Presence of the obesity paradox in a cohort of pre-diabetes and T2DM patients
Obesity and weight loss are inversely related to mortality and cardiovascular outcome in prediabetes and type 2 diabetes: data from the ORIGIN trial
Introduction and methods
In patients with established T2DM or in those with pre-diabetes and high CV risk, the effect of obesity is not fully understood. It seems that with increasing age, a higher body mass index (BMI) range is considered as optimum compared to the ideal BMI of 18.5-25 kg/m² defined by the WHO [1,2]. There are multiple studies that demonstrated benefit with overweight and mild obesity on mortality in patients at risk of with established CVD  and in patients with diabetes without CVD . Weight reduction in the LOOKAHEAD trial in overweight T2DM patients did not improve outcomes of mortality or morbidity . Weight loss was even an independent risk factor for all-cause mortality after 19-year follow-up of the DCGP trial .
LOOK-AHEAD trial included relatively health diabetes patients and the DCGP trial included newly diagnosed T2DM patients with moderate CV risk. In contrast, the ORIGIN trial enrolled 12537 T2DM patients or patients with pre-diabetes with 100% prevalent CV risk factors .
The aim of this analysis was to examine the association between body weight, weight change and CV outcome in the cohort of the ORIGIN trial. Mean follow-up was 6.2 years. (IQR: 5.8-6.7 years). Participants were categorized as underweight (BMI < 22 kg/m²), normal weight (22–<25 kg/m²), overweight (25–<30 kg/m²), obesity Grade 1 (30–<35 kg/m²), Grade 2 (35–<40 kg/m²) and Grade 3 (>40 kg/m²). The primary outcome of this analysis was all-cause mortality. 12521 Participants were included in this study (mean age 63.5 years, 35% female).
- The majority of participants were overweight (40.3%) and mildly obese (28.8%) and only 12.5% had normal weight.
- Overweight and obese participants were younger, a higher prevalence of hypertension, higher BP and higher LDL-c than those with normal weight.
- After adjustment for age, sex and all available covariables, participants with overweight and mild to moderate obesity have a significant lower risk of all-cause mortality (with normal weight as reference group). In addition, patients with low body weight had a higher risk of all-cause mortality and CV mortality. HRs for mortality were as follows: BMI < 22 kg/m²: 1.29, 95%I: 1.01-1.65, P=0.038, overweight (25–<30 kg/m²): 0.79, 95%I: 0.61-0.91, P=0.002, obesity Grade 1 (30–<35 kg/m²): 0.75, 95%CI;0.61-0.93, P=0.008, Grade 2 (35–<40 kg/m²): 0.65, 95%CI:0.46-0.92, P=0.014 and Grade 3 (>40 kg/m²): 0.81, 95%CI: 0.50-1.32, P=0.395.
- Similar findings were observed for CV mortality and a composite of first occurrence of CV death, non-fatal MI, or non-fatal stroke plus revascularization or HF hospitalization.
- During the first year of follow-up, weight gain was associated with lower mortality (all-cause and CV mortality) and with improved outcomes (composite outcomes, stroke, revascularization, or HF hospitalization) when compared to patients with no weight gain. Weight loss was related to higher risk of mortality and worse outcomes compared to patients with no weight loss.
- At 2 years, patients who remained at stable weight had a better mortality outcome compared to patients with sustained loss or gain of body weight.
Patients with T2DM or prediabetes and with prevalent CV risk factors who are overweight or obese have a reduced risk of mortality, CV mortality and a composite of CV death, non-fatal MI or non-fatal stroke plus revascularization or HF hospitalization compared to those with a normal weight. Patients with low BMI (<22 kg/m²) have an increased risk of mortality compared to those with a normal BMI. These findings contrast the conventional consideration that a low body weight improves (CV) outcomes.
In their editorial comment , Naveed Sattar and Paul Welsh lists some possible explanations for the paradoxical association of BMI with CV mortality in those with established cardiometabolic disease. First, these findings could represent a true causal association – high BMI confers some survival capacity.
Non-causal potential mechanisms include residual confounding. Those in the lowest BMI group had the lowest prescription of BP medications, were older and had longest duration of diabetes, while those in the highest BMI group had the lowest prevalence of prior CVD, more likely to be female, were younger and had shortest duration of diabetes. Also, correction for smoking was done in the analysis, but smoking was self-reported and it was not reported how many were actively smoking and how much they were smoking. And there was no correction for alcohol consumption and diet. So, although adjustment was done for many confounding factors, residual confounding can never be fully excluded, the authors in this editorial conclude.
Reverse causality can also be an issue, as weight is sensitive to the effects of a disease. In general, the sickest patients lose weight between 3-10 years before they die due to reduced appetite, and less physical activity. The average BMI in studies with diabetes patients is approximately 30 kg/m², but in this study the reference group had a BMI between 22-24.9 kg/m². Therefore, Sattar and Welsh write that it is plausible that participants in the lowest BMI groups had already lost weight after their diabetes diagnosis.
Finally, unintentional weight loss could be an explanation for the associations of low BMI and weight loss trajectories with high mortality risk.
They conclude their editorial by writing that trials are needed to settle whether intentional weight loss is beneficial or harmful in patients with existing CVD: ‘The appetite for such work is increasing’.