Clinical Approach to Achieving Treatment Targets: Case Vignette Discussion Om P. Ganda, MD; Kirit Tolia, MD, FACE Postcardiac Follow-up in a 66-Year-Old Man Slide 1. Dr. Ganda: Now we will present a case to stimulate some discussion, and that patient is summarized here. This is a typical patient you see in your practice. A 66-year-old man returns for follow-up after having had an acute myocardial infarction (MI). He had had coronary artery bypass surgery 6 months before he comes to see you. He has had type 2 diabetes for the past 16 years. He has hypertension, long-standing obesity, and a family history of coronary artery disease and diabetes. His current medications have included glyburide 10 mg twice a day and metformin 1,000 mg twice a day for many years. He was also on simvastatin 20 mg daily for many years, which was increased to 80 mg after his bypass surgery. He is also on an angiotensin-converting enzyme (ACE) inhibitor, 10 mg daily. Physical and Laboratory Findings
Slide 2. Physical findings reveal he has some nonproliferative diabetic retinopathy. He has distant heart sounds and decreased pedal pulses. He has absent ankle jerk reflexes, and decreased pin and vibratory sensation on the lower extremities. Slide 3. In terms of lab parameters, his total cholesterol is 192 mg/dl, triglycerides 260 mg/dl, high-density lipoprotein cholesterol (HDL-C) is 38 mg/dl, and low-density lipoprotein cholesterol (LDL-C) is 102 mg/dl. His A1C is 7.6%, his alanine aminotransferase (ALT) is 66 mg/dl, and his aspartate aminotransferase (AST) is 55 mg/dl; the normal value for each of these in most labs is less than 40 mg/dl. He has microalbuminuria, defined by 135 microgram (mcg) microalbumin per mg of creatinine. His creatinine level is 1.1 mg/dl. Let me begin by asking Dr. Tolia what his impressions are about this patient's lipid profile. Dr. Tolia: The triglycerides are modestly elevated, and his LDL-C, for a patient with cardiovascular disease and type 2 diabetes, is much higher than you would like. If your goal is less than 70 mg/dl, his LDL-C of 102 mg/dl is way above target. His therapy needs to be intensified in some manner to get him to target. Dr. Ganda: Any comments on his microalbumin of 135 mcg/mg creatinine? The Significance of Microalbuminuria Dr. Tolia: Microalbumin is a very good assessment of endothelial function; patients with microalbuminuria have a very high incidence of cardiovascular disease. Therefore, microalbumin can be used as an assessment of who to screen, who to aggressively treat, and how aggressively to treat them to get them to target. For a patient who is spilling protein into urine (microalbuminuria), your goals need to be much stricter than what they
would be otherwise. If they have never had a stress test, patients should be screened for underlying vascular disease; therefore, C-reactive protein (CRP) level and other inflammatory markers should be checked, and any abnormalities corrected. Utilizing an Aggressive Treatment Approach Dr. Ganda: I would agree that this patient is a typical example of why we need to be very aggressive in our treatment of patients who have type 2 diabetes and cardiovascular disease, given all the evidence that we have. Going by the update of the Adult Treatment Panel III (ATP III) guidelines in 2004, and now also promoted by the American Diabetes Association (ADA), this LDL-C is not acceptable in patients with cardiovascular disease and other major risk factors, such as diabetes, which is a classic major risk factor. These patients are now considered to have very high risk; it has been shown that a patient who has diabetes and pre-existing cardiovascular disease has a risk on the order of 50% that they will have a second MI in the next 7 years. So an attempt should be made to get his LDL-C down. The question is how to do that. Dr. Tolia, what about his A1C goals, given his A1C of 7.6%? Dr. Tolia: Currently, he is on glyburide and metformin at pretty much a maximum dose. So in an effort to get that A1C down to less than 7%, you need to intensify his antidiabetic regimen. The question is what drugs would you choose and what are the options? You have several options currently that the patient is not on. You can start him on a thiazolidinedione (TZD), a dipeptidyl peptidase-iv (DPP-IV) inhibitor, or you can add a bile acid sequestrant to his current regimen, which will lower his LDL-C as well as help with his glycemic control to some extent. Finally, you have the option of adding insulin to his regimen. Those are the choices that you have, and part of that choice is going to be based on the particular patient (how long have they had diabetes, etc.). TZDs are probably not a good option in this individual, so you are left with either starting him on insulin or adding a bile acid sequestrant to try to get glycemic control. Dr. Ganda: We have the luxury of choosing between several agents. Patients like this can be helped, and we can achieve goal without too much of an extra effort. Let us see what happened. Slide 4. Because of his LDL-C of 102 mg/dl, the decision was made to switch him from simvastatin 80 mg to a different statin, in this case atorvastatin 80 mg, hoping that might have some extra benefit on his dietary strategy. He was sent to a dietician with that in mind. He continued his cardiac rehabilitation for a while, which he now has completed. Our patient returns 6 weeks later for an assessment. His lipid levels include total cholesterol of 168 mg/dl, triglycerides of 220 mg/dl, HDL-C of 37 mg/dl, and LDL-C of 87 mg/dl. His A1C is still about the same, 7.5%. ALT is still 70 mg/dl and AST is 52 mg/dl. Knowing that the normal level is less than 40 mg/dl, the patient is concerned about his liver status. Addressing Patient Concerns About Liver Status Dr. Tolia: Hearing about liver side effects in the news media all the time, every time there is even mild elevation of liver enzymes, not just patients, but other providers get very concerned. In general, however, modest elevations of liver enzymes, provided you are getting them to target, are fairly acceptable, at least in my practice.
Therefore, if you get 1.5 to 2 times the upper limit of normal in liver enzyme abnormalities with a high-dose statin, but you can get the patient to goal, then that is not an unreasonable risk to take. If the patient is very concerned and anxious, then that becomes another issue to contend with. In this situation, since the patient brings it up and is concerned about what is going to happen to his liver, I am more apt to back down on the statin because the side effect profile is very much dose-dependent, especially at the 80-mg strength, with which you get a 5% to 6% incidence of liver enzyme abnormality. However, in lower doses, 20 and 40 mg of atorvastatin, the incidence is much less. In this case, I might be more inclined to use combination therapy than a high-dose statin therapy. Non-HDL-cholesterol: How Important Is It? Dr. Ganda: Something we did not talk about is non-hdl-c, which is highly recommended to calculate, by taking the total cholesterol and subtract the HDL-C. The non-hdl-c itself is a very important predictor of clinical events. Therefore, 168 mg/dl (total cholesterol) minus 37 mg/dl (HDL-C) = 131 mg/dl for non-hdl-c, which seems to be more of a problem than the LDL-C. The non-hdl-c goal in any patient is 30 mg/dl above LDL-C goals. Therefore, in this patient, the non-hdl-c should be 100 mg/dl or less, and he is at 131 mg/dl. Elevated non-hdl-c, therefore, is another reason to either intensify the statin therapy for a patient not on high-dose statins or utilize combination therapy. I would agree that in this particular patient, both the LDL-C and the non-hdl-c are not yet at goal with 80 mg of atorvastatin. Would you switch to rosuvastatin? Other Treatment Options for This Patient Dr. Tolia: In my experience, once you get to 80 mg of atorvastatin, the incremental reduction that you will get with rosuvastatin has not been that much. I am always concerned about proteinuria, especially at higher doses of rosuvastatin in patients with diabetes who already have proteinuria. Dr. Ganda: So 80 mg of atorvastatin is roughly equivalent to 40 mg of rosuvastatin, and we try not to go above 40 mg. That is a good reason to consider other options. Another point is that non-alcoholic fatty liver disease is common in people with type 2 diabetes. Even when the A1C is close to normal, that by itself may explain an increase in ALT and AST. There are patients where by improving glycemic control, you can actually reduce these levels. An increase in liver enzymes by itself is not a contraindication to statin use or to an increase in the dose of statin as long as it is monitored. Dr. Tolia: Would you be concerned about his triglyceride level of 220 mg/dl? Dr. Ganda: Triglyceride elevation is clearly related to this patient's obesity and glycemic control. Although his HDL-C is also low, we are not as concerned about this at this point until we get the LDL-C to goal. Slide 5. Adding fenofibrate may be a possibility once you get to the LDL-C goal. As of this date, there has never been a study that has conclusively shown that adding fenofibrate to a statin reduces clinical events, but we might know the answer in the not too distant future from the ongoing ACCORD trial. Adding a cholesterol absorption inhibitor or adding a bile acid sequestrant are the 2 other options. I think we are coming back to some of the old concepts that in patients where we cannot maximize the statin therapy, these could be other options, especially with the additional knowledge that colesevelam, or any bile acid
sequestrant, might also aid in improving glycemic control. We would try to get that additional 0.5% reduction in A1C, which is the average reduction that you see with bile acid sequestrants. Contents of Reducing Cardiovascular Risk: Multiple Risk-Factor Intervention 1. Diabetes and Dyslipidemia: Interrelationships and Clinical Implications 2. Treating Diabetes and Dyslipidemia: Achieving Therapeutic Targets 3. Clinical Approach to Achieving Treatment Targets: Case Vignette Discussion 2009 by Joslin Diabetes Center, Inc. All rights reserved. These materials may be used for personal use only. Any rebroadcast, distribution or reuse of this presentation or any part of it in any form for other than personal use without the express written permission of Joslin Diabetes Center is prohibited.