Biomarker HF Risk Score Envisioned as SGLT2 Inhibitor Lodestar in Diabetes

January 13, 2021

A scoring system that predicts risk for new heart failure (HF) over 5 years that is based solely on a few familiar, readily available biomarkers could potentially help steer patients with diabetes or even prediabetes toward HF preventive therapies, researchers propose based on a new study.

They foresee the risk-stratification tool, based on data pooled from three major community-based cohort studies but not independently validated, as a way to select patients with diabetes and prediabetes for treatment with sodium-glucose cotransporter-2 (SGLT2) inhibitors.

Several members of that drug class, conceived as antidiabetic agents, have been shown to help in prevention or treatment of HF in patients with diabetes and those without diabetes but at increased cardiovascular (CV) risk. Yet their uptake in practice has been lagging, they group notes.

Most HF benefits in the SGLT2 inhibitor trials "were seen in patients who have established cardiovascular disease — basically a history of heart attack or stroke," Ambarish Pandey, MD, MSCS, UT Southwestern Medical Center, Dallas, told theheart.org | Medscape Cardiology.

"So we wanted to see how we can identify high-risk patients without a history of cardiovascular disease using these biomarkers, as an approach to targeting SGLT2 inhibitors, which are fairly expensive therapies," he said. Without such risk stratification, "you end up treating so many more patients to get very modest returns."

The group developed a scoring system based on four biomarkers that are "easily measured with inexpensive tests," Pandey said: high-sensitivity-assay cardiac troponin-T (hs-cTnT) and C-reactive protein (hs-CRP) levels; N-terminal proB-type natriuretic peptide (NT-proBNP) levels; and electrocardiography for evidence of left-ventricular hypertrophy (ECG-LVH).

The derivation cohort consisted of participants in the Atherosclerosis Risk in Communities (ARIC), Dallas Heart Study (DHS), and Multi-Ethnic Study of Atherosclerosis (MESA) epidemiologic studies who were free of coronary heart disease, stroke, or HF for whom there were sufficient data on CV risk factors and the four biomarkers. None were taking SGLT2 inhibitors at enrollment in their respective studies, the researchers note.

Members of the pooled cohorts who had diabetes or prediabetes were assigned 1 point for each abnormal biomarker. The 5-year risk for incident HF went up continuously along with the score in people with diabetes and in those with prediabetes, the latter defined as a fasting plasma glucose level of 100 mg/dL to less than 126 mg/dL.

For those with a score of 1, compared with 0, for example, the risk for HF went up 82% with diabetes and 40% with prediabetes. But for those with a score of 3 or 4, the risk went up more than four and a half times with diabetes and more than three and a half times for those with prediabetes. Risk increases were independent of other likely HF risk factors and consistently significant.

The analysis was published January 6 in JACC: Heart Failure, with lead authors Pandey and Muthiah Vaduganathan, MD, MPH, Brigham and Women's Hospital, Boston.

The biomarker score should be especially useful in patients considered at low to intermediate risk, based on clinical characteristics, as a means to identify residual HF risk and, potentially, select candidates for SGLT2 inhibitor therapy, Pandey said.

"The other purpose of the study was to broaden the scope of heart failure prevention in dysglycemia by looking also at prediabetes, not just diabetes," he said. There isn't much high-quality evidence supporting SGLT2 inhibitor therapy in prediabetes, but it follows that the drugs may be helpful in prediabetes because they are protective in patients with and without diabetes.

"Our work suggests that prediabetes patients who have elevated biomarkers are at a higher risk of heart failure," Pandey said, suggesting that the HF risk score could potentially help select their drug therapy as well.

The current study seems "to provide a proof of concept that one can use circulating biomarkers to more precisely identify patients in whom therapies might be expected to exert greatest benefit," which is especially important for potentially expensive agents like the SGLT2 inhibitors, James L. Januzzi, MD, Massachusetts General Hospital, Boston, told theheart.org | Medscape Cardiology.

Importantly in the analysis, a greater number of biomarker abnormalities not only corresponded to rising levels of risk, the risk increases were "dramatic," and therefore so was the supposed potential benefit of SGLT2 inhibitor therapy, said Januzzi, who isn't a coauthor but was an editor for its publication in JACC: Heart Failure.

The uptake of SGLT2 inhibitors for heart failure in practice has been less rapid than hoped, he observed, so if "this hypothetical construct holds up" for the drug class, "it might actually help kick-start focusing on who might optimally receive the drugs."

Elevated levels of hs-cTnT, hs-CRP, and NT-proBNP, and presence of ECG-LVH, were each independently associated with a significantly increased 5-year risk for HF in unadjusted and adjusted analyses of the 6799 people in the pooled cohort, 33.2% of whom had diabetes and 66.8% of whom had prediabetes, the group writes.

Hazard Ratio (HR)* for Incident Heart Failure Over 5 Years by Biomarker Score and Glycemia Status
Score Tier Diabetes, HR (95% CI) Prediabetes HR (95% CI)
Low: 1 1.82 (1.31–2.53) 1.40 (1.09–1.80)
Intermediate: 2 2.42 (1.71–3.43) 1.83 (1.37–2.45)
High: 3–4 4.72 (3.16–7.04) 3.68 (2.53–5.34)
*Compared with a "very low" score of 0, adjusted for demographics, smoking status, body mass index, systolic blood pressure, total cholesterol, high-density-lipoprotein cholesterol, estimated glomerular filtration rate, fasting plasma glucose, statin or antihypertensive medication use, original study cohort.

The scoring system would require validation in other cohorts before it could be used, Pandey observed; once there is "robust validation," it might be applied first to patients with dysglycemia at intermediate CV risk by standard clinical measures.

Certainly the HF-risk-stratification scoring system requires validation in other studies, Januzzi agreed. But it is intuitively appealing, and the study's results are consistent with "data that we're submitting for publication imminently" based on the CANVAS CV-outcomes trial of the SGLT2 inhibitor canagliflozin (Invokana) in patients with diabetes.

Pandey discloses receiving support from the Gilead Sciences Research Scholar Program and serving on an advisory board of Roche Diagnostics Vaduganathan discloses serving on advisory boards for Amgen, AstraZeneca, Baxter Healthcare, Bayer AG, Boehringer Ingelheim, Cytokinetics, and Relypsa. Disclosures for the other authors are in the report. Januzzi has disclosed receiving grant support from Novartis, Applied Therapeutics, and Innolife; consulting for Abbott Diagnostics, Janssen, Novartis, Quidel, and Roche Diagnostics; and serving on end-point committees or data safety monitoring boards for trials supported by Abbott, AbbVie, Amgen, CVRx, Janssen, MyoKardia, and Takeda.

JACC Heart Fail. Published online January 6, 2021. Full text

Follow Steve Stiles on Twitter: @SteveStiles2. For more from theheart.org | Medscape Cardiology, follow us on Twitter and Facebook.

Comments

3090D553-9492-4563-8681-AD288FA52ACE
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.
Post as:

processing....

Recommendations