Editor's Note: Commentary based on Aminian A, Zajichek A, Arterburn DE, et al. Association of metabolic surgery with major adverse cardiovascular outcomes in patients with type 2 diabetes and obesity. JAMA 2019;322:1271-82.

The benefit of bariatric/metabolic surgery for the treatment of type 2 diabetes mellitus (T2DM) has been increasingly evident and sufficient to be included as an option for T2DM management in the 2019 Standards of Medical Care of the American Diabetes Association.¹ This benefit relates not only to the arbitrary but reasonable definitions of partial remission (A1c <6.5% on no glucose-modifying medications for >1 year), complete remission (A1c <6.0% on no medications for >1 year) and prolonged remission (complete for >5 years) of T2DM. Moreover, the benefit extends to favorable modification of many associated cardiometabolic risk factors that relate to T2DM, e.g. elevated blood pressure, hypertriglyceridemia, hypercholesterolemia, reduced levels of HDL-C, nonalcoholic fatty liver disease (NAFLD) and inflammation.^2,3 Yet, cardiometabolic risk factors are not myocardial infarction, ischemic stroke, congestive heart failure or death from cardiovascular disease (CVD).

Presently, there are some data from non-randomized observational studies that demonstrate beneficial CVD outcomes from 5 to 20 years post bariatric/metabolic surgery in patients with and without T2DM.^4-6 However, despite the matched-cohort study design, the major limitation of all three of these studies was the lack of randomization of participants to surgical versus non-surgical groups, and the observational nature of the data. This lack of randomization was in part a consequence of the higher postoperative mortality of bariatric/metabolic surgery during the 1980s and early 1990s when these studies were conducted. In addition, the number of deaths were far fewer than those in the paper by Aminian et al,⁷ the topic of current consideration.

The paper of interest here is the Cleveland Clinic cohort of 2,287 patients with T2DM undergoing metabolic/bariatric surgery who were retrospectively matched with 11,435 medically-treated patients with T2DM for baseline covariates for CVD risk.⁷ The median overall follow-up of 3.9 years for the primary outcome of cumulative at 8-years of incidence of extended Major Adverse Cardiac Event (MACE), a composite of six outcomes defined as first occurrence of all-cause mortality, coronary artery events, cerebrovascular events, heart failure (HF), nephropathy, and atrial fibrillation. This resulted in 30.8% [95%CI, 27.6%-34.0%] occurrences in the surgical group and 47.7% [95%CI, 46.1%-49.2%] in the non-surgical group [P < .001]. This was an absolute 8-year risk difference of 16.9% [95%CI, 13.1%-20.4%] and adjusted hazard ratio [HR], 0.61 [95%CI, 0.55-0.69]) in the surgical group. All seven prespecified secondary outcomes showed statistically significant differences in favor of bariatric/metabolic surgery, including mortality. The cumulative incidence of all-cause mortality was 10.0% [95%CI, 7.8%-12.2%] in the surgical group and 17.8% [95%CI, 16.6%-19.0%] in the non-surgical group with an adjusted HR, 0.59 [95%CI, 0.48-0.72]). Despite the importance of these data, issues of concern include the expanded 6-component primary outcome, unclear contribution of weight reduction versus related or other metabolic variables to the primary outcome, effect of unmeasured confounders, potential errors in diagnostic coding, prescription adherence, severity of co-morbidities at baseline and subsequently, type of surgical procedures employed, and causes of mortality.

So, where do cardiometabolic physicians, whether endocrinologists, cardiologists or primary care professionals, find themselves in this quagmire of non-randomized clinical trials of bariatric/metabolic surgery and CVD outcomes in patients with T2DM? In general, the earlier a bariatric/metabolic surgical procedure is performed after a diagnosis of T2DM is established and additionally in patients with insulin independence, the greater likelihood of remission of T2DM.⁸ This reflects the importance of preservation of β-cell function in a setting wherein the burden of insulin resistance on insulin secretion is substantially reduced by substantial weight reduction. With more prolonged duration of T2DM, β-cell function declines which in turn jeopardizes the metabolic benefit of reduced adiposity on insulin secretion and glucose tolerance post-operatively.⁹ This metabolic issue is particularly relevant to adolescents with severe obesity and T2DM wherein the decline in β-cell function is more rapid, necessitating insulin therapy at a much earlier period after diagnosis.¹⁰ Whether the benefit of bariatric/metabolic surgery on CVD outcomes ensues irrespective of the duration of T2DM in patients with more advanced CVD/congenital heart disease (CHD) including previous myocardial infarction or even heart failure (HF with preserved ejection fraction (HFpEF) or HF with reduced ejection fraction (HFrEF)) remains to be determined, importantly using a randomized control trial (RCT) design. Yet, how many of our patients who are candidates for bariatric/metabolic surgery would agree to be randomized? Many refuse any type of surgery whereas others are eager to move forward.

A closing consideration is the rapidly changing era of decision making recently impacted by an increasing number of informative cardiovascular outcome trials (CVOTs) using new classes of pharmaceuticals approved for treatment of T2DM. Although initially powered to be non-inferior and safe, many trials using glucagon-like protein-1 (GLP-1) receptor agonists and the sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown CVD benefit.¹¹ Thus, decision based on RCTs would seem to favor a drug in one of these two classes of medications, particularly in patients with T2DM with existing CVD or at high risk of CVD rather than bariatric/metabolic surgery. However, well-designed RCTs using bariatric/metabolic surgery in high CVD risk patients with T2DM and BMI of ≥30 kg/m² may prove otherwise. At present, let's individualize our treatment plan and be poised for what follows.

References

1. American Diabetes Association. Obesity management for the treatment of type 2 diabetes: Standards of Medial In Diabetes-2019. Diabetes Care 2019;42:S81–S89.
2. Schauer PR, Bhatt DL, Kirwan JP, et al. Bariatric surgery versus intensive medical therapy for diabetes - 5-year outcomes. N Engl J Med 2017;376:641-51.
3. Mingrone G, Panunzi S, De Gaetano A, et al. Bariatric-metabolic surgery versus conventional medical treatment in obese patients with type 2 diabetes: 5 year follow-up of an open-label, single-centre, randomised controlled trial. Lancet 2015;386:964-73.
4. Adams TD, Gress RE, Smith SC, et al. Long-term mortality after gastric bypass surgery. N Engl J Med 2007;357:753-61.
5. Christou NV, Sampalis JS, Liberman M, et al. Surgery decreases long-term mortality, morbidity, and health care use in morbidly obese patients. Ann Surg 2004;240:416-23.
6. Sjostrom L, Peltonen M, Jacobson P, et al. Bariatric surgery and long-term cardiovascular events. JAMA 2012;307:56-65.
7. Aminian A, Zajichek A, Arterburn DE, et al. Association of metabolic surgery with major adverse cardiovascular outcomes in patients with type 2 diabetes and obesity. JAMA 2019;322:1271-82.
8. Dang JT, Sheppard C, Kim D, et al. Predictive factors for diabetes remission after bariatric surgery. Can J Surg 2019;62:315-19.
9. Madsbad S, Dirksen C, Holst JJ. Mechanisms of changes in glucose metabolism and bodyweight after bariatric surgery. Lancet Diabetes Endocrinol 2014;2:152-64.
10. Arslanian S, El Ghormli L, Young Kim J, et al. The shape of the glucose response curve during an oral glucose tolerance test: forerunner of heightened glycemic failure rates and accelerated decline in β-cell function in TODAY. Diabetes Care 2019;42:164-72.
11. Eckel RH, Farooki A, Henry RR, Koch GG, Leiter LA. Cardiovascular outcome trials in type 2 diabetes: what do they mean for clinical practice? Clin Diabetes 2019;37:316-37.

Clinical Topics: Arrhythmias and Clinical EP, Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Atrial Fibrillation/Supraventricular Arrhythmias, Homozygous Familial Hypercholesterolemia, Hypertriglyceridemia, Acute Heart Failure

Keywords: Diabetes Mellitus, Diabetes Mellitus, Type 2, Weight Loss, Obesity, Morbid, Insulin, Glucagon, Insulin Resistance, Heart Failure, Adiposity, Risk Factors, Retrospective Studies, Cohort Studies, Cardiovascular Diseases, Hypercholesterolemia, Glucose, Atrial Fibrillation, Insulin-Secreting Cells, Body Mass Index, Coronary Vessels, Blood Pressure, Brain Ischemia, Stroke Volume, Stroke, Bariatric Surgery, Obesity, Insulin, Regular, Human, Hypertriglyceridemia, Myocardial Infarction, Inflammation, Primary Health Care

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