Acarbose Offers No CVD Protection in ACE, but May Cut Diabetes Risk

Miriam E Tucker

September 14, 2017

LISBON, PORTUGAL — The α-glucosidase inhibitor acarbose (Glucobay/Precose/Prandase, Bayer) reduces the incidence of diabetes but not of major cardiovascular events among Chinese patients with established heart disease and impaired glucose tolerance (IGT), new research indicates.

Findings from the Acarbose Cardiovascular Evaluation (ACE) trial were presented September 13 here at the European Association for the Study of Diabetes (EASD) 2017 Annual Meeting by several members of the research team, led by Rury R Holman, director of the University of Oxford Diabetes Trials Unit, United Kingdom. The results were simultaneously published in Lancet Diabetes & Endocrinology.

Acarbose, the first α-glucosidase inhibitor approved for the treatment of type 2 diabetes in the 1990s, acts to impede the absorption of carbohydrates and therefore works primarily to reduce postprandial rises in glucose.

It is widely prescribed to treat type 2 diabetes in China and some other Asian countries, but far less so elsewhere. 

In the randomized, double-blind, placebo-controlled phase 4 ACE trial of 6522 Chinese adults with IGT and cardiovascular disease, there was no difference in the incidence of a composite 5-point major adverse cardiovascular event (MACE) score between those who took 50 mg of acarbose three times daily or placebo for a median of 5 years. However, the drug did reduce the incidence of new-onset diabetes by 18%, with a number needed to treat of 41 for 5 years.

"These results extend the knowledge of the safety of acarbose and its efficacy for delaying the onset of diabetes to a population with both coronary heart disease and impaired glucose tolerance," Dr Holman said, adding that although the CVD event rate wasn't reduced in the study, "the reduced incidence of diabetes seen with acarbose in the ACE trial might help to reduce cardiovascular risk in the longer term by delaying the onset of diabetes in the high-risk population studied."

But audience member Dr Peter H Bennett, former chief of the Phoenix Epidemiology and Clinical Research Branch of the US National Institute of Diabetes and Digestive and Kidney Diseases, wasn't impressed, even with the diabetes-prevention result.

"The reduction in the incidence of diabetes was only about 18% after 5 years, which I would say is very modest, compared with what you see with just lifestyle interventions," he told Medscape Medical News, noting that the number needed to treat with lifestyle intervention to prevent one case of diabetes in 5 years is only about six or seven.

Writing in an editorial accompanying the published ACE study, Drs Michael A Nauck and Juris J Meier (Diabetes Center Bochum-Hattingen, Ruhr-University Bochum, Germany) agree. "Other preventive measures such as intensive lifestyle intervention, metformin, or thiazolidinediones seem to be more effective in quantitative terms."

And regarding the CVD findings, Dr Bennett said, "Clearly, acarbose is not a good medication for secondary prevention of cardiovascular disease in patients with IGT."

"It [acarbose] might work in people with diabetes, but that's not what this trial addressed," he continued. "It's strictly a secondary-prevention trial of CVD in people with previous heart disease who also happened to have IGT, so it's a restricted population."

However, another audience member, Guangwei Li, MD, chief of the department of endocrinology and cardiology at Fu Wai Hospital and Peking Union Medical College, Beijing, China, had a different take: "I think it's a very important trial, in that it shows no harm for cardiovascular disease. Also, there was no hypoglycemia or increased body weight."

Dr Li told Medscape Medical News that he prescribes acarbose for some of his type 2 diabetes patients, particularly those who are newly diagnosed with only mild glycemic elevation and for whom postprandial blood glucose levels are their primary problem: "It's very useful for them."

He also noted that even though acarbose isn't cheap, costing about the equivalent of a $1 a day, it is extremely popular in China for treating diabetes. It is also indicated for prediabetes there, but not widely used in that population because it's covered by the government reimbursement system only for the treatment of diabetes. 


The rationale for the ACE trial had come from the 2002 Study To Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM), which showed that acarbose reduced the incidence of type 2 diabetes by 25% in people with IGT.

A subsequent prespecified secondary analysis suggested a decrease in a composite cardiovascular outcome, although the numbers were low.

At the EASD session, commentator Chantal Mathieu, MD, professor of medicine at the Katholieke Universiteit and chair of endocrinology at the University Hospital Gasthuisberg, Leuven, Belgium, pointed out several differences between STOP-NIDDM and ACE, including in the components of the composite outcome, the populations studied, and the numbers studied.

And Drs Nauck and Meier observe in their editorial: "The results from the ACE trial challenge the conclusions derived from the cardiovascular outcomes reported in STOP-NIDDM, mainly because STOP-NIDDM was not powered for such a secondary analysis and because the results were of borderline significance."

Dr Mathieu also cautioned against comparing the ACE cardiovascular results in people with prediabetes with any of the recent cardiovascular-outcomes trials for various other type 2 diabetes drugs, since those are mostly in people who already have diabetes.

No Difference in Primary Outcome, but an 18% Diabetes Reduction

The ACE composite primary outcome was first occurrence of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, hospital admission for unstable angina, or hospital admission for heart failure.

The originally planned primary outcome had only included the first three of those five components, but the latter two were added due to slow enrollment and low event rates. The original three-point MACE then became a secondary outcome.

The primary outcome occurred in 470 (14.4%) of 3272 participants in the acarbose group (3.33 per 100 person-years) and 479 (14.7%) of 3250 in the placebo group (3.41 per 100 person-years), with a nonsignificant hazard ratio of 0.98 (P = .73). Hazard ratios didn't differ between the acarbose and placebo groups for any of the five MACE components, nor for the three-component MACE.

On the other hand, diabetes developed less frequently in the acarbose group, occurring in 436 (13%) of 3272 (3.17 per 100 person-years) vs 513 (16%) of 3250 placebo subjects (3.84/100 person-years), with rate ratio 0.82 (= .005).

At 1 year into the study, the acarbose group also had significantly lower triglycerides (1.49 vs 1.62 mmol/L, < .0001) and bodyweight (69.9 vs 70.8 kg, < .0001).

The number of participants reporting mild and severe hypoglycemia didn't differ between the acarbose and placebo groups, 11% and 2%, respectively, for both groups.

Gastrointestinal disorders, including flatulence, were the only adverse event category that differed between the two groups. Serious GI events didn't differ (2% in each group), but GI events leading to discontinuation or dose reduction were more common with acarbose than with placebo (215 [7%] of 3263 vs 150 [5%] of 3241, = .0007). Death rates did not differ between the groups.

The ACE trial was sponsored by Bayer AG. Dr Holman reports 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 chairing or participating in independent data monitoring committees for lcelyx, GlaxoSmithKline, Janssen, and Takeda. Disclosures for the coauthors are listed in the paper. Dr Li has received study support from AstraZeneca, Merck, and Novo Nordisk. He was an advisor for Bayer in the past but is not currently. Dr Mathieu has served on advisory panels or has been a speaker for or received research support from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen Pharmaceuticals, Hanmi Pharmaceuticals, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, Roche and Sanofi. Dr Nauck has received compensation for lectures or advisory board membership from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Fractyl, GlaxoSmithKline, Intarcia/Servier, Menarini/Berlin Chemie, Merck Sharp & Dohme, and Novo Nordisk. He has received grant support from AstraZeneca, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Menarini/Berlin-Chemie, Merck, Sharp & Dohme, and Novartis. Dr Meier has received compensation for lectures or advisory board membership from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novo Nordisk, Servier, and Sanofi. He has received research support from Boehringer Ingelheim, Merck, Sharp & Dohme, Novo Nordisk, and Sanofi.

Lancet Diabetes Endocrinol. Published online September 13, 2017. Abstract, Editorial

For more diabetes and endocrinology news, follow us on Twitter and on Facebook.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.