After spending nearly six years researching the relationship between metabolically healthy obesity (MHO) and risk of cardiovascular disease, a team of U.K. doctors are suggesting that even “healthy” obese individuals are more likely to develop heart issues.

Due to limited existing evidence, lead researcher Rishi Caleyachetty, MBBS, PhD, and six others explored the electronic health records of nearly 3.5 million U.K. adults between 1995 and 2015. The team’s endpoint was analyzing the relationship between MHO patients and four different cardiovascular events.

The study was published online Sept. 11 in the Journal of the American College of Cardiology.

Previous research has no investigated a link between MHO patients and such a diverse array of cardiovascular problems before, Caleyachetty and co-authors wrote. This might be because “metabolic health” is defined so differently across various platforms. Caleyachetty’s study broke demographics into body size phenotypes—further specifying the data—and divided cardiovascular events into four subgroups: coronary heart disease (CHD), cerebrovascular disease, heart failure and peripheral vascular disease (PVD).

After sifting through the Health Improvement Network (THIN), a comprehensive database reflective of the general U.K. population, Caleyachetty’s team identified a study group of 3,495,777 adults who had no history of cardiovascular disease (CVD). These subjects were divided into four weight groups—underweight, normal weight, overweight and obese—before being split into 14 specific body size phenotypes based on each patient’s number of metabolic abnormalities.

In all, underweight patients were less likely to have metabolic abnormalities, which included diabetes, hypertension and hyperlipidemia, though the presence of all three was rare. Of all subjects without metabolic abnormalities, Caleyachetty’s study found just 2.7 percent to be underweight, 37.7 percent to be a normal weight, 25.7 percent to be overweight and 14.8 percent to be obese.

MHO individuals were more likely to be male, current smokers, socioeconomically deprived and in a younger age bracket than metabolically unhealthy obese patients, the study stated.

After an average 5.4 years of follow-up with patients, Caleyachetty and co-authors discovered 165,302 initially metabolically healthy people developed some CVD problem, including 61,546 cases of CHD, 54,705 instances of cerebrovascular disease, 25,254 occurrences of heart disease and 23,797 cases of PVD. Of initially MHO patients, 5.6 percent developed diabetes, 11.5 percent developed hyperlipidemia and 10.5 percent developed hypertension, according to the research.

Caleyachetty’s team found the risks of CHD, heart failure and cerebrovascular disease in normal weight, overweight and obese patients all increased with an individual’s number of metabolic abnormalities. Unexpected, though, was the evidence that healthy overweight and MHO subjects had a decreased risk of developing PVD compared to the underweight sample group.

According to the study, several factors seemed to differ with sex and age. Women showed stronger positive associations with cerebrovascular disease and heart failure than men, Caleyachetty and co-authors wrote, and patients younger than 65 years old had stronger positive associations with CHD, cerebrovascular disease, heart failure and PVD than the older age bracket.

Indeed, MHO patients were associated with increased risk of CVD. In comparison to the metabolically healthy, normal weight sample group, the study’s MHO cohort showed a 49 percent increased risk of CHD, a 7 percent increased risk of cerebrovascular disease and a 96 percent increased risk of heart failure.

“To the best of our knowledge, this is the largest prospective study of the association between body size phenotypes with or without metabolic abnormalities (including MHO) and a range of incident CVD events with unprecedented precision and power,” Caleyachetty and co-authors wrote. “Dividing our participants into four BMI groups according to the classification provided by the World Health Organization gave us the possibility of a more granular analysis of the CVD risk in the different body size phenotypes.”

In an editorial comment, Jennifer W. Bea, PhD, and Nancy K. Sweitzer, MD, PhD, called Caleyachetty’s study “timely and significant” due to the nation’s obesity epidemic. The last individual study on the subject was conducted with just 43,000 individuals, Bea and Sweitzer wrote, making this new research more relevant and exhaustive. With such a large population base, Caleyachetty’s team could identify risks to not only obese subjects, but also a normal weight population.

“As in previous analyses, metabolic dysfunction increased risk of obesity futher and also increased CVD risk among normal weight individuals,” Bea and Sweitzer said in their comment. “This is a key finding because approximately one in 10 normal weight individuals had one or more metabolic issues...often, one to two metabolic risk factors in normal weight individuals are dismissed as unimportant because they are of healthy weight; however, these data suggest that the normal weight group is at similar risk compared with overweight, and, at times, obese individuals, when metabolic abnormalities are present.”

Bea and Sweitzer suggest this new information could be important when it comes to screening seemingly healthy patients for possible CVD risks.

Though the doctors noted several limitations of the study—most notably that this study, and most of its type, was conducted only in Europe—they called Caleyachetty and co-authors’ work “pivotal.”

“It is the largest and most conclusive examination of the association between metabolic and body habitus phenotypes and CVD outcomes to date,” they wrote.