Diabetes 2004
Editor's Summary

In this issue of the Diabetes 2004 monograph, we summarize important diabetes data that were presented at the 2004 EuropeanAssociation for the Study of Diabetes (EASD) meeting and the 2004 Scientific Sessions of the American Heart Association (AHA).

Noteworthy among the many scientific presentations made at the EASD meeting was the surprising results of the Diabetes Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI)-2 study. During a “standing-room only” symposium, Drs. Rydén and Malmbergfrom the Karolinska Institute in Stockholm presented late-breaking results of the follow-up study to DIGAMI-1, which reported that plasmaglucose level in patients with diabetes was a powerful indicator of poorer outcome following acute myocardial infarction (AMI). In DIGAMI-2, acutely-introduced intensive insulin therapy in post-AMI patients had no benefit over conventional anti-diabetic therapy. The study did haveseveral important limitations—most importantly it was likely not adequately powered to demonstrate a difference in outcomes. Thus, itappears that a specific strategy compelling intravenous insulin in diabetic patients during their coronary care unit stay for AMI is no longersupported by clear-cut evidence. However, given the very strong epidemiological evidence linking poor in-hospital glucose control withadverse cardiovascular outcomes, glucose levels should not be allowed to remain hyperglycemic during AMI. DIGAMI-2 simply tells us thatthe antihyperglycemic strategy need not include insulin—although, if needed, it should! Lastly, we would add that the DIGAMI-2 results donot in any way disprove the documented benefits from insulin infusion and aggressive glucose control in other critically ill diabetic patientsnor does it argue against aggressive antihyperglycemic therapy in patients following AMI.

More information was forthcoming about silent myocardial ischemia (SMI) in diabetes patients. The frequency of SMI is increased indiabetic patients as well as those with metabolic syndrome, therefore waiting for patients to develop symptomatic angina before proceedingto cardiac evaluation may not be the optimal approach. SMI can be detected with variable precision by available screening modalities, includingregular ECG stress testing, nuclear MPI, stress echo, and electron beam computed tomography (EBCT). Peovska et al. found that almost halfof patients with scintigraphic evidence of restenosis nine months following stenting had recurrent ischemia that was silent, and it was morecommon in patients with diabetes (EASD abstract 1182). In a silent CAD follow-up study conducted by Sejii et al., diabetes patients who had botha positive screen and significant coronary stenoses (defined as >50% of luminal diameter) on angiography had significantly higher incidencesof all-cause mortality and major, non-fatal cardiac events six years after the initial screen, as compared to those who had negative screeningresults (EASD abstract 1210). Taken together, these findings indicate that silent ischemia is frequent in diabetics and its presence identifiesa high-risk group. Whether they should be treated any differently than patients with symptomatic ischemia is not clear. Moreover, whichpatients benefit most from screening and whether screening actually improves clinical outcomes is not yet known.

Evidence for the important consequences of metabolic syndrome was underscored by Verges et al. who documented a significantlygreater rate of in-hospital mortality following MI in patients with the metabolic syndrome compared to those without (EASD abstract 197,AHA abstract 3060). Unfortunately, the pandemic of metabolic syndrome and its off-shoots, diabetes and cardiovascular disease, will likelycontinue for many years, posing challenges to scientists and practitioners alike. According to data presented by Aguilar et al., mean CRP levelsare increased directly with the number of metabolic syndrome risk determinants, providing further evidence of an intimate link between metabolicsyndrome and subclinical vascular inflammation (AHA abstract 2543). Evidence supporting the onset of insulin resistance and cardiovasculardisease years before the diagnosis of diabetes was presented by Akosah et al., who observed metabolic syndrome to be significantly andindependently associated with subclinical atherosclerosis (AHA abstract 2063). Toyofuku et al. found hyperinsulinemia, a marker of insulinresistance, to be a significant risk factor for repeat revascularization following percutaneous coronary intervention (PCI) in patients with andwithout diabetes (AHA abstract 3642).

Numerous presentations suggested there will soon be many exciting changes in the treatment of Type 2 diabetes. Studies of oralinsulin* (EASD abstract 8), buccal insulin spray* (EASD abstract 868), and the long-term efficacy and safety of inhaled insulin* (EASD abstracts114 and 863) suggest a potential for newer routes of insulin delivery. Novel compounds that simultaneously modulate glucagon secretion,delay gastric emptying, and modulate appetite are likely to soon become available including: derivatives of amylin* (a ß-cell product) (EASDabstracts 111 and 785) and agonists/modulators of Glucagon-Like Peptide-1* (GLP-1) (a gut- peptide with glucose-dependent insulinotropicproperties) (EASD abstracts 773, 774, 775). Moreover, long-term studies (>two years) confirmed both the glycemic and non-glycemicactions of the thiazolidinedione (TZD) class of insulin sensitizers. Sustained improvements in ß-cell function (EASD abstract 810) anddyslipidemia (EASD abstracts 723 and 1151) were described. Karagiannis et al. reported that pioglitazone increased HDL-C levels (~15-20%),more so than sulfonylureas or metformin, which translated into 40% of TZD-treated patients lowering their risk for vascular complications byat least one category (EASD abstract 30). In the first, multicenter, double-blind, randomized study comparing TZDs—the results presented byDr. Ronald Goldberg during a “late-breaking” clinical trials session at the AHA meeting—statistically significant differences favoring pioglitazoneover rosiglitazone were observed based on improvements in triglycerides, HDL-cholesterol, non-HDL cholesterol, and LDL-cholesterol particleconcentration and size. More studies are accumulating on the potential benefits of the TZDs on markers or surrogates of the metabolic syndromeand atherosclerosis, including C-reactive protein (EASD abstract 725) and plasminogen activator inhibitor (EASD abstract 1164), carotid intimalmedialthickness (AHA abstracts 1013 and 2056), endothelial function (AHA abstract 860), and exercise tolerance in patients with exerciseinducedangina (AHA abstract 2535). In a retrospective study of 97 diabetic patients with heart failure, TZD-treated patients experiencedsignificantly fewer all-cause hospitalizations, heart failure hospitalizations, and total hospital days, and no change in heart failure over aone-year period as compared to those not treated with a TZD (AHA abstract 2411).* Together, the data continue to suggest that TZDs havebeneficial cardiovascular effects—although true outcomes studies are still underway and meaningful data will not be available for at leastanother year or two.

We would also like to highlight the following noteworthy study findings: In CAD patients undergoing PCI, restenosis rates appear tobe significantly reduced in diabetic patients who receive a drug- (e.g., sirolimus-) stent, although the rates are higher than in non-diabeticpatients (AHA abstracts 3006 and 3497). In a study by McGuire et al., ß-blocker prescription at discharge was independently associated witha 28% decreased mortality hazard (two-year all-cause mortality) in a cohort of 713 patients with diabetes who had been admitted to a CCUwith unstable angina or non Q-wave MI (abstract 3745).

More details on these and other topics are found in this volume of Diabetes 2004.

* The product is not labeled for the use under discussion or the product is still investigational.