Glycemic Control Drives Cardiac-Event–Free Survival in Diabetes

Marlene Busko

April 24, 2017

In a Danish registry study of patients who were newly diagnosed with type 2 diabetes and started on metformin, those who reached an HbA1c target of <6.5% within 6 months — defined as early tight glycemic control — had a lower risk of cardiovascular events or death during a median 2.6-year follow-up.

Patients who started with an HbA1c >7.5% and had a large drop in HbA1c also had a lower risk of this combined end point of acute myocardial infarction (MI), stroke, or death in this study, published online April 12, 2017 in Diabetes Care.

"We did the study to find out if attaining an early HbA1c <6.5% and achieving an early large HbA1c drop were each…predictors of outcomes…independent of baseline pretreatment HbA1c, age, comorbidity, etc, and yes, they were," Reimar W Thomsen, PhD, from the department of clinical epidemiology, Institute of Medicine, Aarhus University Hospital, Denmark, told Medscape Medical News in an email.

However, the study is "observational and just shows that those who [attain] successful early tight glucose control in [real-world clinical] practice have a favorable prognosis," he cautioned.

"You may say, if the therapy guidelines are followed, those who succeed with early glucose control have a good prognosis," he clarified.

On the other hand, poor early glycemic response may be an important predictor of patients with type 2 diabetes who have an increased risk of cardiovascular complications and death and require extra attention.

Impact of Early Glycemic Control on Heart Health, Survival

American Diabetes Association (ADA) and UK National Institute for Health and Care Excellence (NICE) guidelines recommend treating patients with newly diagnosed type 2 diabetes with metformin, with the aim of attaining an HbA1c target of <6.5% (48 mmol/mol), "unless there are special considerations such as old age/frailty/short life expectancy, or the presence of significant comorbidity or a high risk of hypoglycemia," Dr Thomsen noted.

However, it is unclear how attained HbA1c levels or the magnitude of change in HbA1c levels are associated with the risk of MI, stroke, or death.

To investigate this, the researchers identified 24,752 patients age 30 and over living in northern Denmark who received glucose-lowering treatment with metformin monotherapy for the first time between 2000 and 2012 and had HbA1c measurements before and 6 months after the start of therapy.

Initially, 42% of the patients had an HbA1c <6.9%; 23% of the patients had an HbA1c of 7% to 7.9%; and 35% of the patients had an HbA1c of 8% to >10%.

About two in five patients (42%) were <60 years old, and 55% were male.

During a follow-up of as long as 10 years, 439 patients had an MI, 594 patients had a stroke, and 1845 patients died.

Meeting HbA1c Target or Having a Large Drop in HbA1c

After 6 months of metformin therapy, close to half of the patients (48%) had an HbA1c of <6.5%, just over a quarter (27%) had an HbA 1c of 6.5% to 6.99%, 18% had 7% to 7.99%, and the remainder had an HbA1c of >8%.

Compared with patients who had an HbA1c of >8% at 6 months, those who attained an HbA1c <6.5% were more likely to be >70 years old (27% vs 17%) and female (47% vs 38%) with a lower initial HbA1c level and slightly more initial macrovascular and microvascular complications.

The adjusted risk of the composite outcome increased with increasing levels of HbA1c.

Risk of Composite End Point, Higher HbA1c Levels vs HbA1c<6.5%*

HbA1c level at 6 mo, % HR (95% CI)
6.5–6.99 1.18 (1.07–1.30)
7.0–7.49 1.23 (1.09–1.40)
7.5–7.99 1.34 (1.14–1.57)
>8 1.59 (1.37–1.84)
*Composite end point of MI, stroke, or death at 6 months after metformin therapy initiation in patients with type 2 diabetes, adjusted for confounders

After 6 months of metformin therapy, HbA1c dropped by four percentage points or more in 8% of patients, fell by one to two percentage points in 39% of patients, was classified as unchanged (altered by -0.4% to +0.4%) in 45% of patients, and was increased in 2% of patients.

Compared with other patients, those with a large reduction in HbA1c levels tended to be younger and less likely to have complications or comorbidities or to be taking medications to prevent cardiovascular events, at baseline.

Overall, having a larger magnitude of change in HbA1c was an independent predictor of a lower risk of combined MI, stroke, or death during follow-up; however, in the subgroup of patients with a low initial HbA1c (<7.5%) a reduction in HbA1c of 2% was associated with worse outcomes.

Stringent Control Possible, Need to Study "Rapid Responders"

"Our data show that achievement of stringent glycemic levels is possible in real life in at least some elderly patients with comorbidities and that reaching such levels predicts lower risk of vascular events and death," Dr Thomsen and colleagues summarize.

An HbA1c <6.5% is attainable by most patients with type 2 diabetes, Dr Thomsen noted. In a previous study, they showed that among patients who were initiated on metformin in clinical practice in 2010–2012 in Denmark, within 6 months, 53% of patients achieved an HbA1c <6.5% and 80% of patients achieved an HbA1c<7.0% ( Diabetes Obes Metab. 2015;17:771-780 ).

However, "some patients may take longer than 6 months to [attain glycemic] control, and not every patient should be very tightly controlled in the first place, according to the guidelines."

The new study also suggests that there may be a subgroup of patients who have a rapid glycemic response and a lower risk of adverse outcomes.

Further research is needed to determine whether such patients "fare better because of good, appropriate early glucose-lowering therapy, better patient adherence to drugs, better patient-drug-match, good [clinician]-patient [communication] or well-educated patients," or whether better outcomes are "related to a different pathological trajectory/milder variant of type 2 diabetes in patients who are rapid glycemic-[therapy] responders," Dr Thomsen concluded.

The study was funded by a grant from the Danish Agency for Science and a research grant from Novo Nordisk to Aarhus University. Dr Thomsen reports no relevant financial relationships. Disclosures for the coauthors are listed in the paper.

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Diabetes Care. Published online April 12, 2017. Abstract

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