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R e v i e w s / C o m m e n t a r i e s / A D A S t a t e m e n t s
P E R S P E C T I V E S
Cardiovascular Disease in Diabetes
ZACHARY T. BLOOMGARDEN, MD
disease were associated with increasedrisk, the increased event rates among di-abetic patients were not fully explained Perspectives on the News commentaries are part of a free monthly CME activity. The nary artery disease (CAD) equivalent.
Mount Sinai School of Medicine, New York, New York, designates this activity for 2.0 522 diabetic individuals with average age AMA PRA Category 1 credits. If you wish to participate, review this article and visit www. confirmed that “the risk is pretty close in diabetes.procampus.net to complete a post- test and receive a certificate. The Mount stract 692) presented an interesting view Sinai School of Medicine is accredited by the Accreditation Council for Continuing Medi- cal Education (ACCME) to provide continu- ing medical education for physicians. regional perfusion deficit, of moderate or addressing aspects of cardiovascular dis- to 2001. There was striking similarity of Is it, then, possible to stratify patients ease in diabetic patients at the American event rates in both sexes and at all ages Diabetes Association’s 67th Scientific Ses- test? Existing predictive equations, such sions, 22–26 June 2007, in Chicago, Illi- Postgraduate Course, 1–3 February 2008, in San Francisco, California (the course is Study, those with both a history of diabe- available online at http://professional.
tes and prior myocardial infarction had a Diagnostic Criteria in Europe) study data, either under- or overestimate risk of fatal abetic patients with a history of myocar- however, that one must be cautious in as- sex may not be sufficiently precise predic- diabetes “really have CAD,” stating in- atherosclerosis in diabetes may be related stead that, in a typical individual with di- to glycated proteins in the vessel wall; to in patients with diabetes held at the Amer- Furthermore, after a cardiovascular event of insulin resistance; or to specific ele- low HDL cholesterol or the elevated levels readily quantitate the “amount of CAD.” of free fatty acids; small, dense LDL; and established relationship between diabetes large, cholesterol ester–rich VLDL parti- Diabetes Association Scientific Sessions, strated in the East-West Study of a North- tality rate among nondiabetic individuals zone’s study of potential explanatory fac- tion. Subjects with a history of myocardial infarction had an 18.8% risk, while those carotid ultrasound, and level of albumin- without a history of myocardial infarction by the traditional factors of age, sex, race/ but with a history of diabetes had a 20.2% of diabetic subjects had at least one abnor- 7-year risk (1), forming the basis of the ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● tients receiving statins, LDL level was nota significant predictor).
Zachary T. Bloomgarden, MD, is a practicing endocrinologist in New York, New York, and is affiliated withthe Division of Endocrinology, Mount Sinai School of Medicine, New York, New York.
Abbreviations: ADA, American Diabetes Association; apo, apolipoprotein; CAD, coronary artery disease;
are that cardiac stress testing is warranted CETP, cholesterol ester transfer protein; CVD, cardiovascular disease; DCCT, Diabetes Control and Com- for diabetic patients with typical or atyp- plications Trial; IMT, intima-media thickness; PET, positron emission tomography; SPECT, single-photon emission-computed tomography myocardial perfusion imaging; UKPDS, UK Prospective Diabetes Study.
DOI: 10.2337/dc08-zb06 2008 by the American Diabetes Association.
DIABETES CARE, VOLUME 31, NUMBER 6, JUNE 2008 Bloomgarden
questioned whether there is evidence that assessing the a priori likelihood that a per- abetes and without clinical CAD, half had screening will lead to an intervention that will improve outcome. In a trial of nondi- tures are less useful in the diabetic patient, given the greater likelihood of CAD in di- coronary intervention plus medical treat- diabetic patients at younger ages, and the medical treatment alone in risk of death, myocardial infarction, or other major car- in diabetic patients in general. A coronary diovascular events (5). “What do we do,” arteriogram is considered appropriate for asymptomatic diabetic patient?” If there is and -negative stress testing, but typically it is carried out in individuals who have a myocardial perfusion, with the latter ap- positive test and are clinically at high risk, pearing to be more specific, as it also gives there is no strategy clearly differentiating whether a given diabetic patient is at low or high risk, he suggested, “we are left fact, Balady suggested, the sensitivity and specificity of the exercise electrocardio- change in the ejection fraction with stress diabetic patients.” The only medical ther- PET gives additional information pertain- ing to the extent of coronary disease, and cholesterol goal for individuals with es- important that a negative test be associ- large breast size. As with the stress elec- ated with good prognosis. Exercise capac- factor, as is heart rate recovery after exer- cise, with a pulse decrease by Ͻ12 bpm in mented, “will be very expensive and will the first minute associated with increased lead to interventions that will also be very mortality (7). In a study presented at the be seen as additive to the clinical data. As expensive,” as well as being associated creases several years after a normal study.
other procedure-related complications.
Reversibility of ischemia may guide deci- “We’re left with assessing CV risk using the standard risk factors,” with the A1C goal Ͻ7% the one “for which we have less monstrable in individuals with large areas with specificity 0.72 for abnormal dobut- of reversible ischemia (8), although as yet noting that stress testing is designed to is associated with particularly high risk for the heart rate and was 0.85, with spec- ificity 0.39, for an abnormal heart rate re- suggested that coronary calcification as- covery pattern, supporting Balady’s view.
sessment may be a useful screening tool to He suggested that the exercise test can be with myocardial wall stress related to ven- ties in the inferior portion of the heart and cussed the use of coronary artery calcium which is useful in patients with left bun- ening, also contributing. With graded in- sion at rest. The likelihood of events is low systolic blood pressure increase to a goal study, although after several years risk in- leads to formation of osteoblast-like cells creases, and there is uncertainty about the 220 minus years of age, as lower achieved interval after which repeat testing should arterial wall, activated by advanced glyca- heart rates may result in falsely negative be performed. The diagnostic value of the tests. Ischemic ST depression, either hor- vascular function. There are a variety of genetic and environmental factors leading to atherosclerosis and to coronary calcifi- lower for inferior or inferolateral ischemia than for ischemia in the distribution of the CAD in asymptomatic diabetic patients.
DIABETES CARE, VOLUME 31, NUMBER 6, JUNE 2008 Perspectives on the News
NEWS FROM THE FOOD AND DRUG ADMINISTRATION
From time to time, new announcements by the FDA pertaining to aspects of diabetes treatment will be highlighted in this section. At the Postgraduate Course, Alan Chait(Seattle, WA) reviewed approaches to Issues pertaining to regulation of direct-to-consumer (DTC) advertising, includ- ing how it relates to communication with subsets of the general population such are limited data regarding benefits of gly- as the elderly, children, and racial and ethnic minority communities, remain important to the FDA. The Risk Communication Advisory Committee held a hearing on the topic on 15 May 2008. The serious attention being paid to this topic is exemplified in a warning letter sent to Pfizer on 16 April 2008 regarding DTC advertising for sildenafil (Viagra) reminding the company that some tele- vision advertisements have not included warnings about potential adverse effects of sexual activity in individuals with cardiovascular disease and about the po- tential risks of priapism, non-arteritic anterior ischemic optic neuropathy, and hearing loss associated with use of the agent.
(11), and in a meta-analysis of a group of On 27 March 2008, the FDA warned consumers that two products, “Total Body studies (12) suggest that as glucose levels Formula” in Tropical Orange and Peach Nectar flavors and “Total Body Mega Formula” in the Orange/Tangerine flavor, had been sold with hazardous levels of selenium, causing hair loss, muscle cramps, diarrhea, joint pain, deformed fin- however, suggesting that the relationship gernails, and fatigue after 5–10 days of use. Many multivitamin supplements contain selenium, with a report last year showing that supplementation of 200 ␮g daily (twice the recommended daily allowance) is associated with more than the “glucose paradox.” (3) In mice with a doubling of diabetes risk (Stranges S, Marshall JR, Natarajan R, Donahue RP, Trevisan M, Combs GF, Cappuccio FP, Ceriello A, Reid ME: Effects of long-term ing the LDL receptor, he said, “hyperlip- selenium supplementation on the incidence of type 2 diabetes: a randomized trial. Ann Intern Med 147:217-223, 2007). An addendum on 1 May 2008 also noted that toxic levels of chromium were found in these products, suggesting the myocardial infarction in the UKPDS failed importance of careful screening of dietary supplements used by patients with (though barely) to reach statistical signif- icance, and stroke was nonsignificantlyincreased by 11%. (14) There was a sig-nificant 39% decrease in myocardial in-farction and a 41% decrease in stroke in the same study the combination of met- nary calcium level, the latter is the more formin with a sulfonylurea led to signifi- with angioplasty, and at all levels of isch- alone, as well as to a nonsignificant in- crease in diabetes-related events (15). A he also noted that not all diabetic patients cept of diabetes as a CVD risk equivalent obstructive atherosclerosis will not have evidence of ischemia but are at risk of cor- not adjudicated, and incorrect statistical higher- from lower-risk diabetic patients.
mality of sympathetic tone in the setting “Calcium,” he said, “has been one of the very debated markers,” and although “the stress test difficult to interpret, perhaps significance of the association (17,18).
calcified plaque may be stable, the calci- leading to higher false-positive rates in di- fied patient may not be stable,” with a abetic patients. Ideally, screening should high coronary calcium score therefore in- increase heart failure, and neither is asso- dicating a individual with a greater degree from intervention; Raggi suggested that at present “there’s no clarity in the field,” mortality (20). Chait asked, “How do we get a solution to this confusion?” It may for screening too restrictive because they be, he suggested, that glycemic treatment strongly predictive than stenosis of mor- in other vascular beds. Although there is cost-effective, he suggested that coronary score are useful in defining risk, and dia- calcium score or, alternatively, carotid in- cium score are at relatively low risk.
(21), and others have shown that the met- DIABETES CARE, VOLUME 31, NUMBER 6, JUNE 2008 Bloomgarden
abolic syndrome adds risk to that associ- tion of whether fibrates have benefit ad- ceptibility syndrome in which visceral ad- At the Postgraduate Course, Allan Snider- factors, not all of which are included in the current definition of the syndrome.
we are “measuring the right things” in as- Chait considered dyslipidemia the critical apoB is a better index of the concentration of atherogenic lipids in plasma and, there- fore, a better target than LDL cholesterol (apo)B and low HDL cholesterol levels.
erosclerotic lesion, he said, is not simply a pool of cholesterol in the arterial wall but ping of an apoB particle with both protec- without apoAII in the HDL2 fraction.
cholesterol ester transfer protein (CETP) initiating event is the entry and trapping of an apoB lipoprotein particle, typically statin reduced events by ϳ25% in all sub- similar benefit in individuals with diabe- mented, “HDL is incredibly complicated,” tes with or without CHD, with low or high levels. In a meta-analysis, statins were as- of reverse cholesterol transport, including anti-inflammatory and antioxidant effects both type 1 and type 2 diabetes (24). In- terol mass within all apoB-containing par- as part of the innate immune system, such creased CVD risk in individuals with type ticles. The number of LDL particles is ϳ9 1 diabetes was particularly present in the times greater than that of VLDL particles, stances of intensive insulin treatment (25) sured on nonfasting samples because it is (34), and there is particularly good evi- dence of benefit of aggressive blood pres- efit of statins. Certainly, there is a direct in stroke, heart failure, and microvascular particles, each still containing one apoB event rates (27), leading Chait to suggest benefit,” in the blood pressure treatment that “any form of LDL lowering is associ- ated with benefit.” The VA-HIT (Veterans of aspirin in diabetic patients was shown 18 studies that have prospectively evalu- ated apoB vs. LDL, all showing the former vention Trial) (28) showed that gemfibro- study (37) and in the Antiplatelet Trial- to be more strongly associated with CVD.
ists’ Collaboration (38). “Finally,” Chait asked, “where does adiposity fit in?” He noted, “If you block adiposity, you could particle number is a covariate (44). “It is the LDL particle itself which creates the ations, Chait suggested that, particularly atherogenic lesion in the arterial wall,” should offer all individuals with diabetes small nor large particles are preferable; the benefit of intensive treatment with st- rather, it is the number of particles that is atins, angiotensin-directed antihyperten- renal effect (29), so the important ques- DIABETES CARE, VOLUME 31, NUMBER 6, JUNE 2008 Perspectives on the News
relatively inexpensive, accurate, and stan- and stroke. He pointed out that stroke is dardized and does not require fasting.
tients include statins (57) and blood pres- and the third leading cause of death in the US and, because of its higher frequency in with angiotensin-directed agents (58,59).
levels from those with elevations in both, tifactorial intervention (41). In its most diabetic patients with the intensive inter- diagnosis of type III hyperlipidemia, fa- erosclerosis alone, by emboli as seen with atrial fibrillation and heart failure, and by a variety of other conditions. Risk factors rette use, alcohol excess, and diabetes. In- sulin resistance is associated with stroke.
A variety of measures, including proinsu- there may be such a relationship (26).
lin, fasting insulin, postload insulin, and not characteristically high in type 2 dia- betes, apoB is elevated in the majority of glucose ratio are stroke risk factors (45– type 2 diabetic individuals, “so this is a 49), and obesity is associated with stroke major problem in your patients.” A sub- stantial number of diabetic patients have hattan Stroke) study of 3,298 stroke-free abetic populations in macrovascular risk.
with history of a stroke before study en- due to lipohyalinosis associated with fibrin Sniderman said, “the evidence supports” diabetic glomerular disease, contributing to References
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