A Conversation with Dr. Robert Eckel About Treating Patients with Both Diabetes and Hypercholesterolemia
In March 2014, Arteriosclerosis, Thrombosis, and Vascular Biology, a journal of the American Heart Association, published the results of ETC-1002-005, Esperion’s Phase 2a clinical study of ETC-1002 in patients with hypercholesterolemia and type 2 diabetes, along with an editorial about targeting low-density lipoprotein cholesterol (LDL-C) and diabetes in those patients. ETC-1002-005 was a randomized, double-blind, placebo-controlled, single-center study. Results showed that ETC-1002 lowered LDL-C by up to 43 percent compared with placebo and was well tolerated in this high-risk, difficult-to-treat patient population. ETC-1002 also was associated with improvements in other cardiometabolic risk markers.
To put the findings of the ETC-1002-005 clinical study and the accompanying editorial in perspective, Esperion had a conversation with noted diabetes and lipid expert Dr. Robert H. Eckel.
Esperion: Why is it so important to treat hypercholesterolemia in patients with diabetes?
Dr. Eckel: Hypercholesterolemia increases the risk of cardiovascular disease (CVD) in patients with or without diabetes. In those with diabetes, hypercholesterolemia is less commonly manifested by increases in LDL-C but more likely very low density lipoprotein cholesterol (VLDL-C). However, diabetes patients with even normal or high-normal levels of LDL-C are at greater risk for CVD, and steps must be taken to lower their LDL-C level.
Esperion: What is the biggest challenge in treating patients with diabetes and hypercholesterolemia?
Dr. Eckel: We know that lowering LDL-C is beneficial in reducing CVD risk in these patients and that glycemic control also is beneficial. Because we don’t have an existing single therapy that can treat both diabetes and hypercholesterolemia effectively, we use lifestyle changes and multiple drug therapies to modify a patient’s glycemic burden (hemoglobin A1c [HbA1c]) and LDL-C levels.
Esperion: What are the shortcomings of current therapies for these patients?
Dr. Eckel: The effects of currently available drug therapies on both glucose and LDL-C are fairly modest. For example, metformin is the drug of choice for controlling glucose in patients with type 2 diabetes, but it is not effective in lowering LDL-C. Statins have been demonstrated via evidence-based medicine to reduce risk for CVD by lowering LDL-C, but they don’t reduce glucose. In fact, for patients with glucose intolerance, statins may increase the risk of developing new onset type 2 diabetes. Furthermore, up to 20 percent of hypercholesterolemic patients are intolerant to statins.
Esperion: How frequently do you see statin intolerance in your patients?
Dr. Eckel: Among my patients, about 40 percent are statin intolerant. Of new patients referred to the University of Colorado Hospital Lipid Clinic for treatment, often the most challenging cases, about two-thirds are statin intolerant.
Esperion: Why are new treatments for patients with diabetes and hypercholesterolemia so important?
Dr. Eckel: Novel compounds are needed for several reasons. For one, nearly all drugs that treat diabetes do not lower LDL-C. An exception is Welchol (colesevelam), which is difficult for patients to swallow, has only a modest effect on lowering LDL-C and HbA1c, and is associated with bloating and constipation. Another reason is that statins effectively lower LDL-C but may have a modest adverse glycemic effect. A third reason is that up to 20 percent of patients with hypercholesterolemia cannot take the evidence-based doses of statins that are required because of statin intolerance, so managing their hypercholesterolemia is difficult.
Esperion: What is the most interesting takeaway from the ETC-1002-005 study?
Dr. Eckel: The most important finding was that ETC-1002 reduced LDL-C by 43 percent overall, and over a short time period. That reduction was impressive and may confer a reduction in CVD risk, although this would need to be confirmed at some time with a cardiovascular outcomes study.
Esperion: What do you think are the most important points made in the accompanying editorial?
Dr. Eckel: The potential combined effect of ETC-1002 on LDL-C and glucose levels is of interest. Because the ETC-1002-005 study lasted only one month, it is difficult to be conclusive about the glycemic reduction, but it trended downward. That effect may indicate that better diabetes control could ensue over a longer period of time. It is also interesting that levels of C-reactive protein (CRP), a marker of inflammation associated with CVD, also fell. A number of statin trials have demonstrated a benefit with reduced CRP. The development of a drug that lowers LDL-C and modifies glucose levels, and has an anti-inflammatory effect, would be of great interest in the treatment of type 2 diabetes.
Esperion: What do you think about the link made in the editorial between the mechanism of action (MOA) of ETC-1002 and its impact on diabetes patients?
Dr. Eckel: ETC-1002 has a combined MOA that works by inhibiting ATP citrate lyase and activating the enzyme AMPK. ATP citrate lyase is important in the pathway of lipid biosynthesis and is probably mediating the cholesterol-lowering effects of ETC-1002. The LDL-C-lowering effect seen in ETC-1002-005 was pretty dramatic, which speaks to LDL receptors being induced. The effect of ETC-1002 on AMPK resembles metformin and probably induces glucose lowering by activating AMP kinase in liver and/or muscle. This combined biochemistry of two enzyme systems that affect metabolism could affect both glucose and lipids.
Esperion: What is your personal experience, if any, with ETC-1002?
Dr. Eckel: My laboratory has been involved in preclinical studies evaluating the metabolic effects of ETC-1002 on food intake, energy expenditure and glucose tolerance in diet-induced obese animals.
Esperion: What do you think about the potential of ETC-1002 for patients with diabetes and hypercholesterolemia?
Dr. Eckel: I think the most important opportunity for ETC-1002 will be as an add-on therapy for diabetes patients with hypercholesterolemia who are intolerant to statins. Other drugs, such as ezetimibe and bile acid sequestrants, don’t come close to the 43 percent reduction in LDL-C demonstrated in the ETC-1002-005 study. Additionally, individuals with LDL-C levels between 70 and 100 mg/dL have benefited from statins, and many have attributed that benefit to reductions in CRP. ETC-1002 may reduce CRP as an additive benefit to LDL-C reduction on CVD risk. If the glucose-lowering capabilities of ETC-1002 are confirmed, this compound would be more promising, as it would be beneficial to have an agent with an effect on both LDL-C and glucose.