These pages are best viewed with Netscape version 3.0 or higher or Internet Explorer version 3.0 or higher. When viewed with other browsers, some characters or attributes may not be rendered correctly.SUMMARY Impact of Glucose Control in Type 2 Diabetes Session summary Michael P. Stern, MD The first article in this session, by Dr. Lebovitz, provides a clear and concise review of the effects of oral antidiabetic agents on cardiovascular risk factors. It includes three highly useful tables that summarize in parallel format the effects of sulfonylureas, metformin, and troglitazone on the following risk factors: body weight, blood pressure, triglycerides, total and HDL cholesterol, lipoprotein(a), procoagulant state, and insulinemia and insulin resistance. Metformin is the only oral agent that offers the possibility of drug-induced weight loss. Troglitazone, on the other hand, offers the most marked correction of the high triglyceride/low HDL dyslipidemic pattern commonly seen in diabetic subjects, although it may also raise LDL cholesterol levels. In the discussion that followed Dr. Lebovitz's presentation,
considerable attention was paid to the possible cardiotoxic effects of sulfonylureas. One
of the participants called attention to evidence indicating that the sulfonylurea
receptors in myocardium and vascular smooth muscle are low-affinity receptors, unlike
sulfonylurea receptor 1 in the pancreatic Another topic discussed was compositional changes in lipoproteins that result from the various oral antidiabetic agents. Attention was called to a cross-over study showing a greater decline in plasma triglyceride concentration during insulin treatment than during treatment with glibenclamide, despite similar levels of blood glucose control with the two agents (7). Although the percentage distribution of VLDL subfractions in this study was shifted toward small VLDL particles during insulin treatment compared with glibenclamide treatment, the absolute levels of all VLDL subfractions (large, intermediate, and small) were lower during insulin therapy. In addition, HDL2 was higher and HDL3 was lower during insulin treatment compared with glibenclamide. In another cross-over study, this one double-blinded, troglitazone increased large, buoyant LDL and decreased small dense LDL concentrations with no change in apolipoprotein B concentrations (8). Troglitazone treatment was also associated with increased resistance of LDL to oxidation (8). The problem of lactic acidosis and biguanides was also addressed. It was pointed out that, although the risk is low if the known contraindications are strictly adhered to, there is likely to be an increased number of cases in routine clinical practice. Most of the reported cases of lactic acidosis in patients on metformin have occurred in patients with known contraindications, such as elevated serum creatinine. One participant stated that he was aware of a number of renal dialysis patients who had received metformin. On the other hand, published data indicate that in Sweden, the number of fatalities secondary to metformin-induced lactic acidosis is similar to the number of fatalities secondary to glibenclamide (glyburide)-induced hypoglycemia, implying that the risks of the two drugs are similar (9). There was also discussion of whether the lipid-lowering effects of various oral antidiabetic agents were independent of their glycemia-lowering effects. Very little is known about this, but it is possible that the triglyceride-lowering effect of thiazolidinediones are secondary to suppression of free fatty acids and, to that extent, independent of their glycemia-lowering effect. In a study of Darglitazone, for example, patients who experienced very little glucose-lowering nevertheless exhibited a lowering of their triglyceride levels (H. Lebovitz, personal communication). The second article in this session, by Drs. Boyne and Saudek, reviews the effects of exogenous insulin on cardiovascular risk factors. The animal and epidemiological evidence supporting an atherogenic effect of insulin is nicely summarized, and an important distinction is made between endogenous hyperinsulinemia in nondiabetic subjects and exogenous insulin administration to diabetic patients. The latter have the possibility of benefiting from having their diabetes controlled, whereas the former do not. The authors stress that the metabolic abnormalities associated with uncontrolled diabetes go well beyond just hyperglycemia, and that these additional abnormalities undoubtedly contribute to the enhanced atherogenesis associated with the diabetic state. Moreover, hyperglycemia itself can promote atherogenesis, and the possible mechanisms mediating this effect are summarized in the article. The article concludes with an interesting summary of the mechanisms whereby insulin treatment promotes weight gain. The discussion of Drs. Boyne and Saudek's paper began with a recognition that insulin was often started late in the course of type 2 diabetes when endogenous insulin secretion was already severely compromised, thereby rendering control difficult, as is the case with type 1 patients. The suggestion was made that better results might occur if insulin treatment were started earlier. The results of the UKPDS are significant in this regard, as in this study newly diagnosed diabetic patients were enrolled, some of whom were randomly allocated to early insulin treatment (5). It was also noted that in the DIGAMI Study, patients with acute myocardial infarction without a prior history of insulin treatment experienced a 52% reduction in mortality over 1 year when treated intensively with insulin, compared with only a 14% reduction among those who had been previously treated with insulin but whose therapy was intensified (10). A possible explanation for this difference is that the patients who were not previously treated with insulin were at an earlier stage of type 2 diabetes than those who had already been treated with insulin. Unfortunately, the DIGAMI protocol does not permit one to distinguish between acute intravenous insulin administration in the immediate post–myocardial infarction period and long-term intensive insulin management. There was also considerable discussion regarding a truly physiological method of delivering insulin, i.e., via the portal route and with pulsatility. Data on these points are limited, but there is some evidence that pulsatile delivery may lead to better glycemic control (11). It was also noted that Bergman and colleagues (12,13) have presented data suggesting that the effect of insulin on hepatic glucose output is indirect, in which case there would be little theoretical reason to expect much of a difference in glucose control between portal versus peripheral delivery of insulin. Data by Lewis and colleagues (14–17) and Cherrington and colleagues (18–21), on the other hand, suggest a direct effect of insulin on hepatic glucose output, which would argue for a theoretical advantage to portal delivery. There is also a theoretical concern that portal delivery of insulin could raise hepatic triglyceride production rates, and, indeed, some data suggest that triglyceride levels rise with this method of insulin delivery (22). Perhaps more to the point, there are no data on the effects of portal insulin administration on VLDL composition. There are, however, data that suggest a slight improvement in HDL cholesterol levels with portal insulin delivery (23). The third article, by Dr. Haffner, reviews the role of glycemia as a cardiovascular risk factor. Whereas several early studies failed to find an association between the level of hyperglycemia in diabetic subjects and their risk of macrovascular complications, more recent studies have consistently corroborated this relationship. The data for impaired glucose tolerance (IGT), however, are much weaker. Most studies have either failed to find or at best find a weak association between IGT and macrovascular complications. A major part of the discussion of Dr. Haffner's paper pertained to whether or not we should recommend treating the prediabetic state, defined as IGT or in some other way. One viewpoint was that, inasmuch as diabetes itself is so often inadequately treated, we should concentrate on first improving the level of diabetic control in routine clinical practice. The question was also raised, if the prediabetic state is to be treated, what precisely should we treat? It was pointed out that guidelines already exist for screening and treating conventional cardiovascular risk factors. Some participants felt that in view of the high cardiovascular risk in prediabetic individuals, it might be desirable to advocate more vigorous interventions than are ordinarily advocated for cardiovascular risk factors—for example, lower blood pressure targets. Moreover, as the prediabetic state includes features of the insulin resistance syndrome, the question arises whether features such as hyperinsulinemia, low HDL, small dense LDL, etc., for which guidelines are not currently available, should also be targeted for treatment. Along these same lines, it was noted that for diabetic patients, the presence of microalbuminuria constitutes an indication for treatment with ACE inhibitors. But microalbuminuria is also a cardiovascular risk factor in nondiabetic individuals (24). Because, however, these individuals are not at increased risk for renal disease, treatment with ACE inhibitors seems questionable. Thus, if the notion of treatment for microalbuminuria is entertained for nondiabetic subjects, it is not clear which risk factors should be treated. Reference was made to the Heart Outcomes Prevention Evaluations (HOPE) Study, which includes nearly 6,000 nondiabetic subjects, 15% of whom have microalbuminuria. Because these subjects are randomized to ACE inhibitors, vitamin E, or placebo in a factorial design, this study should provide a least some answers about treating microalbuminuria in nondiabetic subjects (25,26). The point was also raised whether treatment recommendations should be restricted to risk factors for which clinical trial data provide convincing evidence of benefit. On the other hand, it was noted that the original National Cholesterol Education Program guidelines were not based on clinical trial data, although, fortuitously, subsequent clinical trials tended to validate these recommendations. It was also noted that only 17% of the participants in the Air Force Coronary Atherosclerosis Prevention Study (AFCAPS) met current guidelines for treatment of their LDL-cholesterol concentration, even though the study convincingly demonstrated a treatment benefit in the entire active drug group (27). The comment was also made that in this era of managed care, the cost-effectiveness of preventive treatment will need to be firmly established. One of the principal risks for prediabetic individuals, of course, is the development of diabetes itself. Indeed, it may be that the entire enhanced cardiovascular risk associated with the prediabetic state is confined to individuals who subsequently convert to diabetes, in which case prevention of conversion becomes the preeminent therapeutic goal. The currently ongoing Diabetes Prevention Program (DPP) should provide useful information on whether this goal is achievable and, if so, how. There was also discussion of the adequacy of carotid wall thickness as measured by ultrasonography as a surrogate for atherosclerosis, particularly coronary atherosclerosis. It was noted that carotid wall thickness is thought to provide a measure of early atherosclerosis, whereas coronary angiograms provide a measure of later, and in some cases more complicated, lesions. The possible superiority of intravascular ultrasound was mentioned, although it was noted that this superiority has not yet been firmly established. It was further noted that data from ultrafast or electron-beam computed tomography of the coronary arteries suggest that as many as 50% of type 1 diabetic subjects aged 20–50 years have intracoronary calcifications (28). Further discussion related to possible sex differences in the effects of diabetes on risk factors and disease. For example, Framingham data indicate that diabetes increases the risk of stroke equally in men and women, unlike coronary disease, for which diabetes increases the risk approximately twice as much in women as in men (29). There are also data indicating that whereas diabetes has an equal impact on the triglyceride levels of men and women, diabetic women have lower HDL levels than do diabetic men (30). Moreover, the effects of glucose levels on small dense LDL are greater in women than in men (31). References 2. Engler RL, Yellon DM: Sulfonylurea KATP blockade in type II diabetes and preconditioning in cardiovascular disease: time for reconsideration. Circulation 94:2297–2301, 1996 3. Mühlhauser I, Sawicki PT, Berger M: Possible risk of
sulfonylureas in the treatment of non-insulin-dependent diabetes mellitus and coronary
artery disease (Letter). 4. Yudkin JS: Vascular events and diabetes: acute myocardial infarction and stroke. In International Textbook of Diabetes Mellitus. 2nd ed. Alberti KGMM, Zimmet P, DeFronzo RA, Keen H (Honorary), Eds. New York, Wiley, 1997, p. 1255–1279 5. UK Prospective Diabetes Study (UKPDS) Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352:837–853, 1998 6. UK Prospective Diabetes Study (UKPDS) Group: Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:854–865, 1998 7. Romano G, Patti L, Innelli F, Di Marino L, Annuzzi G, Iavicoli M, Coronel GA, Riccardi G, Rivellese AA: Insulin and sulfonylurea therapy in NIDDM patients: are the effects on lipoprotein metabolism different even with similar blood glucose control? Diabetes 46:1601–1606, 1997 8. Tack CJJ, Smits P, Demacker PNM, Stalenhoef AFH: Troglitazone decreases the proportion of small, dense LDL and increases the resistance of LDL to oxidation in obese subjects. Diabetes Care 21:796–799, 1998 9. Campbell IW: Metformin and the sulphonylureas: the comparative risk. Horm Metab Res (Suppl.) 15:105–111, 1985 10. Malmberg K, Ryden L, Efendic S, Herlitz J, Nicol P, Waldenstrom A, Wedel H, Welin L on behalf of the DIGAMI Study Group: Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): effects on mortality at 1 year. J Am Coll Cardiol 26:57–65, 1995 11. Bratusch-Marrain PR, Komjati M, Waldhausl WK: Efficacy of pulsatile versus continuous insulin administration on hepatic glucose production and glucose utilization in type I diabetic humans. Diabetes 35:922–926, 1986 12. Bergman RN: New concepts in extracellular signaling for insulin action: the single gateway hypothesis. Rec Progr Horm Res 52:359–387, 1997 13. Mittelman S, Fu YY, Rebrin K, Steil G, Bergman RN: Indirect effect of insulin to suppress endogenous glucose production is dominant, even with hyperglucagonemia. J Clin Invest 100:3121–3130, 1997 14. Lewis GF, Zinman B, Groenewoud Y, Vranic M, Giacca A: Hepatic glucose production is regulated both by direct hepatic and extrahepatic effects of insulin in humans. Diabetes 45:454–462, 1996 15. Lewis GF, Vranic M, Giacca A: Glucagon enhances the direct suppressive effect of insulin on hepatic glucose production in humans. Am J Physiol 272:E371–E378, 1997 16. Lewis GF, Vranic M, Harley P, Giacca A: Fatty acids mediate the acute extrahepatic effects of insulin on hepatic glucose production in humans. Diabetes 46:1111–1119, 1997 17. Lewis GF, Vranic M, Giacca A: Role of free fatty acids and glucagon in the extrahepatic effect of insulin on glucose production in humans. Am J Physiol 275:E177–E186, 1998 18. Sindelar DK, Balcom JH, Chu CA, Neal DW, Cherrington AD: A comparison of the effects of selective increases in peripheral or portal insulin on hepatic glucose production in the conscious dog. Diabetes 45:1594–1604, 1996 19. Sindelar DK, Chu CA, Rohlie M, Neal DW, Swift LL, Cherrington AD: The role of fatty acids in mediating the effects of peripheral insulin on hepatic glucose production in the conscious dog. Diabetes 46:187–196, 1997 20. Sindelar DK, Chu CA, Neal DW, Cherrington AD: Interaction of equal increments in arterial and portal vein insulin on hepatic glucose production in the dog. Am J Physiol 273:E972–E980, 1997 21. Sindelar DK, Chu CA, Venson P, Donahue EP, Neal DW, Cherrington AD: Basal hepatic glucose production is regulated by the portal vein insulin concentration. Diabetes 47:523–529, 1998 22. Bagdade JD, Kelley DE, Henry RR, Eckel RH, Ritter MC: Effects of multiple daily insulin injections and intraperitoneal insulin therapy on cholesterol ester transfer and lipoprotein lipase activities in NIDDM. Diabetes 46:414–420, 1997 23. Ruotolo G, Micossi P, Galimberti G, Librenti MC, Petrella G, Marcovina S, Pozza G, Howard BV: Effects of intraperitoneal versus subcutaneous insulin administration on lipoprotein metabolism in type I diabetes. Metabolism 39:598–604, 1990 24. Yudkin JS, Forrest RD, Jackson CA: Micoalbuminuria as predictor of vascular disease in non-diabetic subjects: Islington Diabetes Survey. Lancet 2:530–533, 1988 25. HOPE Study Investigators: The HOPE (Heart Outcomes Prevention Evaluations) Study: the design of a large, simple randomized trial of an angiotensin converting enzyme inhibitor (ramipril) and vitamin E in patients at high risk of cardiovascular events. Can J Cardiol 12:127–137, 1996 26. Gerstein HC, Bosch J, Pogue J, Taylor DW, Zinman B, Yusuf S: Rationale and design of a large study to evaluate the renal and cardiovascular effects of an ACE inhibitor and vitamin in E in high-risk patients with diabetes: the MICRO-HOPE study. Diabetes Care 19:1225–1228, 1996 27. Downs JR, Clearfield M, Weis S, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr: Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS: Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 279:1659–1661, 1998 28. Rewers M, Ehrlich J, Jensen L, Seigel R, Barriga K, Garg S, Janowitz W, Eckel R: High prevalence of asymptomatic coronary atherosclerosis detected by electron beam computed tomography in young adults with IDDM (Abstract). Diabetes 47 (Suppl. 1):A12, 1998 29. Kannel WB, McGee DL: Diabetes and glucose tolerance as risk factors for cardiovascular disease: the Framingham study. Diabetes Care 2:120–126, 1979 30. Assman G, Schulte H: The Prospective Cardiovascular Munster (PROCAM) Study: prevalence of hyperlipidemia in persons with hypertension and/or diabetes mellitus and the relationship to coronary heart disease. Am Heart J 116:1713–1724, 1988 31. Haffner SM, Mykkänen L, Stern MP, Paidi M, Howard BV: Greater effect of diabetes on LDL size in women than in men. Diabetes Care 17:1164–1171, 1994 From the University of Texas Health Science Center, San Antonio, Texas. Address correspondence and reprint requests to Michael P. Stern, MD, University of Texas Health Science Center, 7703 Floyd Curl Dr., San Antonio, TX 78284-7873. Received for publication 2 November 1998 and accepted 4 November 1998. Abbreviations: DIGAMI, Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction; IGT, impaired glucose tolerance; UKPDS, U.K. Prospective Diabetes Study. A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. This article is based on presentations at a conference organized by the Indiana University Diabetes Research and Training Center. The conference and the publication of this article were made possible by an unrestricted educational grant from Eli Lilly and Company. Copyright © 1999 American Diabetes Association For Technical Issues contact webmaster@diabetes.org |
-cell, which is a high-affinity receptor. Given this low affinity, it is
possible that the plasma levels of sulfonylurea achieved at ordinary pharmacological doses
are insufficient to close the ATP-sensitive K+ channels in
heart and vascular smooth muscle (L. Aguilar-Bryan, personal communication). Nevertheless,
studies of experimental ischemia in animals have shown that pretreatment with
sulfonylureas can inhibit protective responses to ischemia, such as ischemic
preconditioning and coronary vasodilatation, and can lead to increased infarct size (