Advances in dyslipidemia: discussion session II

Dr. Guyton: Dr. Capuzzi, are there any studies directly comparing Niaspan with other sustained-release preparations such as Slo-Niacin? As a follow-up, are there studies of the hepatotoxicity of sustained-release niacin preparations? David M. Capuzzi, MD, PhD (Philadelphia, Pennsylvania): I am not aware of any clinical trials that directly compared the efficacy and/or safety of different brands of sustained-release niacin. We must be very cautious concerning the over-the-counter (OTC) preparations because the US Food and Drug and Administration (FDA) does not regulate OTC slow-release brands of niacin as medications, but rather as dietary supplements. As for the question about slow niacin hepatotoxicity, reports suggest greater patient intolerance to OTC slow-release than to OTC immediaterelease niacins. Moreover, several cases have been reported in which Brand X slow-release niacin produced hepatotoxicity after several days of dosing. In some cases, such patients required liver transplantation after short-term exposure to 5–6 grams of an OTC slow-release product. Dr. Guyton: Dr. Kreisberg, how do you diagnose insulin resistance? Do you routinely look for insulin resistance in your patients? Robert A. Kreisberg, MD (Birmingham, Alabama): We don’t recommend measuring insulin levels because there is tremendous interindividual variability. The statistical relation that you see in most studies is due to the very large number of patients. But, in the clinical setting, it is fairly easy to pick out the person with insulin resistance. Family history is a strong indicator. Just as osteoporosis run in families, diabetes and insulin resistance run in families. There may be a personal or family history of type 2 diabetes, gestational diabetes, central obesity, high triglycerides, low HDL cholesterol, hyperuricemia—any number of different characteristics that allow us clinically to establish the diagnosis and prescribe appropriate intervention. Dr. Guyton: In a diabetic patient taking troglitazone, warfarin, and pravastatin and who still has triglycerides of 387 and an HDL of 24, what is the safety and efficacy of adding Niaspan? Also, as a general point, how would you characterize the diabetic patient who can be put on niacin or Niaspan? Dr. Kreisberg: I know that everybody is worried about the interaction of all of these drugs and risk factors. First of all, there is no evidence that warfarin produces liver disease. The evidence that troglitazone produces liver disease consists of 35 reported cases, 2 of which resulted in liver failure. It is a concern, but the vast majority of patients who take that drug are going to be safe. I don’t know of any studies that look at troglitazone interactions with other potentially hepatotoxic agents. Pravastatin—and any of the other statins, for that matter—does not in my opinion produce significant hepatic toxicity, although physicians frequently believe that statins have this effect. So would I use Niaspan or nicotinic acid in such a patient? Yes, I would, and it would be a study of one. I do lots of those studies. I try to convince patients that a decision to use a drug isn’t a commitment to take it for a lifetime, and that we could stop at any time. And I would look at how the patient tolerated the drug, what effect it had, and whether it was worth it in that individual. Now the downside is that the diabetes might get worse, but we don’t know how much worse or whether that will substantially affect diabetic control. In my mind, glycemic control is more of an issue for microvascular disease than for macrovascular disease. If you remember the event curve from the Diabetes Control and Complications Trial, it flattens out at the 5–7% hemoglobin A1C range. So if you were to lose a half of a percent point of control, as reflected by the hemoglobin A1C, but you had in return a marked improvement in lipoprotein profile, I would consider that a very acceptable tradeoff. Dennis L. Sprecher, MD (Cleveland, Ohio): We have been very shy of using niacin in the setting of diabetes. We do prescribe this regimen, and we watch our patients very closely. But we are using much more gemfibrozil in diabetic patients in the setting that you were describing. Dr. Capuzzi: We have to treat patients here and now in light of all currently available data. My opinion is that preclinical data, observational study results, and smaller clinical trial data can and should be utilized prudently to render clinical decision making. Though definitive clinical trial data in dyslipidemic diabetics are lacking, small clinical study results suggest that a low dosage of niacin, for example, 1.5 grams per day, is unlikely to decontrol glucose regulation in diabetics. In addition, dyslipidemia is not the only atherogenic risk with diabetics. Literature reports indicate that patients with type II diabetes often have prothrombotic coagulation abnormalities due to increased levels of plasminogen activator inhibitor-1 (PAI-1), fibrinogen, and increased platelet activation and aggregation. In addition, diminished activity of tissue plasminogen activator (tPA) and decreased plasmin From the Departments of Medicine and Pathology, Sarah W. Stedman Center for Nutritional Studies, Duke University Medical Center, Durham, North Carolina. Address for reprints: John R. Guyton, MD, Department of Medicine, Box 3510, Duke University Medical Center, Durham, North Carolina 27710.