Special Patient Subset: Diabetes Mellitus



Diabetes mellitus affects a significant portion of the population; 1 in 10 adults in the United States has diabetes, with 90% to 95% of patients having type 2 diabetes.1 In 2012, nearly 20.1 million Americans ≥20 years of age were diagnosed with diabetes mellitus, 8.1 million Americans had undiagnosed diabetes mellitus, and an estimated 80.8 million (35.3%) had prediabetes (ie, fasting blood glucose of 100 to <126 mg/dL).1 The prevalence of diabetes mellitus is rapidly increasing and is attributed to the increased frequency of obesity, suboptimal nutritional habits, and aging of the population (Fig. 40-1).2 The total prevalence of diabetes mellitus in the United States is expected to more than double from 2005 to 2050 (from 5.6% to 12.0%) in all age, sex, and race/ethnicity groups, with minorities disproportionately affected.1 This increase, however, is not limited to the United States. The global prevalence of diabetes mellitus for all age groups is also increasing. In 2010, the prevalence of diabetes mellitus worldwide was estimated to be 6.4% and is projected to increase to 7.7% in 2030; the total number of people with diabetes mellitus is projected to increase from 285 million in 2010 to 439 million in 2030.1,3

Figure 40-1

Numbers of people with diabetes (in millions) for 2000 and 2010 (top and middle values, respectively), and the percentage increase. (Reprinted by permission from Macmillan Publishers Ltd: Nature, Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature. 2001;414:782-787, Copyright © 2001.)



The interventional cardiologist often encounters patients with diabetes mellitus in more advanced stages, when vascular complications have already occurred. The pathophysiology of vascular disease involves derangements in endothelial, vascular smooth muscle cell, and platelet function.4 The hyperglycemia, increased availability of free fatty acids, and insulin resistance in the diabetic patient collectively decrease nitric oxide availability, increase oxidative stress, disrupt intracellular signal transduction, and activate receptors for free radical–producing advanced glycation end products.4 In addition, several deregulatory factors play a part in the derangements of coagulation and platelet activity seen in patients with diabetes, mostly mediated by enhancement of the prothrombotic state due to insulin resistance and hyperglycemia.5 Subsequently, atherosclerosis ensues, and as such, the risk for adverse cardiovascular events increases.

The concept of diabetes as a coronary artery disease (CAD) risk equivalent has its roots in a landmark Finnish-based study that demonstrated that the presence of diabetes alone increased the 7-year risk of fatal and nonfatal myocardial infarction (MI).6 These results laid the foundation for the recommendation that patients with diabetes receive secondary level prevention per the Adult Treatment Panel III of the National Cholesterol Education Program.7

Indeed, CAD is prevalent in the patient with diabetes even when asymptomatic. Occult CAD was discovered in asymptomatic patients with diabetes who underwent coronary computed tomography angiography despite having a normal stress test (using single-photon emission computed tomography pharmacologic stress testing), a normal electrocardiogram, a lack of symptoms, and a lack of peripheral arterial disease.8 A separate study of an autopsy cohort from Olmstead County, Minnesota, examined patients with diabetes without prior evidence of clinical CAD and found that they were more likely than their nondiabetic counterparts to have high-grade atherosclerosis (68% vs 46%; P < .001) and more likely to have multivessel CAD (50% vs 31%; P < .001).9

Moreover, the presence of angina was not found to be predictive of future mortality or cardiac events. In a post hoc analysis of the Bypass Angioplasty Revascularization Investigation in Patients With Diabetes (BARI 2D) trial, the prognostic significance of angina or its equivalents was examined, and it was determined that the presence of angina did not significantly affect the 5-year risk of cardiovascular events or all-cause mortality.10

The patient with diabetes and underlying ischemic heart disease is more likely to be female and have a higher prevalence of hypertension, hypercholesterolemia, renal insufficiency, peripheral vascular disease, and congestive heart failure.11 There is an excess mortality associated with CAD in patients with diabetes, particularly in patients with acute coronary syndromes (ACS),12 and females have a relative risk for fatal CAD that is 50% higher than males.13



It is well established that patients with CAD across the spectrum of stable ischemic heart disease, ACS, and ST-segment elevation MI (STEMI) should be treated with guideline-directed medical therapy (GDMT).14-16 However, in patients with diabetes, with more rapid progression of atherosclerosis17 and a higher incidence of adverse events,12,13 special considerations exist. It has been shown that diabetes is a clinical predictor of nonresponse to aspirin and clopidogrel therapy, suggesting that patients with diabetes may require more aggressive antiplatelet regimens. Using aggregation-based testing in a prospective evaluation of 635 patients with non-STEMI to evaluate the clinical predictors of nonresponse to aspirin and clopidogrel therapy, diabetes was associated with an attenuated response to these antiplatelet agents.18

In addition, subgroup analysis of patients with diabetes in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) examined the net effect of diabetes on the efficacy and safety profiles of prasugrel as compared with clopidogrel. For patients with diabetes treated with prasugrel for high-risk ACS, the rate of cardiovascular death, nonfatal MI, and nonfatal stroke was significantly reduced as compared with clopidogrel (Fig. 40-2).19

Figure 40-2

Kaplan-Meier curves for prasugrel versus clopidogrel stratified by diabetes status. A. Primary efficacy end point (cardiovascular death, nonfatal myocardial infarction [MI], or nonfatal stroke) stratified by diabetic status. B. MI (fatal or nonfatal). DM, diabetes mellitus; HR, hazard ratio. (Reproduced with permission Wiviott SD, Braunwald E, Angiolillo DJ, et al. Greater clinical benefit of more intensive oral antiplatelet therapy with prasugrel in patients with diabetes mellitus in the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel-Thrombolysis in Myocardial I. Circulation. 2008;118:1626-1636.)

The BARI 2D trial compared GDMT with and without coronary revascularization in a relatively low-risk population and revealed that an initial strategy of percutaneous coronary intervention (PCI; n = 1605) or coronary artery bypass graft (CABG; n = 763) plus GDMT did not improve outcomes compared with GDMT alone (freedom from death, MI, or stroke: 77.2% vs 75.9%). However, in the CABG-stratified group (more advanced CAD and class C lesions), freedom from death, MI, or stroke was significantly lower in patients treated with CABG plus GDMT compared with GDMT alone (77.6% vs 69.5%), suggesting that patients with advanced CAD may benefit from CABG.20



Nearly 25% of all revascularization procedures are performed in patients with diabetes1; in the National Cardiovascular Data Registry, 36.2% of patients undergoing PCI between 2010 and 2011 had diabetes.21 Although acute procedural success and complications are similar in patients with and without diabetes undergoing PCI,11,22 patients with diabetes are more likely to have advanced CAD, with more multivessel disease, total occlusions, and diffuse disease.11,23 This finding may translate to higher in-hospital mortality rates. In an analysis of the National Heart, Lung, and Blood Institute (NHLBI) Dynamic Registry, a significantly higher in-hospital mortality in patients with diabetes compared to patients without diabetes (diabetes 2.3% vs no diabetes 1.3%; P = .02) undergoing PCI was observed.11 Patients with diabetes who undergo PCI are at increased risk not only for death and MI during subsequent follow-up, but also for repeat revascularization and angiographic restenosis.11,24,25 Patients with diabetes, in particular type 1 diabetes with poor glycemic control, who underwent CABG had increased long-term risk of major adverse coronary events and all-cause mortality.26 In addition, patients with type 1 diabetes who underwent CABG were found to have a more than 2-fold increased risk of death at 6 years compared with the general population, whereas patients with type 2 diabetes had only a slightly worse prognosis after CABG.27

Revascularization considerations for patients with diabetes across the spectrum of CAD have been noted earlier for patients with stable ischemic heart disease where CABG may play a role in patients with advanced disease. Although the last 2 decades have witnessed an innovative expansion of catheter-based therapy for CAD, for the patient with stable ischemic heart disease, this expansion has not resulted in a survival improvement but rather a decrease in restenosis. A meta-analysis comparing these methods to medical therapy in stable CAD did not improve the rates of death or MI.28

In patients with ACS, in whom 30-day mortality is higher in patients with diabetes compared to without diabetes, the benefit seen overall in terms of a decrease in major adverse cardiac events is similar in patients with and without diabetes. However, patients with diabetes experienced a reduction in nonfatal MI (relative risk [RR], 0.71; 95% confidence interval [CI], 0.55-0.92) not seen in patients without diabetes.29 It is noteworthy that the American College of Cardiology/American Heart Association guidelines suggest that the invasive strategy is preferred in patients with diabetes and ACS.30 For patients with STEMI and diabetes, management should be similar to that for patients without diabetes, where primary PCI is the preferred strategy if accomplished within guideline-recommended time to reperfusion.



There is evidence that the metabolic abnormalities associated with the diabetic state (hyperglycemia and hyperinsulinemia) can lead to enhanced platelet adhesion, activation, and aggregation, in addition to thrombus formation, endothelial cell dysfunction, and alterations in local growth factor production.31 Smooth muscle cell proliferation and extracellular matrix deposition, crucial elements in the cellular response to vessel injury and subsequent development of restenosis following PCI, are also enhanced in diabetic patients.31 It has been observed that the mechanism of increased restenosis in patients with compared to without diabetes following coronary stent placement was due to increased late loss of minimal lumen diameter, suggesting more aggressive neointimal hyperplasia with diabetes.32

The presence of diabetes is an independent risk factor for restenosis after PCI. Among patients with diabetes who underwent standard balloon angioplasty in the first report from the NHLBI Percutaneous Transluminal Coronary Angioplasty Registry in the early 1980s, restenosis occurred in 47%, compared with 32% in patients without diabetes.33 This finding is not limited to patients undergoing balloon angioplasty, but extends to those who are treated with stents. In a study that included over 12,000 patients with diabetes undergoing stent implantation (bare metal and first- and second-generation drug-eluting stents), diabetes was an independent risk factor for restenosis (odds ratio, 1.32; 95% CI, 1.19-1.46).34 Although drug-eluting stents have been shown to have significantly lower rates of restenosis as compared to bare metal stents,35 restenosis still occurs and may be related to longer stent length and small vessel size in patients with diabetes.36



In 2010, approximately 75% of stents used during PCI were drug-eluting stents and 25% were bare metal stents.1 As compared with bare metal stents, drug-eluting stents reduce cardiac events in a broad selection of patients with angina or ACS, a finding driven by a reduction in restenosis.35 In the patient with diabetes, the advantages of drug-eluting stents have also been observed. In all patients with diabetes who underwent PCI with stents between April 1, 2003, and September 30, 2004, in the state of Massachusetts, drug-eluting stents reduced mortality, MI, and revascularization compared with bare metal stents (Fig. 40-3).37

Figure 40-3

Clinical outcomes after stenting in patients with diabetes mellitus. Cumulative incidence of mortality (A), myocardial infarction (B), and target vessel revascularization (C) at 3 years in the matched cohort of patients with diabetes. Solid lines indicate drug-eluting stents (DES); dashed lines indicate bare metal stents (BMS). Error bars are 95% confidence intervals. (Reproduced with permission from Garg P, Normand S-LT, Silbaugh TS, et al. Drug-eluting or bare-metal stenting in patients with diabetes mellitus: results from the Massachusetts Data Analysis Center Registry. Circulation. 2008;118:2277-2285.)

In a collaborative network meta-analysis of 35 trials, sirolimus- and paclitaxel-eluting stents were found to be safe and effective in both patients with and without diabetes when combined with greater than 6 months of dual antiplatelet therapy.38 In another analysis, the outcomes of various commercially available drug-eluting stents (including sirolimus-, paclitaxel-, zotarolimus-, and everolimus-eluting stents) were examined. In this mixed treatment comparative meta-analysis of 42 trials with over 10,000 patients with diabetes, all of the drug-eluting stents showed a reduction in target vessel revascularization compared with bare metal stents. The efficacy varied between stents, with everolimus-eluting stents having the lowest rate of target vessel revascularization compared to zotarolimus, sirolimus, and paclitaxel stents.39



The optimal method of revascularization, percutaneous or surgical, has been debated for nearly 2 decades. Complicating the interpretation of the initial studies, which compared the outcomes of surgical versus percutaneous modalities of revascularization in the patient with diabetes, are the recent advances in both surgical and percutaneous techniques and materials. Table 40-1 presents an overview of the major trials comparing PCI with CABG in patients with diabetes and multivessel CAD.40

Table 40-1abcdefRandomized Clinical Trials Comparing CABG Surgery with PCI in Patients with Diabetes and Significant Multivessel CAD
Jan 13, 2019 | Posted by in CARDIOLOGY | Comments Off on Special Patient Subset: Diabetes Mellitus

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