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Postprandial Glucose Drug No Help for Established Heart Disease

— Acarbose delayed diabetes onset but didn't prevent CV events

MedpageToday

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LISBON -- For people with both coronary heart disease and impaired glucose tolerance, acarbose (Precose) had no effect on major cardiovascular events but did delay diabetes onset, the Chinese showed.

With a primary composite endpoint of cardiovascular death, non-fatal MI or stroke, and hospital admission for unstable angina or heart failure, patients receiving the alpha-glucosidase inhibitor had about the same rates after a median of about 5 years as those assigned to placebo (14% versus 15%, HR 0.98, 95% CI 0.86-1.11), Rury Holman, FRCP, of the Diabetes Trials Unit at the University of Oxford in England, and colleagues found.

Action Points

  • Note that this large randomized trial found that acarbose did not improve cardiovascular outcomes among patients with post-prandial hyperglycemia.
  • Be aware that acarbose works best when the diet is high in complex carbohydrates.

Nor did the agent, which tackles postprandial hyperglycemia by slowing complex carbohydrate digestion, improve composite risk of the primary endpoints plus death from any cause and fatal MI or stroke, and impaired renal function, the group reported here at the European Association for the Study of Diabetes and simultaneously .

"On the basis of the data from this trial and the study," they wrote, "it seems that, despite the strong epidemiological data linking postprandial hyperglycemia to increased cardiovascular risk, directly targeting postprandial hyperglycemia does not directly reduce the risk of cardiovascular events in populations at high risk of cardiovascular events and with impaired glucose tolerance."

The drug did slow diabetes onset, as expected. The rate was lower in the acarbose group during the median 5 years of treatment in the trial (13% versus 16%, rate ratio 0.82, 95% CI 0.71-0.94). The number needed to treat for 5 years to prevent one case of progression to diabetes was 41.

An accompanying editorial by Michael Nauck, MD, and Juris Meier, MD, suggested that "other preventive measures such as intensive lifestyle intervention, metformin, or thiazolidinediones seem to be more effective in quantitative terms."

The ACE findings are not likely to boost acarbose use much in Western lands, commented Clifford Bailey, PhD, of England's Aston University.

"The agent is not strongly potent, and therefore other agents tend to be used in preference to it," Bailey said. With the proliferation of diabetes drugs since acarbose came on the market in the 1990s, "it's no longer used to any extent in the U.S.," he noted.

The drug's mechanism of action really only helps with a diet of complex carbohydrates. "So acarbose tends not to be used so much in the U.S. or indeed in Europe, where we now have diets that perhaps don't have as much complex carbohydrates as we ought. But the drug is very useful in those countries where diet is largely complex carbohydrates [potatoes, pasta, rice], for example China, hence the ACE study is being undertaken in China."

And as the kicker, "it also has one or two side effects, one of which is not particularly dangerous but is considered not very social -- that is that it will promote flatulence," Bailey added.

GI disorders were the most common adverse event associated with drug discontinuation or dose changes (7% versus 5%, P=0.0007). Non-cardiovascular and cancer deaths came out similar between groups.

The phase IV Acarbose Cardiovascular Evaluation (ACE) trial included 6,522 patients with coronary heart disease and impaired glucose tolerance at 176 hospital outpatient clinics in China. Participants were randomly assigned to double-blind treatment with oral acarbose (50 mg three times a day) or matched placebo, both atop a standardized cardiovascular secondary prevention regimen.

Limitations included a substantial number of participants lost to follow-up and the need for a protocol amendment changing the composition of the primary composite endpoint to increase the number of events. However, this shouldn't invalidate the conclusions, Nauck and Meier, both of the Diabetes Center Bochum-Hattingen, in Germany, wrote in their editorial. Despite those concerns, "based on the large number of patients included in the study, the uniform outcomes of various sensitivity analyses, and the narrow CIs, the absence of an effect on cardiovascular outcomes seems to be robust."

They concluded: "Will these findings lay to rest the discussion about postprandial glucose concentrations specifically predicting cardiovascular events? Probably not entirely."

"Overall, ACE is an important milestone in the debate about whether or not postprandial glucose rises are a specific risk factor predictive of cardiovascular events. The new state-of-the-art answer, at least for people with impaired glucose tolerance, seems to be no. But this might not be the ultimate conclusion for all populations, including patients with advanced stages of diabetes, for whom treatment with acarbose or drugs with a preferential postprandial mechanism of action might still provide some cardiovascular benefit."

Disclosures

The study was funded by Bayer.

Holman disclosed grants from Bayer AG (related to the present study); personal fees from Amgen, Bayer AG (related to the present study), and Servier; grants from AstraZeneca; grants and personal fees from Boehringer Ingelheim and Merck Sharp & Dohme; and chaired or participated in independent data monitoring committees for Elcelyx, GlaxoSmithKline, Janssen, and Takeda.

Nauck reported relationships with AstraZeneca, Boehringer Ingelheim, Eli Lilly, Fractyl, GlaxoSmithKline, Intarcia/Servier, Menarini/Berlin Chemie, Merck Sharp & Dohme, Novo Nordisk, and Novartis.

Meier reported relationships with AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novo Nordisk, Servier, and Sanofi.

Primary Source

Lancet Diabetes and Endocrinology

Holman RR, et al "Effects of acarbose on cardiovascular and diabetes outcomes in patients with coronary heart disease and impaired glucose tolerance (ACE): a randomised, double-blind, placebo-controlled trial" Lancet Diabetes Endocrinol 2017; DOI: 10.1016/ S2213-8587(17)30309-1.

Secondary Source

Lancet Diabetes and Endocrinology

Nauck MA, Meier JJ "Break point instead of ACE: acarbose, post-load glycaemic excursions, and cardiovascular events" Lancet Diabetes Endocrinol 2017; DOI: 10.1016/ S2213-8587(17)30318-2.