The Obesity Paradox in Diabetes: Conceptual and Clinical Approaches

Overweight and obesity are established risk factors for the development of metabolic diseases, including diabetes, hypertension, dyslipidemia, and cardiovascular disease, as well as sleep apnea and some cancers.¹

Previous research has identified a strange phenomenon of a U- or J-shaped association between body mass index (BMI) and higher mortality in both underweight and obese individuals.^2,3 Other studies have suggested that adults with higher BMI actually have lower mortality than those with lower BMI.⁴

“This paradox is especially perplexing in a condition like diabetes, where we know that there definitely is risk related to obesity or excess adiposity and we treat it with recommendations to modify lifestyle and reduce weight,” Edward J. Boyko, MD, MPH, professor, University of Washington and staff physician, VA Puget Sound, Washington, told Endocrinology Advisor.

“I have been researching the relationship between body composition and diabetes for roughly 26 years, and this paradox doesn’t seem to make sense, which is why it interested me,” he said.

Review of the Literature

Dr Boyko and Seung Jin Han, MD, PhD, conducted a literature review of clinical and epidemiological studies that investigated the association between overweight or obesity and mortality in type 2 diabetes.⁵

Studies had to include at least 1000 participants who were followed for more than 1 year. Using these criteria, the researchers identified 17 studies, with 11 studies suggesting that overweight or obesity was associated with lower mortality rate. Findings of all the studies are summarized in Table 1.

Reverse Causation?

Reverse causation “refers to the outcome causing a change in the exposure instead of the other way around,” the authors explain.

In the case of the obesity paradox, it is possible that the onset of diabetes resulted in a change in body weight, so that more severe disease resulted in weight loss and the disease severity contributed to mortality.

“When thinner individuals develop type 2 diabetes, they may have a more severe form of the disease, which can raise their risk for mortality,” Dr Boyko suggested.

“I can speculate about why that may be the case,” he continued. “For example, they might be very sensitive to having just a little excess body fat, which may lead to more insulin resistance, a worse clinical course with poorer glycemic control, and more complications, including cardiovascular complications.”

This reverse causation could result in an association between lower body weight/BMI and a higher rate of complications or mortality.

“Since most of the research on the obesity paradox in diabetes measured body composition much further down the road after disease onset, the findings may be susceptible to reverse causation bias,” Dr Boyko remarked.

A “notable exception” was the study of 2 populations that included measurements of body weight and height both before and after diabetes diagnosis in incident cases.⁶ The study found no evidence of the obesity paradox.

To reduce the chances of reverse causation by weight loss induced by chronic disease, future analyses should consider excluding patients with major illnesses (eg, cancer, cardiovascular disease, and pulmonary disease) at baseline, or those who died early during follow-up, Dr Boyko and Dr Han suggest.

Confounding Factors

Dr Boyko raised the possibility that other factors, such as smoking, may put thinner individuals at high risk for poor outcomes.

“Multiple investigations found that the obesity paradox was more pronounced in individuals who were smokers,” he said.

For example, a UK-based study⁷ of 502,631 individuals, along with 3 subgroups of patients with type 2 diabetes (n=23,842), coronary heart disease (n=24,268), and cancer (n=45,790), found that the obesity paradox was observed among patients with type 2 diabetes and was especially pronounced in current smokers and absent in never-smokers. “Smoking status consistently modified the adiposity-mortality relationship,” the authors concluded.

Cardiorespiratory fitness is another potentially confounding factor, Dr Boyko said. For example, 1 study⁸ found no significant association between BMI and mortality after adjustment for fitness in patients with diabetes, and in fact, fitness predicted mortality independent of BMI.

Limitations of BMI as an Obesity Index

“BMI may not be a good indicator of excess adipose tissue,” Dr Boyko remarked.

“We tend to define obesity based on BMI because it is very easy to obtain, based on height and weight, and even possible to get it reasonably accurately through self-report,” he continued.

However, BMI “misclassifies” individuals, in terms of their degree of adiposity by not capturing information regarding body fat distribution, he said. Normal-weight individuals who have visceral fat, abdominal fat, or ectopic fat in the liver, heart muscle, pancreas, or vasculature are more susceptible to adverse cardiometabolic outcomes.

Although imaging can assess visceral fat, a satisfactory surrogate measure is waist circumference, waist/hip ratio, and waist/night ratio, which are all positively associated with mortality.⁵

A study of 130,473 individuals conducted by Bowman et al found that for nonsmokers without disease-associated weight loss, having central adiposity and a BMI corresponding to normal weight or overweight was associated with substantial excess mortality.⁹

“The claimed BMI-defined overweight risk paradox may result in part from failing to account for central adiposity, rather than reflecting a protective physiologic effect of higher body-fat content in later life,”⁹ the researchers concluded.

BMI also does not capture the difference between fat and muscle mass, Dr Boyko noted. A person who is very muscular may have high BMI and be incorrectly classified as overweight or obese.

Low muscle mass is independently associated with mortality, so higher mortality in normal-weight people might be associated with low muscle mass rather than low adiposity. Moreover, some obese people may have increased muscle mass, which may confer better survival.⁵

Clinical implications

Dr Boyko suggested that any person who develops diabetes should have an initial evaluation to determine that he or she actually has type 2 diabetes, rather than type 1 diabetes or maturity onset diabetes of the young, which would require a different therapeutic approach from that used in type 2 diabetes.

In patients with type 2 diabetes, lifestyle interventions are appropriate, he said.

The initial evaluation should include a nutritional assessment that examines not only the caloric intake but also at the dietary composition of the patient’s food intake.

“Some individuals may be drinking excessive amounts of sweetened beverages or have other major dietary indiscretions,” he said.

“We also recommend that people should try to stay moderately active, which would apply to thin people and obese people and virtually anyone we see in medical practice,” he added.

He suggested that in an obese person, recommendations for weight reduction should include not only caloric reduction but also increased activity.

He noted that the Look AHEAD trial^10,11 found that individuals with diabetes who were overweight or obese and engaged in intensive lifestyle intervention to reduce weight and increased fitness did not show a decline in cardiovascular mortality.

“On the other hand, participants also did not show an increase in mortality, which one would expect if being heavier were actually healthier, as the obesity paradox would seem to indicate,” he observed.

Conclusion

“We believe that the obesity paradox most likely represents a non-causal association between higher BMI and mortality in diabetes, but await a comprehensive explanation of the remaining loose ends,” Dr Han and Dr Boyko wrote.

“We believe that the findings of obesity paradox should not change current clinical advice regarding the importance of weight reduction in patients with type 2 diabetes mellitus who are overweight or obese,” they concluded.

Table 1

Studies Investigating Association of BMI in Diabetes

Study	N	End point	Findings
Kokkinos et al12	4156	Total mortality	Inverse association
Tseng13	89,056	Total mortality, cancer or noncancer mortality	Inverse association
Jackson et al14	2035	Total mortality	Inverse association
Thomas et al15	47,509	Total mortality	Inverse association
Zoppini et al16	3398	Total mortality, CV mortality, cancer mortality	Inverse association (age ≥65 years) Direct association (age <65 years)
Mulnier et al17	27,725	Total mortality	U-shaped association
Logue et al18	106,640	Total mortality, CV mortality	U-shaped association
Zhao et al19	34,832	Total mortality	U-shaped association
Lee et al20	905,877	Total mortality	U-shaped association
Carnethon et al21	2625	Total mortality, CV or non-CV mortality	NW association with higher mortality than OW or OB
Costanzo et al22	10,568	Total mortality	OW associated with < mortality risk
Chaturvedi et al23	2960	Total mortality	No association
Church et al8	2196	Total mortality	No association
Sluik et al24	5435	Total mortality, CV mortality	No association
Bozorgmanesh et al25	1322	Total mortality	No association
Eeg-Olofsson et al26	13,087	Total mortality	Direct association
Tobias et al6	11,427	Total mortality, CV mortality	Direct association (never smoked)
Badrick et al27	10,464	Total mortality	>Mortality risk from BMI >25 kg/m2 (never smoked)

BMI, body mass index; CV, cardiovascular; NW, normal weight; OB, obese; OW, overweight.

Han SJ, Boyko EJ. Diabetes Metab J. 2018;42(3):179-187.

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