PracticeUpdate: Endocrinology

DIABETES

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Medical treatment and revascularisation options in patients with type 2 diabetes and coronary disease Comment by Benjamin Scirica, MD In this pooled analysis from three landmark trials in coronary artery disease, the investigators of the COURAGE, BARI 2D, and FREEDOM trials evaluate the long-term benefit of early revas- cularisation with CABG or PCI when added to optimal medical therapy (OMT) in stable patients with diabetes. While conceptually similar, these trials had subtle, yet important differences in randomisation strategies and inclusion criteria with varying extent of coronary disease. F or example, COURAGE, which compared OMT vs PCI + OMT excluded patients As recommended by current practice guidelines, all patients, and in particular those with diabetes and symptomatic coronary disease, should be evaluated by a “heart team” that includes surgeons and cardiologists.

JOURNAL SCAN Magnitude of weight loss and changes in physical fitness linked with long- term cardiovascular disease outcomes in overweight diabetics The Lancet Diabetes & Endocrinology Take-home message • In this secondary analysis of the Look AHEAD trial, investigators found that greater weight loss and greater change in fitness level was as- sociated with reduced cardiovascular disease. This was in contrast to the primary intention- to-treat analysis, in which the investigators did not find a reduction in cardiovascular disease with intensive lifestyle modification. • There may be an association between greater quantity of weight lost and reduced risk of subsequent cardiovascular disease in over- weight people with type 2 diabetes. Abstract BACKGROUND Findings from the Look AHEAD trial showed no significant reductions in the primary outcome of cardiovascular disease incidence in adults with type 2 diabetes randomly assigned to an intensive lifestyle intervention for weight loss compared with those randomly assigned to diabe- tes support and education (control). We examined whether the incidence of cardiovascular disease in Look AHEAD varied by changes in weight or fitness. METHODS Look AHEAD was a randomised clinical trial done at 16 clinical sites in the USA, recruiting patients from Aug 22, 2001, to April 30, 2004. In the trial, 5145 overweight or obese adults aged 45–76 years with type 2 diabetes were assigned (1:1) to an intensive lifestyle intervention or diabe- tes support and education. In this observational, post-hoc analysis, we examined the association of magnitude of weight loss and fitness change over the first year with incidence of cardiovascular disease. The primary outcome of the trial and of this analysis was a composite of death from car- diovascular causes, non-fatal acute myocardial infarction, non-fatal stroke, or admission to hospital for angina. The secondary outcome included the same indices plus coronary artery bypass grafting, carotid endartectomy, percutaneous coronary inter- vention, hospitalisation for congestive heart failure, peripheral vascular disease, or total mortality. We adjusted analyses for baseline differences in weight or fitness, demographic characteristics, and risk factors for cardiovascular disease. FINDINGS For the analyses related to weight change, we excluded 311 ineligible participants, leaving a population of 4834; for the analyses related to fit- ness change, we excluded 739 participants, leaving a population of 4406. In analyses of the full cohort (ie, combining both study groups), over a median 10.2 years of follow-up (IQR 9.5–10.7), individuals who lost at least 10% of their bodyweight in the first year of the study had a 21% lower risk of the primary outcome (adjusted hazard ratio [HR] 0.79, 95% CI 0.64–0.98; p=0.034) and a 24% reduced risk of the secondary outcome (adjusted HR 0.76, 95% CI 0.63–0.91; p=0.003) compared with individuals with stable weight or weight gain. Achieving an in- crease of at least 2 metabolic equivalents in fitness change was associated with a significant reduction in the secondary outcome (adjusted HR 0.77, 95% CI 0.61–0.96; p=0.023) but not the primary outcome (adjusted HR 0.78, 0.60–1.03; p=0.079). In analyses treating the control group as the reference group, participants in the intensive lifestyle intervention group who lost at least 10% of their bodyweight had a 20% lower risk of the primary outcome (adjusted HR 0.80, 95% CI 0.65–0.99; p=0.039), and a 21% lower risk of the secondary outcome (adjusted HR 0.79, 95% CI 0.66–0.95; p=0.011); however, change in fitness was not significantly associated with a change in the primary outcome. INTERPRETATION The results of this post-hoc analysis of Look AHEAD suggest an association between the magnitude of weight loss and incidence of car- diovascular disease in people with type 2 diabetes. These findings suggest a need to continue to refine approaches to identify individuals who are most likely to benefit from lifestyle interventions and to develop strategies to improve the magnitude of sustained weight loss with lifestyle interventions. Association of the magnitude of weight loss and changes in physical fitness with long-term cardiovascular disease outcomes in overweight or obese people with type 2 diabetes: a post- hoc analysis of the Look AHEAD randomised clinical trial. Lancet Diabetes Endocrinol 2016 Aug 30;[Epub ahead of print], The Look AHEAD Research Group.

who required CABG and therefore focused on less complex coronary disease, whereas BARI 2D and FREEDOM specifically included patients with multivessel disease. In contrast to FREEDOM, which ran- domised patients to PCI vs CABG,

BARI 2D randomised patients to OMT vs OMT + revascularisation; the decision for PCI vs CABG was

made prior to randomisation and used as a stratification variable. Thus, this is not a straightfor- ward patient-level analysis from similarly designed trials. However, these pooled findings reinforce the primary messages from each indi- vidual trial and together provide an important summary for this common clinical scenario. 1. CABG + OMT is the best revascu- larisation strategy in patients with diabetes and coronary disease, even single-vessel disease of the LAD. CABG reduced MI by almost 50% compared with OMT or PCI, and compared with PCI, reduced mor- tality by just over 20%. 2. In patients with less complex dis- ease who would not be considered for CABG, PCI, when compared with OMT alone, does not provide any benefit in terms of death or MI. PCI tends to improve anginal symptoms earlier than OMT, but it does not improve any “hard” clinical events. 3. Patients who undergo CABG suf- fer numerically more strokes, but that difference is minimal over the nearly 5-year follow-up. Importantly, optimal medical therapy is the cornerstone of sec- ondary prevention. This includes antiplatelet therapy, aggressive lipid control with high-intensity statins, ezetimibe, and even PCSK9 in- hibitors, blood pressure control, and diet and lifestyle modifications. The choice of anti-hyperglycaemic strategies should consider agents with proven cardiovascular benefits. As recommended by current practice guidelines, all patients, and in particular those with diabetes and symptomatic coronary disease, should be evaluated by a “heart team” that includes surgeons and cardiolo- gists. As these data suggest, in most stable patients with diabetes with coronary artery disease, CABG + OMT is likely to provide the longest life and fewest number of infarcts. Dr Scirica is Attending Cardiologist and Director, Quality Initiatives, Cardiovascular Division, Brigham and Women’s Hospital; Associate Professor of Medicine, Harvard Medical School; Senior Investigator, TIMI Study Group, Boston, Massachusetts.

Medical treatment and revascularization options in patients with type 2 diabetes and coronary disease Journal of American College of Cardiology Take-home message • This study (N = 5034) investigated the effect of optimal medical therapy (OMT) on long-term outcomes in patients with type 2 diabetes and coronary artery disease. After a median 4.5-year follow-up, improved results were noted in patients who received coronary artery bypass grafting (CABG) plus OMT compared with percutaneous coronary intervention (PCI) plus OMT for the primary endpoint (HR, 0.71), death (HR, 0.75), and MI (HR, 0.50), but not stroke (HR, 1.54). There were no marked differences observed for OMT versus PCI plus OMT. • For patients with type 2 diabetes and stable coronary artery disease, CABG plus OMT is the preferred approach to management, supported by the reduction of the primary endpoint during long-term follow-up. Abstract

BACKGROUND There are scant outcomes data in pa- tients with type 2 diabetes and stable coronary artery disease (CAD) stratified by detailed angiographic bur- den of CAD or left ventricular ejection fraction (LVEF). OBJECTIVES This study determined the effect of optimal medical therapy (OMT), with or without percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG), on long-term outcomes with respect to LVEF and number of diseased vessels, including proximal left anterior descending artery involvement. METHODS A patient-level pooled analysis was un- dertaken in 3 federally-funded trials. The primary endpoint was the composite of death, myocardial infarction (MI), or stroke, adjusted for trial and rand- omization strategy. RESULTS Among 5,034 subjects, 15% had LVEF <50%, 77%hadmultivessel CAD, and 28%had proximal left an- terior descending artery involvement. During a median 4.5-year follow-up, CABG + OMT was superior to PCI +

OMT for the primary endpoint (hazard ratio [HR]: 0.71; 95% confidence interval [CI]: 0.59 to 0.85; p = 0.0002), death (HR: 0.76; 95% CI: 0.60 to 0.96; p = 0.024), and MI (HR: 0.50; 95% CI: 0.38 to 0.67; p = 0.0001), but not stroke (HR: 1.54; 95% CI: 0.96 to 2.48; p = 0.074). CABG + OMT was also superior to OMT alone for prevention of the primary endpoint (HR: 0.79; 95% CI: 0.64 to 0.97; p = 0.022) and MI (HR: 0.55; 95% CI: 0.41 to 0.74; p = 0.0001), and was superior to PCI + OMT for the primary endpoint in patientswith 3-vessel CAD (HR: 0.72; 95%CI: 0.58 to 0.89; p = 0.002) and normal LVEF (HR: 0.71; 95% CI: 0.58 to 0.87; p = 0.0012). There were no significant differences in OMT versus PCI + OMT. CONCLUSIONS CABG + OMT reduced the primary endpoint during long-term follow-up in patients with type 2 diabetes and stable CAD, supporting this as the preferred management strategy. J Am Coll Cardiol 2016 Sep 06;68:985-995, Mancini GB, Farkouh ME, Brooks MM et al.

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