Obesity is an important driving factor for the development of type 2 diabetes mellitus (T2DM).¹ Further, the majority of individuals with T2DM are overweight. Both obesity and diabetes predispose to cardiovascular abnormalities.² As a result, patients are often prescribed weight loss, which can lead to short-term improvements in cardiometabolic risk factors. However, the long-term cardiovascular benefit of a weight loss prescription in patients with diabetes is debated. For example, the Look AHEAD Trial did not observe cardiovascular benefits of overweight or obese individuals with T2DM who lost significant amounts of weight through intensive lifestyle modification, including exercise and diet.³ This may be because many weight reduction regimes, such as certain fad diets, result only in temporary weight loss and instead cause long term weight gain, also known as weight cycling.⁴ Evidence suggests that the weight fluctuations that often accompany weight loss strategies are more prognostic to informing cardiovascular risk, than an individual's single baseline weight measurement.

Although patients with T2DM are commonly given a weight loss recommendation, there is little evidence discussing the consequences of weight variability specifically in patients with T2DM. Bangalore et al. addresses this critical knowledge gap in their 2018 publication in Circulation: Cardiovascular Quality and Outcomes, by evaluating the cardiovascular risk associated with body weight variability amongst individuals with T2DM.⁵ The authors assessed this relationship in 6,049 individuals with T2DM enrolled in three clinical trials evaluating atorvastatin therapy (CARDS, ASPEN and TNT). The authors defined any coronary event, a composite of myocardial infarction (MI), coronary heart disease (CHD), death, resuscitated cardiac arrest (apart from CARDS), coronary revascularization and unstable/new onset angina, as the primary endpoint. Body weight variability was defined as the average absolute difference between successive values starting from the 3-month visit until trials end, with median (range) of 12 (2-15) body weight measurements. Body weight increased on average by 0.9±5.2 kg, with median variability of 1.72 kg, indicating that average weight gain is common even in the context of a clinical trial. Overall, rates of coronary and total cardiovascular events were higher among individuals with higher body weight variability in a dose-response relationship across quintiles of weight fluctuation.⁵ In fully-adjusted models accounting for demographics and other non-weight cardiovascular risk factors, each 1 standard deviation of body weight variability was associated with an increased risk of any coronary event (HR, 1.08; 95% CI, 1.01–1.14), major coronary event (HR, 1.12; 95% CI, 1.04–1.20), any cardiovascular event (HR, 1.08; 95% CI, 1.03–1.14) and death (HR, 1.16; 95% CI, 1.10–1.22). Furthermore, the authors observed that risks of coronary and cardiovascular events associated with higher body weight variability were more pronounced among individuals who were overweight or obese than those with normal body mass index (BMI).⁵ Additionally, another recently published post-hoc analysis from the ACCORD trial complements Bangalore et al.'s findings, by showing that weight fluctuations were significantly associated with a higher risk for macro- and micro-vascular complications in patients with T2DM, even after accounting for BMI.⁶

Since significant weight cycling after the development of T2DM are associated with harms, there should be a strong focus on primordial prevention efforts to avoid the development of elevated BMI in the first place. Prior evidence has suggested that the assessment of lifetime weight trajectory is more prognostic of an individual's cardiovascular risk than a single measure of BMI. Fliotsos et al. found that self-reported weights of Multi-Ethnic Study of Atherosclerosis (MESA) participants from early and mid-adulthood were independently associated with future heart failure risk, and to a lesser degree atherosclerotic cardiovascular disease, even after accounting for BMI in later life.⁷ Individuals who are overweight earlier in their life generally remain obese in adulthood.⁷ Thus, weight awareness programs should be initiated early in life. Considering Bangalore et al.'s recent findings on weight variability, clinicians should make use of an individual's weight throughout the decades of adulthood to more effectively assess a patient's cardiovascular risk. Since most physicians do not have access to their patient's complete lifetime weight history, self-reported weight through mobile tracking methods may offer opportunities to incorporate patient's long-term weight trajectory into clinical management, providing clinicians with better judgement of cardiovascular risk.⁸

In addition, it is sensible to focus on a patient's long-term weight trajectory rather than a single BMI measure, as attempts at short-term weight loss might conflict with treatment goals that are momentarily a priority in a patient's diabetes management. For example in the ACCORD study, individuals in the intensive glycemic treatment group with the greatest Hemoglobin A1C (HbA1C) reduction also gained the most weight.⁹ Insulin and thiazolidinediones (TZDs), which are frequently used agents in diabetes treatment, are often associated with weight gain.

Thus, Bangalore's et al.'s finding should guide weight management strategies in individuals with T2DM that limit weight cycling and focus on sustainable long-term weight loss. The 2019 American Diabetes Association (ADA) guidelines recommend a comprehensive weight maintenance program for patients to ensure long-term weight loss, including self-monitoring of weight and physical activity, as well as low-calorie diet and regular exercise.¹⁰ Physical activity has been shown to be especially effective in preventing weight regain after successful weight loss.¹¹ For individuals who reached their short-term weight loss goals, current ADA guidelines recommend 200-300 minutes/week of exercise as part of long-term comprehensive weight management programs.¹⁰

Additionally, on a background of lifestyle changes, newer pharmacological agents may facilitate both long-term weight loss and reduction in cardiovascular risk. The 2019 ADA guidelines recommend GLP-1 receptor agonists and/or SGLT-2 inhibitors as add-on anti-diabetic drugs if weight reduction is a priority.¹⁰ Results from recent FDA-mandated cardiovascular outcome trials also demonstrated beneficial cardiovascular risk reduction for both of these agents. Regarding GLP-1 receptor agonists, liraglutide, albiglutide, dulaglutide and semaglutide have all been associated with significant reduction of cardiovascular events. Cardiovascular benefits have also been noted for the two FDA-approved SGLT-2 inhibitors, empagliflozin and canagliflozin. The DIALECT-1 study, a observational cohort study, showed that GLP-1 receptor agonists were associated with a significant decline of BMI over the 18-20 year follow-up period.¹² A systematic review of 17 randomized trials demonstrated a weight reduction of approximately 1.5-2.5 kg over 30 weeks with GLP-1 receptor agonists, compared to placebo or other active comparators (Insulin glargine, DPP-4 inhibitors, TZDs and sulfonylureas).¹³ SGLT-2 inhibitors cause weight loss due to urinary excretion of glucose, and thereby calories. However, due to compensatory energy intake through mechanisms such as increased appetite, the weight loss of SGLT-2 inhibitors is less than noted for GLP-1 receptor agonists.¹⁴ A more effective approach is combining SGLT-2 inhibitors with other antidiabetics to circumvent the adaptive response of SGLT-2 inhibitors which stall weight loss. The DURATION-8 trial for instance, showed that patients lost more weight when subscribed exenatide as well as dapagliflozin, compared to individuals only adhering to monotherapy therapy.¹⁵ Similar results were observed in AWARD-10, where dulaglutide was subscribed to patients inadequately controlled with SGLT-2 inhibitors. Here, beneficial changes on weight as well as HbA1c levels were noted.¹⁶ In summary, monotherapy with GLP-1 receptor agonists in combination with SGLT-2 inhibitors are sensible choices for patients with T2DM to improve glycemic control, reduce cardiovascular risk as well as induce weight loss.

For those who are overweight or obese at high cardiovascular risk, another consideration for weight loss pharmacotherapy is lorcaserin, a selective serotonin 2C receptor agonist that promotes appetite suppression. In the CAMELLIA-TIMI 61 trial,¹⁷ locaserin led to sustained weight loss without any increased risk for cardiovascular events (although no demonstrated cardiovascular benefits), as well as decreased the risk of incident diabetes.¹⁸ As a last resort, more aggressive weight loss regimes such as surgical intervention may be an option. The current ADA guidelines recommend bariatric surgery for T2DM patients with BMI > 40 (BMI 37.5 for Asian American patients) for individuals who do not achieve long-lasting weight loss.¹⁰ A substantial body of evidence suggests that long term weight loss is achievable with bariatric surgery in T2DM patients, dramatically reducing cardiovascular risk factors and improving glycemic control.¹⁹

In summary, body weight fluctuations over a course of a lifetime seem to be more relevant to evaluate a patient's cardiovascular risk than a single measure of BMI. Furthermore, after the development of T2DM, significant cycling in weight may be harmful. As high body weight variability is associated with an increased risk of cardiovascular events in patients with T2DM, clinicians should endorse weight reduction strategies that focus on sustainable, long-term weight loss. New anti-diabetics, such as GLP-1 receptor agonists and SGLT-2 inhibitors offer a promising approach to simultaneously improve both glycemic control and cardiovascular outcomes as well as induce weight loss.

Table 1: Weight effect of physical exercise and pharmacological intervention

Intervention		Weight effect
Physical exercise		↓
Antidiabetics	GLP-1 analogs	↓
	Metformin	± or ↓
	a-Glucosidase inhibitors	±
	DPP-4 inhibitors	±
	Insulin	↑
	Sulfonylureas	↑
	Glinides	↑
	Thiazolidinediones	↑
Weight loss drug	Lorcaserin	↓
Intervention		Weight effect
Physical exercise		↓
Antidiabetics	GLP-1 analogs	↓
	Metformin	± or ↓
	a-Glucosidase inhibitors	±
	DPP-4 inhibitors	±
	Insulin	↑
	Sulfonylureas	↑
	Glinides	↑
	Thiazolidinediones	↑
Weight loss drug	Lorcaserin	↓

References

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16. Ludvik B, Frías JP, Tinahones FJ, et al. Dulaglutide as add-on therapy to SGLT2 inhibitors in patients with inadequately controlled type 2 diabetes (AWARD-10): a 24-week, randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 2018;6:370-81.
17. Bohula EA, Scirica BM, Inzucchi SE, et al. Effect of lorcaserin on prevention and remission of type 2 diabetes in overweight and obese patients (CAMELLIA-TIMI 61): a randomised, placebo-controlled trial. Lancet 2018;392:2269-79.
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Keywords: Hemoglobin A, Weight Loss, Body Mass Index, Thiazolidinediones, Weight Gain, Hypoglycemic Agents, Diabetes Mellitus, Type 2, Diabetes Mellitus, Glucagon-Like Peptide 1, Trinitrotoluene, Insulin, Caloric Restriction, Risk Factors, Glucose, Cardiovascular Diseases, Prognosis, Follow-Up Studies, Overweight, Glucosides, Immunoglobulin Fc Fragments, Recombinant Fusion Proteins, Peptides, Benzhydryl Compounds, Obesity, Life Style, Exercise, Myocardial Infarction, Coronary Disease, Atherosclerosis, Heart Failure, Primary Prevention, Heart Arrest, Demography, Cardiovascular Abnormalities, Metabolic Syndrome

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