Niacin, similarly, should be used with caution, but can be used in conjunction with statins in appropriate individuals.

Gemfibrozil probably should be avoided in almost all individuals receiving statins because it is associated with a much higher likelihood of statin-induced muscle pain and statin-induced rhabdomyolysis. [However], that certainly occurs much less commonly than the muscle pain syndromes. There are, fortunately, other alternatives that can be used in conjunction with statins when an individual is not able to tolerate the dose of statin that one would like to give or when an individual receiving a statin does not achieve adequate lipid goals.

Ezetimibe is a drug that blocks one of the cholesterol transporters in the gut and is a potent [drug for lowering] of LDL (low-density lipoprotein) cholesterol, although not as potent as the statins. And the recent IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial) study showed that, interestingly [and] particularly in the diabetes subset, there was demonstrable benefit in reducing cardiovascular endpoints in individuals receiving statin plus ezetimibe.

Other agents, such as the bile acid sequestrants (bile acid—binding resins) can be used. One of these is called sevelamer, which has been widely studied. Interestingly, it is of modest, but definite, benefit in lowering blood sugar and may be particularly useful in individuals with diabetes. It has a complicated effect on lipids and may increase triglyceride levels somewhat, so it has to be used with caution in appropriate individuals. But, certainly, it works well either with statins or in individuals who are intolerant of statins as monotherapy.

Both ezetimibe and the bile acid—binding resins are only able to lower the LDL cholesterol by about 20%. So, recently, the combination of a series of population-based genetic studies led to the realization that PCSK9 (proprotein convertase subtilisin/kexin type 9), which is an enzyme involved in chaperoning the LDL receptor to and from the plasma membrane of the hepatocyte, may be very important in determining LDL receptor levels. Hence, PCSK9 antibodies may actually lower cholesterol. A slew of large-scale clinical trials have demonstrated that these are extraordinarily potent agents in lowering LDL cholesterol, actually showing a greater LDL-lowering effect than maximum-dose statins.

So, we may be at the cusp of entering a new era of lipid therapy where the PCSK9 drugs, perhaps given in conjuction with statins with which they work well, may be able to take individuals who have extremely high LDL cholesterol levels (those with familial hypercholesterolemia [FH], for example) or individuals without FH, but who have ASCVD (atherosclerotic cardiovascular disease), and bring them down to levels that were previously unachievable and might really reduce the likelihood of atherosclerotic complications.