A ‘chicken or egg’ problem: Targeting timing of CV complications in type 2 diabetes
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Lifestyle or medical therapy in prediabetes to reduce later cardiovascular events in type 2 diabetes may seem wise, yet little evidence demonstrates such strategies make a difference, according to a speaker.
“While logical, the evidence that preventing type 2 diabetes actually reduces CVD is scant,” Silvio E. Inzucchi, MD, professor of medicine at Yale University School of Medicine and Yale-New Haven Hospital, said during an online presentation at the virtual Heart in Diabetes conference. “These are low-risk patients in most of these trials, and the follow-up is short.”
Impaired glucose tolerance is often observed in adults before any increases are seen in fasting glucose or in HbA1c, and microvascular complications tend not to occur until overt type 2 diabetes is already established — typically 10 or even 15 years later, Inzucchi said. However, macrovascular complications, such as coronary artery disease and cerebrovascular disease, are often well established in the setting of conditions such as metabolic syndrome, obesity and prediabetes.
“Here, we already see a problem,” Inzucchi said. “If these atherosclerotic problems are already established, is it possible to prevent them by simply preventing the transition from prediabetes to type 2 diabetes?”
A question of timing
A recent meta-analysis of 129 studies published in The BMJ with more than 10 million individuals followed for more than 10 years demonstrated that all-cause mortality and CV mortality are increased among adults with prediabetes vs. those with normal glucose tolerance, Inzucchi said.
“Importantly, once [atherosclerotic] CVD is established, prediabetes has an ever greater relative risk for mortality and the composite CVD outcomes, upwards of 30% to 35%, whereas the [coronary heart disease] relative risk is approximately the same and the risk for stroke, for some reason, disappears,” he said. “Obviously, those associative data do not tell us that preventing prediabetes or preventing the progression from prediabetes to diabetes would necessarily mitigate that risk. It could, however, because once diabetes is established, the risk for macrovascular complications goes up even more, by twofold.”
Due to rising incidence of type 2 diabetes worldwide, there is a need for effective and safe interventions to prevent the disease, Inzucchi said. More than a dozen large diabetes prevention randomized controlled trials have demonstrated relative risk reductions from 32% to 58% with lifestyle changes and 19% to 78% with certain glucose-lowering and weight-loss medications, although whether these drugs prevent or merely delay type 2 diabetes remains controversial, Inzucchi said.
Promise of lifestyle, medical therapy
Follow-up studies of lifestyle intervention trials do suggest there could be a long-term CV benefit with intervention, Inzucchi said. The Diabetes Prevention Program Outcomes Study (DPPOS, 2002-2013), the long-term follow-up of the original DPP study, demonstrated a persistent reduction of type 2 diabetes development during an average 22-year follow-up period; prevention effects in the original lifestyle and metformin arms of the DPP study saw 25% and 18% reductions, respectively, in risk for type 2 diabetes vs. placebo. Those participants who did not go on to develop type 2 diabetes had a 39% reduction in risk for major adverse CV events, Inzucchi said. However, despite benefits seen with diabetes prevention overall, there was no substantial benefit seen with the individual interventions for major adverse CV outcomes.
Similarly, the Da Qing study, an analysis of 577 participants randomly assigned to receive lifestyle intervention or usual care for 6 years, did show a reduction in risk for development of type 2 diabetes, CV mortality and all-cause mortality for those in the lifestyle arm at 30 years of follow-up, Inzucchi said.
Two diabetes medications, the thiazolidinedione pioglitazone and the SGLT2 inhibitor dapagliflozin (Farxiga), have been assessed for new-onset diabetes as part of large CV outcomes trials — IRIS and DAPA-HF, respectively. Both studies involved high-risk participants with stroke and heart failure with reduced ejection fraction, respectively.
“In these trials, participants randomized to active therapy developed new-onset diabetes less frequently — 52% in IRIS and 32% in DAPA-HF,” Inzucchi said. “It is not yet known to what degree, if any, diabetes prevention might be linked to the CV benefits of these agents. That requires further study.”
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Inzucchi SE. Preventing diabetes to prevent CVD: Is it chicken or egg (or turkey)? Presented at: Heart in Diabetes CME Conference; Aug. 21- 24, 2020, 2019; (virtual meeting).
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