Predicting Cardiovascular Disease Events in Type 2 Diabetes

Inflammation and endothelial stress increase the risk for cardiovascular disease, and the severity of atherosclerosis raises the risk further in patients with no prior history of CVD.

With Jan Nilsson, MD, PhD, and Mikhail Kosiborod, MD

Every physician and many patients know the statistic: A diagnosis of type 2 diabetes immediately doubles the risk of acute myocardial infarction (MI) and stroke.1 Yet, the best way to predict who is at greatest risk for cardiovascular disease (CVD) or repeat episodes of MI remains uncertain.

"The traditional risk factors [used in those without T2D] do not work to predict CVD risk in those with diabetes," said Jan Nilsson, MD, PhD, professor of cardiovascular research at Lund University in Sweden,2 in reporting on the results SUMMIT VIP Study.

Identifying useful markers of risk for CVD events, both in those with and without CVD, is needed, he said. "As such, that is what our study set out to do,"2 said lead author, Dr. Nilsson.

The SUMMIT VIP study evaluated surrogate markers for micro- and macrovascular hard endpoints to derive innovative diabetes tools using vascular imaging to make better risk predictions,2 as published in Diabetes Care.

Heart disease risks present differently in those with T2D and those without diabetes.

The bottom line?  Individuals with and without a history of CVD have distinct risk factors.

"Patients with diabetes but no cardiovascular event history have an increased risk of suffering an event if they have more severe atherosclerosis as assessed by ultrasound," Dr. Nilsson told EndocrineWeb,  "whereas patients with diabetes who already experienced cardiovascular events had an increased risk of suffering a new event if they had signs of increased inflammation as measured by high sensitivity C-reactive protein (CRP) and interleukin-6 (Il-6)."

"Looking at those with a history of CVD, those who developed a new cardiovascular event during follow-up had significantly higher levels of inflammatory biomarkers than those not experiencing a new event," he said.

Prior Research Leading to the SUMMIT VIP Study

The need to improve CVD risk estimates in patients with type 2 diabetes is urgent,2 the authors wrote. Historically, all those individuals with diabetes were viewed as having a higher risk based on studies that suggested that risk of cardiovascular disease was equivalent to those without diabetes but who had a prior coronary event.3

But more recent research suggests the CV risk in T2D is highly heterogeneous. In fact, some with type 2 diabetes have a much lower risk of CVD than those with established CVD and no diabetes.3

To fine-tune the predictive accuracy, the researchers studied a cohort of 936 men and women with T2D at baseline.

Participants in the Surrogate Markers for Micro-and Macrovascular Hard End Point for Innovative Diabetes Tools (SUMMIT VIP) study came from existing population cohorts and hospital registries in Sweden and the United Kingdom in November 2010 and June 2013.2

The diabetes diagnosis was made using World Health Organization criteria4 or being on current medication for diabetes. Researchers analyzed carotid intima-media thickness and plaque area, ankle-brachial pressure index, arterial stiffness, endothelial function and circulating biomarkers at baseline. They monitored CV events during a three-year follow-up.

Findings Reveal Differences in CVD Based on Diabetes Diagnosis

The CV event rate in patients with T2D (n=440) was higher in those with than those without manifest CVD (n=496) at baseline (5.53 vs. 2.15/100 life-years, P < 0.0001).2

The average age of individuals with preexisting CVD was 69.4 years and 66.5 years in the group without cardiovascular disease at baseline. The duration of diabetes was 12.1 years in those with CVD and 9.1 years in those without CVD at the start. The body weight (based on body mass index calculations) was similar—29.9 in the CVD group and 30.6 in the group without prior CVD.2

During the follow-up phase, 105 participations experienced a CV event.2 Those with T2D and manifest CVD at baseline had more than a two-fold higher cardiovascular event rate than those free of CVD at the start of the study.

The authors attributed the higher CV event rate in those with manifest CVD to elevated baseline levels of inflammatory biomarkers (il-6, chemokine ligand 3, pentraxin 3, and CRP) and endothelial mitogens (hepatocyte growth factor and vascular endothelial growth factor A).2

In those without manifest CVD, events were linked to more severe baseline atherosclerosis (median carotid plaque area 34.5 mm2 [16.1-92.2] vs. 19.5 mm2 [9.5-40.5], P=0.01.2

Conventional risk factors were not linked with CV events, nor were measurements of arterial stiffness and endothelial reactivity, according to the authors’ evaluation.

Caveats, Limitations & Strengths of the SUMMIT VIP Results

Among the study limitations,2 the authors acknowledged, was a lack of direct coronary artery assessment. "We did vascular measurements but only in the carotid artery (carotid IMT) and peripheral arteries (ABPI and pulse wave velocity); we did not assess for the presence of atherosclerosis," said Dr. Nilsson.

Also, because one of the criteria for entry into the study was the use of anti-diabetic medication, it is possible that some participants with prediabetes were included in the study. "However, since they [too] have metabolic disturbances that are very close to those with diabetes, we anticipate the impact on outcomes to be very little," he said

Dr. Nilsson's team also shared some strengths in support of the study findings, including the comprehensive vascular assessments and the examination of established and emerging biomarkers.2 The comparison of groups with and without established CVD was another major strength, according to the authors.

"The question itself—'Can we do better at evaluating individual CVD risk among patients with type 2 diabetes?' is an important one to raise," said Mikhail Kosiborod, MD, FACC, FAHA, a cardiologist at St. Luke's Mid-America Heart Institute and professor of medicine at the University of Missouri—Kansas City School of Medicine who was not involved in the study because "the existing tools we have, the risk prediction models, are limited."

Furthermore, the study ''provides some intriguing data to suggest that perhaps the factors that contribute to CVD may differ in those with type 2 diabetes based on the presence or absence of established atherosclerotic CVD,'' he said.

"What this study introduces is for those with established atherosclerotic CVD and diabetes, inflammation may be an important risk modifier,” he told EndocrineWeb, and “that has previously been shown in a more general population. To me, this data [also] provides additional support to the existing body of data that the burden of atherosclerosis in those who don't have a history of CVD is an important predictor of future events."

"It is another piece of evidence suggesting that the measurement of atherosclerosis in patients with diabetes who don't have established CVD is something clinicians should consider. In people with established CVD, this provides additional data suggesting that inflammation may be an important predictor of risk," said Dr. Kosiborod.

Inflammation Represents an Opportunity of Significant Clinical Importance

"The inflammation hypothesis is becoming increasingly important to our understanding of atherosclerotic CVD progression,” he said. That concept has been the focus of other investigators.5,6

"A more recent subgroup analysis from the Canakinumab Anti-inflammatory Thrombosis Outcomes (CANTOS) study found the risk reduction extends to patients with type 2 diabetes," 6 said Dr. Kosiborod, “As the authors of the CANTOS trial suggested: the value in specifically targeting inflammation in high-risk patients may provide additional risk reduction."

According to results from the CANTOS trial,the researchers concluded that IL-1B inhibition with canakinumab had similar effects on major CV events among those with and without diabetes. However, treatment over the median of 3.7 years did not reduce incident diabetes. 

"Although these data are intriguing, the extent to which they will have an impact on clinical practice remains unclear, at present," Dr. Kosiborod told EndocrineWeb.

Dr. Nilsson was more positive, suggesting that the results from the SUMMIT VIP study were sufficient to change practice already.2 For instance, a patient who has not yet suffered an event may be a candidate for more intensive therapy in terms of statins. And, he said those with a CVD history who already receive statin therapy may also need their inflammation targeted.

Neither Dr. Nilsson nor Dr. Kosiborod had relevant financial disclosures with regard to this study.

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