Remission From Prediabetes Halves CV Risk: Registry Data

Achieving remission from prediabetes appears to substantially lower the risk of cardiovascular death or hospitalization for heart failure decades later, according to global registry data.

In a pooled meta-analysis of the US Diabetes Prevention Program Outcomes Study (DPPOS) and the Chinese DaQing Diabetes Prevention Outcomes Study (DaQingDPOS), the adjusted hazard ratio of the combined endpoint was 0.47 (95% CI 0.30-0.72) over three decades of follow-up for patients who reached remission compared with those who did not.

“We were surprised by the clarity of and the magnitude of the effects” of lowering glucose in patients with prediabetes, senior author Andreas L. Birkenfeld, MD (University Hospital of Tübingen, Germany), told TCTMD, adding that the results should be practice-changing and support a modification of guidelines to incorporate glucose thresholds.

Current European, UK, and American guidelines advise prediabetic patients to lose 5-7% of their body weight through diet and exercise, but they do not include specific recommendations for glucose levels. Also, there has been debate as to whether prediabetes should be included as an evidence-based treatment target to reduce CV events.

“Lifestyle interventions are still the first-line therapy, and people can reach prediabetes remission over time,” he said. “But if there are really people that have a high risk for cardiovascular disease and they just cannot bring their glucose levels down, I would say one should think about using medications.”

Prediabetes is a “focused opportunity for prevention,” said Jonathan Newman, MD (NYU Langone Health, New York, NY), who was not involved in the study. The significance here, he told TCTMD, is that the researchers have taken “long-term data from two prevention programs to show that in a nonrandomized comparison.”

With all that is known about how prediabetes and diabetes can trigger later cardiovascular disease, the new data are “particularly important,” Newman said. “It’s interesting to see that maybe an intervention up front [and] early can prevent sequelae and long-term problems. We didn’t really have exactly these data with regards to the effects of remission.”

Long-term Results

The study, published online this week in the Lancet Diabetes & Endocrinology with first author Elsa Vazquez Arreola, PhD (National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ), included 2,402 patients from DPPOS and 540 from DaQingDPOS, both of which tested the efficacy of long-term lifestyle interventions among patients with prediabetes.

In DPPOS, 11.5% reached remission as defined by the American Diabetes Association (ADA) after 1 year of intervention. Over a median follow-up period of 20 years, the prevalence of the combined primary endpoint of cardiovascular death or heart failure hospitalization was lower among those who reached remission compared with those who did not (1.74 vs 4.17 events per 1,000 person-years; adjusted HR 0.41; 95% CI 0.20-0.84). Notably, fewer patients reaching remission were diagnosed with type 2 diabetes by the end of DPPOS compared those who did not (34% vs 57%; P < 0.0001).

Similarly, in DaQingDPOS, over a median follow-up period of 30 years, the rate of the primary endpoint also was lower among those who did versus did not reach remission (9.5 vs 17.0 events per 1,000 person-years; adjusted HR 0.49; 95% CI 0.28-0.84).

Results were similar when researchers used the World Health Organization (WHO) glucose definitions for prediabetes. An additional pooled analysis of all patients reaching remission at least once during follow-up (36% by ADA criteria and 66% by WHO criteria) showed a lower risk of the primary composite endpoint (HR 0.43; 95% CI 0.29-0.63; P < 0.0001).

Now that it’s clear that patients should receive focused treatment to lower their glucose levels, Birkenfeld said, the question remains: “Which patients respond best to which intervention?”

Some patients respond better to physical exercise, while some may achieve results more efficiently with specific diets, such as low-carb or Mediterranean. “Once we understand this, we can really have individualized treatment recommendations,” he said, adding that he’d like to see more randomized trials of these interventions in patients with prediabetes.

“Then we would need to test also GLP-1 receptor agonists and how they can bring people into remission, and how this translates to improved cardiovascular death and heart attacks and also heart failure,” Birkenfeld said.

‘A Legacy Effect’

Newman noted an inherent bias within the study, given that patients who achieved remission were generally younger, had less severe measures of prediabetes, and had lower fasting glucose levels. “They tried to account for this statistically, but . . . we don’t really know everything about the group that achieved remission,” he said. “If you are able to achieve remission, these data would suggest that there’s a long-term benefit.”

He also pointed to the relatively low rate of patients (about 10%) who achieved remission in both studies. “Folks that are in a clinical trial do better than those that [are not] because they’re being monitored, they’re coming to doctors, they’re getting followed up by study coordinators,” Newman said. “Even with all these other interventions as part of clinical trials, a pretty small proportion of people could achieve remission.”

He highlighted what he termed a “real legacy effect,” noting, “When you normalize someone and you get them off the prediabetes track, maybe you really reduce their risk function over time. I think that’s a pretty compelling message to focus on something like prediabetes.”