Coronary artery disease (CAD) arising from atherosclerosis is a leading cause of death and morbidity worldwide. The underlying pathogenesis involves an imbalanced lipid metabolism and a maladaptive immune response entailing a chronic inflammation of the arterial wall. The disturbed equilibrium of lipid accumulation, immune responses and their clearance is shaped by leukocyte trafficking and homeostasis governed by chemokines and their receptors. New pro- and anti-inflammatory pathways linking lipid and inflammation biology have been discovered, and genetic profiling studies have unveiled variations involved in human CAD. The growing understanding of the inflammatory processes and mediators has uncovered an intriguing diversity of targetable mechanisms that can be exploited to complement lipid-lowering therapies. Here we aim to systematically survey recently identified molecular mechanisms, translational developments and clinical strategies for targeting lipid-related inflammation in atherosclerosis and CAD.

Atherosclerosis: current pathogenesis and therapeutic options

Obesity is a risk factor for diabetes, cardiovascular disease events, cancer and overall mortality. Weight loss may protect against these conditions, but robust evidence for this has been lacking. The Swedish Obese Subjects (SOS) study is the first long-term, prospective, controlled trial to provide information on the effects of bariatric surgery on the incidence of these objective endpoints. The SOS study involved 2010 obese subjects who underwent bariatric surgery [gastric bypass (13%), banding (19%) and vertical banded gastroplasty (68%)] and 2037 contemporaneously matched obese control subjects receiving usual care. The age of participants was 37-60 years and body mass index (BMI) was ≥34 kg m(-2) in men and ≥38 kg m(-2) in women. Here, we review the key SOS study results published between 2004 and 2012. Follow-up periods varied from 10 to 20 years in different reports. The mean changes in body weight after 2, 10, 15 and 20 years were -23%, -17%, -16% and -18% in the surgery group and 0%, 1%, -1% and -1% in the control group respectively. Compared with usual care, bariatric surgery was associated with a long-term reduction in overall mortality (primary endpoint) [adjusted hazard ratio (HR) = 0.71, 95% confidence interval (CI) 0.54-0.92; P = 0.01] and decreased incidences of diabetes (adjusted HR=0.17; P < 0.001), myocardial infarction (adjusted HR = 0.71; P = 0.02), stroke (adjusted HR=0.66; P = 0.008) and cancer (women: adjusted HR = 0.58; P = 0.0008; men: n.s.]. The diabetes remission rate was increased severalfold at 2 years [adjusted odds ratio (OR) = 8.42; P < 0.001] and 10 years (adjusted OR = 3.45; P < 0.001). Whereas high insulin and/or high glucose at baseline predicted favourable treatment effects, high baseline BMI did not, indicating that current selection criteria for bariatric surgery need to be revised.

https://onlinelibrary.wiley.com/doi/epdf/10.1111/joim.12012

Review of the key results from the Swedish Obese Subjects (SOS) trial – a prospective controlled intervention study of bariatric surgery

Context Obesity is a risk factor for cardiovascular events. Weight loss might protect against cardiovascular events, but solid evidence is lacking. Objective To study the association between bariatric surgery, weight loss, and cardiovascular events. Design, Setting, and Participants The Swedish Obese Subjects (SOS) study is an ongoing, nonrandomized, prospective, controlled study conducted at 25 public surgical departments and 480 primary health care centers in Sweden of 2010 obese participants who underwent bariatric surgery and 2037 contemporaneously matched obese controls who received usual care. Patients were recruited between September 1, 1987, and January 31, 2001. Date of analysis was December 31, 2009, with median follow-up of 14.7 years (range, 0-20 years). Inclusion criteria were age 37 to 60 years and a body mass index of at least 34 in men and at least 38 in women. Exclusion criteria were identical in surgery and control patients. Surgery patients underwent gastric bypass (13.2%), banding (18.7%), or vertical banded gastroplasty (68.1%), and controls received usual care in the Swedish primary health care system. Physical and biochemical examinations and database cross-checks were undertaken at preplanned intervals. Main Outcome Measures The primary end point of the SOS study (total mortality) was published in 2007. Myocardial infarction and stroke were predefined secondary end points, considered separately and combined. Results Bariatric surgery was associated with a reduced number of cardiovascular deaths (28 events among 2010 patients in the surgery group vs 49 events among 2037 patients in the control group; adjusted hazard ratio [HR], 0.47; 95% CI, 0.29-0.76; P = .002). The number of total first time (fatal or nonfatal) cardiovascular events (myocardial infarction or stroke, whichever came first) was lower in the surgery group (199 events among 2010 patients) than in the control group (234 events among 2037 patients; adjusted HR, 0.67; 95% CI, 0.54-0.83; P  Conclusion Compared with usual care, bariatric surgery was associated with reduced number of cardiovascular deaths and lower incidence of cardiovascular events in obese adults.

/pdf/bariatric-surgery-and-long-term-cardiovascular-events-4nwupopjn1.pdf

Bariatric Surgery and Long-term Cardiovascular Events

Importance Short-term studies show that bariatric surgery causes remission of diabetes. The long-term outcomes for remission and diabetes-related complications are not known. Objectives To determine the long-term diabetes remission rates and the cumulative incidence of microvascular and macrovascular diabetes complications after bariatric surgery. Design, Setting, and Participants The Swedish Obese Subjects (SOS) is a prospective matched cohort study conducted at 25 surgical departments and 480 primary health care centers in Sweden. Of patients recruited between September 1, 1987, and January 31, 2001, 260 of 2037 control patients and 343 of 2010 surgery patients had type 2 diabetes at baseline. For the current analysis, diabetes status was determined at SOS health examinations until May 22, 2013. Information on diabetes complications was obtained from national health registers until December 31, 2012. Participation rates at the 2-, 10-, and 15-year examinations were 81%, 58%, and 41% in the control group and 90%, 76%, and 47% in the surgery group. For diabetes assessment, the median follow-up time was 10 years (interquartile range [IQR], 2-15) and 10 years (IQR, 10-15) in the control and surgery groups, respectively. For diabetes complications, the median follow-up time was 17.6 years (IQR, 14.2-19.8) and 18.1 years (IQR, 15.2-21.1) in the control and surgery groups, respectively. Interventions Adjustable or nonadjustable banding (n = 61), vertical banded gastroplasty (n = 227), or gastric bypass (n = 55) procedures were performed in the surgery group, and usual obesity and diabetes care was provided to the control group. Main Outcomes and Measures Diabetes remission, relapse, and diabetes complications. Remission was defined as blood glucose Results The diabetes remission rate 2 years after surgery was 16.4% (95% CI, 11.7%-22.2%; 34/207) for control patients and 72.3% (95% CI, 66.9%-77.2%; 219/303) for bariatric surgery patients (odds ratio [OR], 13.3; 95% CI, 8.5-20.7; P P P P  = .001). Conclusions and Relevance In this very long-term follow-up observational study of obese patients with type 2 diabetes, bariatric surgery was associated with more frequent diabetes remission and fewer complications than usual care. These findings require confirmation in randomized trials. Trial Registration clinicaltrials.gov Identifier:NCT01479452

https://jamanetwork.com/journals/jama/articlepdf/1878719/joi140067.pdf

Association of Bariatric Surgery With Long-term Remission of Type 2 Diabetes and With Microvascular and Macrovascular Complications

Context: Abdominal obesity is associated with metabolic abnormalities and increased risk of atherosclerotic cardiovascular disease. However, no obesity management strategy has demonstrated the ability to slow progression of coronary disease. Objective: To determine whether weight loss and metabolic effects of the selective cannabinoid type 1 receptor antagonist rimonabant reduces progression of coronary disease in patients with abdominal obesity and the metabolic syndrome. Design, Setting, and Patients: Randomized, double-blinded, placebo-controlled, 2-group, parallel-group trial (enrollment December 2004-December 2005) comparing rimonabant with placebo in 839 patients at 112 centers in North America, Europe, and Australia. Interventions: Patients received dietary counseling, were randomized to receive rimonabant (20 mg daily) or matching placebo, and underwent coronary intravascular ultrasonography at baseline (n=839) and study completion (n=676). Main Outcome Measures: The primary efficacy parameter was change in percent atheroma volume (PAV); the secondary efficacy parameter was change in normalized total atheroma volume (TAV). Results: In the rimonabant vs placebo groups, PAV (95% confidence interval [CI]) increased 0.25% (-0.04% to 0.54%) vs 0.51% (0.22% to 0.80%) (P=.22), respectively, and TAV decreased 2.2mm3 (-4.09 to -0.24) vs an increase of 0.88mm3 (-1.03 to 2.79) (P=.03). In the rimonabant vs placebo groups, imputing results based on baseline characteristics for patients not completing the trial, PAV increased 0.25% (-0.04% to 0.55%) vs 0.57% (0.29% to 0.84%) (P=.13), and TAV decreased 1.95mm3 (-3.8 to -0.10) vs an increase of 1.19 mm3 (-0.73 to 3.12) (P=.02). Rimonabant-treated patients had a larger reduction in body weight (4.3 kg [-5.1 to -3.5] vs 0.5 kg [-1.3 to 0.3]) and greater decrease in waist circumference (4.5 cm [-5.4 to -3.7] vs 1.0 cm [-1.9 to -0.2]) (P<.001 for both comparisons). In the rimonabant vs placebo groups, high-density lipoprotein cholesterol levels increased 5.8mg/dL (4.9 to 6.8) (22.4%) vs 1.8mg/dL (0.9 to 2.7) (6.9%) (P<.001), and median triglyceride levels decreased 24.8mg/dL (-35.4 to -17.3) (20.5%) vs 8.9mg/dL (-14.2 to -1.8) (6.2%) (P<.001). Rimonabant-treated patients had greater decreases in high-sensitivity C-reactive protein (1.3 mg/dL [-1.7 to -1.2] [50.3%] vs 0.9 mg/dL [-1.4 to -0.5] [30.9%]) and less increase in glycated hemoglobin levels (0.11%[0.02% to 0.20%] vs 0.40% [0.31% to 0.49%]) (P<.001 for both comparisons). Psychiatric adverse effects were more common in the rimonabant group (43.4% vs 28.4%, P<.001). Conclusions: After 18 months of treatment, the study failed to show an effect for rimonabant on disease progression for the primary end point (PAV) but showed a favorable effect on the secondary end point (TAV). Determining whether rimonabant is useful in management of coronary disease will require additional imaging and outcomes trials, which are currently under way. Trial Registration: clinicaltrials.gov Identifier: NCT00124332.

https://jamanetwork.com/journals/jama/articlepdf/181727/joc80023_1547_1560.pdf

Effect of rimonabant on progression of atherosclerosis in patients with abdominal obesity and coronary artery disease: The STRADIVARIUS randomized controlled trial

Josep Rodés-Cabau

Papers

Effect of rimonabant on progression of atherosclerosis in patients with abdominal obesity and coronary artery disease: The STRADIVARIUS randomized controlled trial