Circulation

ORIGINAL RESEARCH ARTICLE

Heart Failure Risk Stratification and Efficacy

of Sodium-Glucose Cotransporter-2 Inhibitors
in Patients With Type 2 Diabetes Mellitus

BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) are at David D. Berg, MD
increased risk of developing heart failure. Sodium-glucose cotransporter-2 Stephen D. Wiviott, MD
inhibitors reduce the risk of hospitalization for heart failure (HHF) in Benjamin M. Scirica, MD,
patients with T2DM. We aimed to develop and validate a practical MPH
clinical risk score for HHF in patients with T2DM and assess whether this Yared Gurmu, PhD
score can identify high-risk patients with T2DM who have the greatest Ofri Mosenzon, MD
reduction in risk for HHF with a sodium-glucose cotransporter-2 inhibitor. Sabina A. Murphy, MPH
Deepak L. Bhatt, MD, MPH
METHODS: We developed a clinical risk score for HHF in 8212 patients Lawrence A. Leiter, MD
with T2DM in the placebo arm of SAVOR-TIMI 53 (Saxagliptin Assessment Darren K. McGuire, MD,
of Vascular Outcomes Recorded in Patients With Diabetes Mellitus– MHSc
Thrombolysis in Myocardial Infarction 53). Candidate variables were John P.H. Wilding, MD
assessed using multivariable Cox regression, and independent clinical risk Per Johanson, MD, PhD
Downloaded from http://ahajournals.org by on August 31, 2019

Peter A. Johansson, MSc

indicators achieving statistical significance of P<0.001 were included in
Anna Maria Langkilde,
the risk score. We externally validated the score in 8578 patients with MD, PhD
T2DM in the placebo arm of DECLARE-TIMI 58 (Dapagliflozin Effect on Itamar Raz, MD
Cardiovascular Events–Thrombolysis in Myocardial Infarction 58). The Eugene Braunwald, MD
relative and absolute risk reductions in HHF with the sodium-glucose Marc S. Sabatine, MD,
cotransporter-2 inhibitor dapagliflozin were assessed by baseline HHF risk. MPH

RESULTS: Five clinical variables were independent risk predictors of HHF:

prior heart failure, history of atrial fibrillation, coronary artery disease,
estimated glomerular filtration rate, and urine albumin-to-creatinine ratio.
A simple integer-based score (0–7 points) using these predictors identified
a >20-fold gradient of HHF risk (P for trend <0.001) in both the derivation
and validation cohorts, with C indices of 0.81 and 0.78, respectively.
Although relative risk reductions with dapagliflozin were similar for
patients across the risk scores (25%–34%), absolute risk reductions were
greater in those at higher baseline risk (1-sided P for trend=0.04), with
high-risk (2 points) and very-high-risk (≥3 points) patients having 1.5%
and 2.7% absolute reductions in Kaplan-Meier estimates of HHF risk at 4
years, respectively.
Key Words:  diabetes mellitus ◼ heart
CONCLUSIONS: Risk stratification using a novel clinical risk score for HHF failure ◼ risk factors ◼ sodium-glucose
in patients with T2DM identifies patients at higher risk for HHF who derive cotransporter-2 inhibitors

greater absolute benefit from sodium-glucose cotransporter-2 inhibition. Sources of Funding, see page XXX

CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. © 2019 American Heart Association, Inc.

Unique identifiers: NCT01107886 and NCT01730534. https://www.ahajournals.org/journal/circ

Circulation. 2019;140:00–00. DOI: 10.1161/CIRCULATIONAHA.119.042685 xxx xxx, 2019 1

 Berg et al
Clinical Perspective
ORIGINAL RESEARCH
What Is New?
ARTICLE
• We developed and externally validated the TIMI
(Thrombolysis in Myocardial Infarction) Risk Score
for Heart Failure in Diabetes (TRS-HFDM), a novel,
integer-based clinical risk score for predicting hos-
pitalization for heart failure (HHF) in patients with
type 2 diabetes mellitus that includes prior heart
failure, history of atrial fibrillation, coronary artery
disease, estimated glomerular filtration rate, and
urine albumin-to-creatinine ratio.
• The risk score had excellent discrimination in 2
large clinical trial cohorts, was well calibrated, and
identified a strong gradient of increasing absolute
reduction in risk of HHF with the sodium-glucose
cotransporter-2 inhibitor dapagliflozin.
What Are the Clinical Implications?
• This analysis confirms that the relative risk reduc-
tion in HHF with sodium-glucose cotransporter-2
inhibitors is consistent regardless of baseline
heart failure risk.
• However, by using TRS-HFDM, a simple, validated
clinical risk score for HHF, clinicians can better edu-
cate patients about their risk of HHF and identify
those patients who have a greater absolute reduc-
tion in HHF risk with sodium-glucose cotrans-
porter-2 inhibitors.
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T
ype 2 diabetes mellitus (T2DM) and heart failure
(HF) are highly prevalent diseases associated with
substantial morbidity and mortality.1–4 Even after
adjustment for the presence of coronary artery disease
(CAD) and its risk factors, T2DM remains an important
independent risk factor for HF.5–7 Moreover, in contrast
to the risks of myocardial infarction (MI) and stroke, the
risk of HF in patients with T2DM persists even when
traditional cardiovascular risk factors, such as smoking,
hypertension, and low-density lipoprotein cholesterol,
are well controlled.8 Sodium-glucose cotransporter-2
(SGLT2) inhibitors are a novel class of glucose-lowering
therapies that have been shown to reduce the risk of
hospitalization for HF (HHF) in patients with T2DM.9–12
The impact of SGLT2 inhibitors on HHF has highlighted
the need for improved models of HF risk stratification in
patients with T2DM, both to tailor individual treatment
approaches and to inform future clinical trial design.
We therefore sought to identify independent clini-
cal risk predictors of HHF in patients with T2DM and
to assess whether those clinical characteristics identify
high-risk patients with T2DM who have the greatest re-
duction in risk of HHF with an SGLT2 inhibitor. In the
present analysis, we derive a practical, multivariable
clinical risk score for HHF in patients with T2DM en-
2 xxx xxx, 2019
Heart Failure Risk Stratification in Diabetes
rolled in the placebo arm of the SAVOR-TIMI 53 trial
(Saxagliptin Assessment of Vascular Outcomes Record-
ed in Patients With Diabetes Mellitus–Thrombolysis in
Myocardial Infarction 53)13 and externally validate this
score in placebo-treated patients in the DECLARE-TIMI
58 trial (Dapagliflozin Effect on Cardiovascular Events–
Thrombolysis in Myocardial Infarction 58). We then
evaluate this risk stratification scheme as it relates to
the clinical efficacy of the SGLT2 inhibitor dapagliflozin.
METHODS
Study Population
The SAVOR-TIMI 53 and DECLARE-TIMI 58 trials were multina-
tional, randomized, placebo-controlled trials enrolling patients
with T2DM and either a history of established cardiovascular
disease or multiple risk factors for cardiovascular disease. In
SAVOR-TIMI 53, 16 492 patients (79% with established cardio-
vascular disease and 21% with multiple risk factors for car-
diovascular disease) were randomized to treatment with either
the dipeptidyl peptidase 4 inhibitor saxagliptin (5 mg daily) or
placebo and were followed up for a median of 2.1 years. In
DECLARE-TIMI 58, 17 160 patients (41% with established car-
diovascular disease and 59% with multiple risk factors for car-
diovascular disease) were randomized to treatment with either
dapagliflozin (10 mg daily) or placebo and were followed up for
a median of 4.2 years. The ethics committees at participating
centers approved the protocols for each trial. Written informed
consent was obtained from all patients. We encourage parties
interested in collaboration and data sharing to contact the cor-
responding author directly for further discussions.
Clinical End Point
The primary outcome for this analysis was HHF, which was
adjudicated centrally by the TIMI Clinical Events Committee
using established definitions in both the SAVOR-TIMI 53 and
DECLARE-TIMI 58 trials. In both trials, HHF was defined as an
event that met all of the following criteria: (1) admission to
the hospital for at least 12 hours (SAVOR-TIMI 53) or 24 hours
(DECLARE-TIMI 58); (2) objective evidence of new or worsen-
ing HF (eg, orthopnea, jugular venous distension, pulmonary
basilar crackles); and (3) intensification of HF therapy (eg, ini-
tiation of intravenous diuretic agents or inotropic agents). In
the DECLARE-TIMI 58 trial, the definition of HHF also required
a primary diagnosis of HF and new or worsening symptoms
that were attributed to HF on presentation.
Candidate Risk Indicators
We selected 25 candidate risk indicators for this analysis,
based on their prevalence, clinical relevance, and the ability
to readily obtain the variables from the medical records of
typical patients with T2DM. Selected risk indicators included
age, sex, race, body mass index, duration of T2DM, glycated
hemoglobin (HbA1c), baseline insulin use, history of diabetic
retinopathy, history of diabetic nephropathy, estimated glo-
merular filtration rate (eGFR), urine albumin-to-creatinine
ratio (UACR), established CAD, previous MI, established
peripheral artery disease, previous ischemic stroke, preexisting
Circulation. 2019;140:00–00. DOI: 10.1161/CIRCULATIONAHA.119.042685
 Berg et al Heart Failure Risk Stratification in Diabetes

HF, history of atrial fibrillation, previous percutaneous coro- We selected 5 independent clinical risk indicators of HHF

ORIGINAL RESEARCH
nary intervention, previous coronary artery bypass grafting, that achieved statistical significance at a stringent thresh-
dyslipidemia, hypertension, current smoking, heart rate, sys- old of P<0.001 using an Akaike information criterion for
tolic blood pressure, and diastolic blood pressure. model building based on consistency of forward and back-

Statistical Analysis
In the derivation cohort (ie, 8212 placebo-treated patients in
SAVOR-TIMI 53), we evaluated the univariable associations
between candidate risk indicators and the clinical outcome
of HHF using a Cox proportional hazards model with the risk
indicator as the independent variable (Table  1). Age, body
mass index, duration of T2DM, HbA1c, eGFR, UACR, heart
rate, systolic blood pressure, and diastolic blood pressure were
modeled as continuous variables. All risk indicators achieving
a significance level of P<0.10 on the univariable screen were
included in a multivariable model.
ARTICLE
ward selection procedures. Additional statistical methods
are detailed in the online-only Data Supplement. Each of
the 5 independent clinical risk indicators was assigned an
integer weight proportional to the regression coefficient to
create the TIMI Risk Score for Heart Failure in Diabetes (TRS-
HFDM). Based on the distribution of integer risk scores within
the derivation cohort, simple risk categories were defined
to approximate quartiles of risk in the derivation cohort: 0
points (low risk), 1 point (intermediate risk), 2 points (high
risk), and ≥3 points (very high risk).
We internally validated the risk score model using 1000
bootstrap samples. Within each bootstrap sample, we refitted
the risk score model and compared the apparent performance

Table 1.  Univariable Risk of Hospitalization for Heart Failure by Baseline Characteristics in the Derivation Cohort

Derivation Cohort, Unadjusted Hazard Ratio

Variable % (n=8212) (95% CI) P Value
Demographics
  Age, y 65 (60–71) 1.46 (1.28–1.68)* <0.001
  Female sex 32.7 0.77 (0.57–1.05) 0.10
  White race 75.1 1.16 (0.84–1.60) 0.37
  Body mass index, kg/m2 30 (27–35) 1.16 (1.02–1.32)* 0.023
Diabetes history
  Duration of type 2 diabetes mellitus, y 10.3 (5.3–16.6) 1.31 (1.16–1.47)* <0.001
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  Glycated hemoglobin, % 7.6 (6.9–8.7) 1.07 (0.94–1.22)* 0.32

  Baseline insulin use 41.0 2.18 (1.66–2.87) <0.001
  Diabetic retinopathy 12.3 1.35 (0.94–1.95) 0.11
  Diabetic nephropathy 17.6 2.35 (1.77–3.13) <0.001
 Estimated glomerular filtration rate, 75.7 (59.2–90.3) 0.50 (0.44–0.57)* <0.001
mL·min−1·1.73 m−2
  Urine albumin-to-creatinine ratio, mg/g 17 (6–70) 1.21 (1.15–1.28)* <0.001
Other comorbidities
  Coronary artery disease 62.4 3.00 (2.13–4.24) <0.001
  Prior myocardial infarction 37.6 1.92 (1.47–2.52) <0.001
  Peripheral artery disease 12.2 1.29 (0.88–1.89) 0.19
  Ischemic stroke 12.7 1.14 (0.77–1.69) 0.51
  Prior heart failure 12.8 6.27 (4.79–8.21) <0.001
  Atrial fibrillation 7.4 3.78 (2.74–5.23) <0.001
  Percutaneous coronary intervention 25.0 1.33 (0.99–1.79) 0.06
  Coronary artery bypass grafting 23.5 2.25 (1.71–2.96) <0.001
  Dyslipidemia 71.2 1.44 (1.04–1.98) 0.027
  Hypertension 82.4 1.10 (0.77–1.58) 0.61
  Current smoker 14.0 1.01 (0.68–1.48) 0.98
Vital signs
  Heart rate, bpm 70 (63–78) 1.04 (0.91–1.18)* 0.61
  Systolic blood pressure, mm Hg 137 (125–147) 0.77 (0.67–0.88)* <0.001
  Diastolic blood pressure, mm Hg 80 (71–85) 0.66 (0.58–0.75)* <0.001

Data are percentages or median (interquartile range)  among patients with data for that variable. bpm indicates beats per
minute.
*For continuous variables, hazard ratios are shown per 1 SD.

Circulation. 2019;140:00–00. DOI: 10.1161/CIRCULATIONAHA.119.042685 xxx xxx, 2019 3

 Berg et al
in the bootstrap sample with the overall performance of the
ORIGINAL RESEARCH
risk score model. In addition, we externally validated the inte-
ger risk score model in 8578 patients from the placebo arm
of DECLARE-TIMI 58.
ARTICLE
Discrimination was assessed using the Harrell C index.
Calibration was assessed graphically in the external validation
cohort by comparing observed event rates with predicted risk,
as well as by calculating the Nam-D’Agostino statistic.
We performed subgroup analyses to assess the perfor-
mance of the risk score in patients (1) with versus without
a prior history of HF and (2) with established atherosclerotic
cardiovascular disease versus multiple risk factors for cardio-
vascular disease, calculating the risk score distribution and
Harrell C index in each group.
To test for a heterogeneous treatment effect of dapa-
gliflozin according to baseline HHF risk (ie, relative risk reduc-
tion), we used Cox proportional hazards regression modeling
with a treatment (dapagliflozin versus placebo)–by–risk score
interaction term. To compare absolute differences in the
treatment effect of dapagliflozin according to baseline HHF
risk, we calculated the absolute risk reduction (ARR) by sub-
tracting the Kaplan-Meier event rates for HHF at 4 years in
patients treated with dapagliflozin from the Kaplan-Meier
event rates for HHF at 4 years in patients treated with pla-
cebo across all simple risk score categories. To assess the
increasing trend in ARR in HHF with dapagliflozin by baseline
HHF risk, we used a weighted least-squares model, regress-
ing ARR on integer risk score bin. Because we hypothesized
that ARR would increase with increasing risk score, we used a
1-sided P for trend value for statistical hypothesis testing. We
calculated the numbers needed to treat to prevent 1 HHF at 4
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years using the formula 1/ARR. All analyses were performed
based on intention to treat, with hematuria (randomization
stratification factor in DECLARE-TIMI 58) as a covariate. As
an exploratory analysis, we also tested for heterogeneity in
the relative and absolute increase in risk of HHF with saxa-
gliptin versus placebo according to baseline HHF risk using
the same approach.
All statistical analyses were performed in R version 3.5.3.
All P values are 2-sided unless otherwise specified.
RESULTS
Study Population
Baseline characteristics of the 8212 patients with T2DM
in the derivation cohort are summarized in Table 1. The
median age was 65 years; 33% were women, and
75% were white. The median duration of T2DM was
10 years, and the median HbA1c was 7.6%. A substan-
tial proportion of patients had renal dysfunction as
evidenced by either an eGFR <60 mL·min−1·1.73 m−2
(26%) or UACR >30 mg/g (39%). Sixty-two percent of
patients had established CAD, 7% had atrial fibrillation,
and 13% had preexisting HF. During a median follow-
up of 2.1 years, 228 patients in the derivation cohort
(2.8%) experienced at least 1 HHF event.
Baseline characteristics of the 8578 patients with
T2DM in the external validation cohort are shown in
4 xxx xxx, 2019
Heart Failure Risk Stratification in Diabetes
Table I in the online-only Data Supplement. The median
age was 65 years; 38% were women, and 79% were
white. The median duration of T2DM was 10 years, and
the median HbA1c was 8.0%. Eight percent of patients
had an eGFR <60 mL·min−1·1.73 m−2, and 31% had a
UACR >30 mg/g. Thirty-three percent of patients had
established CAD, 7% had atrial fibrillation, and 10%
had preexisting HF. During a median follow-up of 4.2
years, 286 patients in the external validation cohort
(3.3%) experienced at least 1 HHF event.
Development of a Novel Risk Score for
HHF
The univariable associations between the 25 candidate
baseline characteristics and risk of HHF are shown in
Table 1. Of these, 17 were included in a multivariable
risk model based on achieving a significance level of
P<0.10 on the univariable screen. Five were then se-
lected for inclusion in the final risk model based on
achieving statistical significance at a stringent threshold
of P<0.001. These variables were history of HF, history
of atrial fibrillation, CAD, eGFR, and UACR (Figure I in
the online-only Data Supplement).
After UACR and eGFR were modeled as categorical
variables, the regression coefficients of preexisting HF
and UACR >300 mg/g (severely increased albuminuria)
were approximately double the magnitude of the other
regression coefficients (which were all similar). There-
fore, these variables were assigned weights of 2 points,
whereas the remaining variables were assigned weights
of 1 point (Table 2).
This simple integer-based scheme identified a >20-
fold gradient of HHF risk in the derivation cohort (χ2
819.4; P trend <0.001; Figure 1). Moreover, the integer-
based score yielded a Harrell C index of 0.81 (95% CI,
0.78–0.84), closely approximating the C index of 0.82
(95% CI, 0.79–0.84) for the noninteger 5-variable risk
model (Table II in the online-only Data Supplement).
The internal bootstrap validation yielded an optimism-
corrected C index of 0.81 (95% CI, 0.78–0.83), which
suggests minimal overfitting of the model (Table II in
the online-only Data Supplement).
In the external validation cohort, the integer-based
score also demonstrated a strong graded relationship
with HHF risk (Figure 1; Figure II in the online-only Data
Supplement) and yielded a C index of 0.78 (95% CI,
0.75–0.81; Table II in the online-only Data Supplement).
In addition, the integer score was well calibrated in the
external validation cohort, with observed Kaplan-Meier
HHF event rates at 4 years closely matching predicted
Kaplan-Meier event rates at 4 years. Furthermore, the
Nam-D’Agostino statistic for calibration (nonsignificant
P values indicate adequate calibration) for the integer
score at 4 years was 4.64 (P=0.20; Figure III in the on-
line-only Data Supplement).
Circulation. 2019;140:00–00. DOI: 10.1161/CIRCULATIONAHA.119.042685
 Berg et al Heart Failure Risk Stratification in Diabetes

Table 2. TRS-HFDM in the Derivation Cohort comes than they were for HHF (Figure IV in the online-

ORIGINAL RESEARCH
Risk Indicator Adjusted HR (95% CI) P Value Points only Data Supplement).
Prior heart failure 4.22 (3.18–5.59) <0.001 2

ARTICLE
Atrial fibrillation 2.26 (1.62–3.14) <0.001 1 Efficacy of Dapagliflozin by Baseline Risk
Coronary artery disease 2.06 (1.45–2.93) <0.001 1 of HHF
eGFR <60 mL·min−1·1.73 m−2 1.85 (1.40–2.46) <0.001 1
The efficacy of dapagliflozin versus placebo was as-
Urine albumin-to-creatinine ratio sessed in the DECLARE-TIMI 58 trial. Risk categories,
 >300 mg/g 4.50 (3.18–6.36) <0.001 2 defined as low (0 points), intermediate (1 point), high
 30–300 mg/g 2.08 (1.50–2.87) <0.001 1 (2 points), and very high (≥3 points), represented 41%
eGFR <60 mL·min−1·1.73 m−2 represents chronic kidney disease. Urine
(n=6953), 32% (n=5325), 15% (n=2488), and 12%
albumin-to-creatinine ratio 30–300 mg/g represents moderately increased (n=2076) of the analysis population, respectively. Using
albuminuria, whereas >300 mg/g represents severely increased albuminuria. this simplified scheme, the strong gradient of HHF risk
eGFR indicates estimated glomerular filtration rate; HR, hazard ratio; TIMI,
Thrombolysis in Myocardial Infarction; and TRS-HFDM, TIMI Risk Score for Heart
was consistent in placebo- and dapagliflozin-treated
Failure in Diabetes. patients within this population (P for trend <0.001 for
each).
In the subgroup of patients with a prior history of Although relative risk reductions in HHF with dapa-
HF in the derivation cohort (n=988), the median risk gliflozin were similar across the risk score categories
score was 4 (interquartile range, 3–5), and the risk (25%–34%; P for interaction=0.95), ARRs were great-
score range was 2 to 7. In patients with no prior his- er in those patients at higher baseline risk (χ2=3.24;
tory of HF (n=6825), the median risk score was 1 (in- 1-sided P for trend=0.04). Specifically, patients with
terquartile range, 1–2), and the risk score range was low, intermediate, high, and very high risk of HHF
0 to 5. There was a significant graded risk of HHF by had ARRs of 0.3% (95% CI, −0.1% to 0.8%), 0.6%
risk score in each subgroup, and the Harrell C indices (95% CI, −0.1% to 1.3%), 1.5% (95% CI, −0.1% to
were 0.70 (95% CI, 0.65–0.75) and 0.77 (95% CI, 3.2%), and 2.7% (95% CI, 0.3% to 5.7%), which
0.72–0.81), respectively. Similarly, the risk score per- translates into numbers needed to treat of 303, 172,
65, and 36, respectively, to prevent 1 HF hospitaliza-
formed well both in patients with established cardio-
tion at 4 years (Figure 2).
vascular disease (n=6221; Harrell C index 0.80; 95%
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CI, 0.76–0.83) and in patients with multiple risk fac-

tors for cardiovascular disease (n=1592; Harrell C in-
dex, 0.77; 95% CI, 0.65–0.90; Table III in the online-
only Data Supplement).
Although the risk score also identified gradients of
risk for major adverse cardiovascular events (ie, cardio-
vascular death, MI, or ischemic stroke) and noncardio-
vascular death, the discrimination and fold increases
in risk were substantially more modest for those out-
Safety of Saxagliptin by Baseline Risk of
HHF
In the SAVOR-TIMI 53 trial, the low (0 points), inter-
mediate (1 point), high (2 points), and very high (≥3
points) risk categories represented 18% (n=2882),
35% (n=5443), 22% (n=3467), and 25% (n=3894) of
the analysis population, respectively. The strong gradi-
ent of HHF risk was consistent in both the placebo- and

Figure 1. Incidence rate of HHF by risk score in the derivation and validation cohorts.
The incidence rates of hospitalization for heart failure (HHF) in the derivation and validation cohorts are shown. The integer-based scheme identified a >20-fold
gradient of risk in both the derivation (χ2=819.4; P for trend <0.001) and validation cohorts (χ2=724.3; P for trend <0.001).

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 Berg et al
ORIGINAL RESEARCH
ARTICLE
saxagliptin-treated patients within this population (P
for trend <0.001 for each). In addition, there was an
increasing gradient of absolute risk differences for HHF
by treatment arm (χ2=4.53; 1-sided P for trend=0.02;
Figure V in the online-only Data Supplement).
DISCUSSION
In this analysis, we developed and externally validated a
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novel, integer-based clinical risk score for predicting HHF
in patients with T2DM. This simple risk score includes
5 routinely assessed clinical variables: history of HF, his-
tory of atrial fibrillation, CAD, eGFR, and UACR. The
risk score had excellent discrimination, with a C index
of 0.78 to 0.81 and a >20-fold gradient of HHF risk in 2
large clinical trial cohorts of patients with T2DM. Nota-
bly, the risk score appeared to perform well both in pa-
tients with and without a prior history of HF. Although
the relative risk reductions in HHF with the SGLT2 inhibi-
tor dapagliflozin were similar for patients across the risk
score categories, given the strong gradient of baseline
risk, the score identified a strong gradient of increasing
absolute reduction in HHF risk with dapagliflozin. The
results of this analysis therefore offer a practical tool to
assist clinicians with risk stratification, counseling, and
therapeutic decision making in patients with T2DM.
Application of the Risk Score in the
Treatment of Patients With T2DM
It is well established that HF is both a frequent and
prognostically important cardiovascular complication of
T2DM.5–7 Data from both observational studies and clini-
cal trial cohorts suggest that the development of HF in
patients with T2DM is associated with anywhere from a
4- to 10-fold increase in mortality risk.14,15 Moreover, in
6 xxx xxx, 2019
Heart Failure Risk Stratification in Diabetes
Figure 2. Treatment effect of dapagliflozin by
baseline risk of hospitalization for heart failure.
Although relative risk reductions were similar across
risk score categories, absolute reductions in Kaplan-
Meier estimates of hospitalization for heart failure risk
at 4 years were greater in those at higher baseline
risk (χ2=3.24; 1-sided P for trend=0.04). ARR indicates
absolute risk reduction; HR, hazard ratio; and NNT,
number needed to treat.
contrast to the risk of MI, the risk of HF in patients with
T2DM persists even when other traditional cardiovascu-
lar risk factors, such as hypertension and hyperlipidemia,
are well controlled.8 Several mechanisms have been sug-
gested to explain the relationship between T2DM and
HF, but the pathophysiology and underlying molecular
mechanisms remain incompletely understood.16,17
Further complicating the relationship between T2DM
and HF is the fact that several glucose-lowering therapies,
most notably the thiazolidinediones,18,19 have been shown
to increase the risk of developing HF. Because of concerns
about the cardiovascular safety of new glucose-lowering
therapies, the US Food and Drug Administration and Eu-
ropean Medicines Agency mandated that all new diabetes
therapies undergo rigorous evaluation in large-scale, post-
marketing cardiovascular outcomes trials.20 Over the past
decade, the results of these trials have dramatically shifted
the focus of diabetes care from just reducing HbA1c to also
improving cardiovascular and renal outcomes.
Notably, members of 2 new drug classes—SGLT2 inhibi-
tors and glucagon-like peptide 1 receptor agonists—have
been shown to reduce the risk of major adverse cardiovas-
cular events, defined as the composite of MI, stroke, and
cardiovascular death, in patients with established athero-
sclerotic cardiovascular disease.21 In addition, SGLT2 inhibi-
tors have a particularly robust effect on reducing the risk of
HHF in patients with T2DM.21 The mechanisms by which
each of these drug classes achieve their cardiovascular ben-
efits remain unclear; however, multiple mechanistic stud-
ies are seeking to address this question. Regardless, the
distinct profile of cardiovascular benefit for each of these
drug classes highlights the need for improved models of
risk stratification to optimally treat patients with T2DM.
SGLT2 inhibitors safely reduce HbA1c without causing
hypoglycemia, lower systolic blood pressure, and aug-
ment weight loss and are therefore an effective therapy
for all patients with T2DM. Moreover, SGLT2 inhibitors
Circulation. 2019;140:00–00. DOI: 10.1161/CIRCULATIONAHA.119.042685
 Berg et al
also prevent the progression of kidney disease, reduce the
risk of major adverse cardiovascular events in patients with
established atherosclerotic cardiovascular disease, and re-
duce the risk of HHF regardless of baseline atherosclerotic
risk category or prior HF status.12 Our analysis confirms
that the relative risk reduction in HHF is consistent regard-
less of baseline risk. However, by using a simple, validated
clinical risk score for HHF, clinicians can better characterize
the risk profile of their patients and identify those patients
who have the greatest absolute reduction in risk of HHF
from treatment with SGLT2 inhibitors.
Beyond the immediate clinical application for identi-
fying risk of HHF and the ARR in HHF with SGLT2 inhi-
bition in patients with T2DM, our risk score could also
be used as an aid in the design of future clinical trials.
Given the results of cardiovascular outcomes trials of
glucose-lowering therapies to date, HHF has emerged
as an important end point in such trials. Thus, our risk
score could serve as a stratification tool to select pa-
tients with T2DM who may have the greatest potential
risk or benefit from future therapeutic interventions.
Study Limitations
There are several limitations to this analysis. First, the
derivation cohort database did not include details of
the HF history or echocardiographic data, including in-
dicators of HHF risk such as left ventricular ejection frac-
tion and diastolic dysfunction.22 As such, these variables
Downloaded from http://ahajournals.org by on August 31, 2019
were not included as candidate risk variables in the
derivation of our risk score. Although these variables
might have theoretically enhanced the prognostic per-
formance of the risk model, the objective of this analy-
sis was to develop and validate a clinical risk score for
HHF using patient characteristics that can be readily ob-
tained from the medical record of a typical patient with
T2DM. Second, because creatinine clearance <60 mL/
min was an exclusion criterion in the DECLARE-TIMI 58
trial, the range of diabetic renal disease among patients
enrolled in that trial was more restricted, and thus, the
proportion of patients with higher risk scores was lower
in the validation cohort than in the derivation cohort.
Third, our risk score was derived and validated in 2 clini-
cal trial cohorts, which could influence the generaliz-
ability of these results. Future validation studies in non–
clinical trial populations will be important in assessing
the performance of the score in a broad population of
patients with T2DM. Finally, despite the great scientific
interest in the role of serum biomarkers and genetic
variants in HF risk stratification of patients with T2DM,
these variables were also excluded from the risk model
to prioritize parsimony and practicality. Future analyses
may seek to evaluate whether biomarkers and genetic
variants add to clinical variables in identifying high-risk
patients with T2DM who have the greatest reduction in
risk of HHF with an SGLT2 inhibitor.
Circulation. 2019;140:00–00. DOI: 10.1161/CIRCULATIONAHA.119.042685
Heart Failure Risk Stratification in Diabetes
CONCLUSIONS
ORIGINAL RESEARCH
Improved models of HF risk stratification are needed for
patients with T2DM. We developed and externally vali-
ARTICLE
dated a novel and practical clinical risk score for predic-
tion of HHF in patients with T2DM that includes prior
HF, history of atrial fibrillation, CAD, eGFR, and UACR
using 2 large clinical trial cohorts. This simple clinical
risk prediction tool has excellent discrimination, is well
calibrated, and can help clinicians counsel patients
about their risk of HHF and identify those patients at
higher risk for HHF who have a greater absolute reduc-
tion in HHF risk with SGLT2 inhibitors.
ARTICLE INFORMATION
Received July 10, 2019; accepted August 2, 2019.
The online-only Data Supplement is available with this article at https://www.
ahajournals.org/doi/suppl/10.1161/circulationaha.119.042685.
Correspondence
Marc S. Sabatine, MD, MPH, TIMI Study Group, 60 Fenwood Road, Suite 7022,
Boston, MA 02115. Email msabatine@bwh.harvard.edu
Affiliations
TIMI Study Group, Brigham and Women’s Hospital, Harvard Medical School,
Boston, MA (D.D.B., S.D.W., B.M.S., Y.G., S.A.M., D.L.B., E.B., M.S.S.). Ha-
dassah Hebrew University Hospital, Jerusalem, Israel (O.M., I.R.). Li Ka Shing
Knowledge Institute, St Michael’s Hospital, University of Toronto, Canada
(L.A.L.). University of Texas Southwestern Medical Center, Dallas (D.K.M.).
University of Liverpool, United Kingdom (J.P.H.W.). AstraZeneca, Gothenburg,
Sweden (P.J., P.A.J., A.M.L.).
Sources of Funding
Dr Berg is supported by a T32 postdoctoral training grant from the National
Heart, Lung, and Blood Institute (T32 HL007604). The SAVOR-TIMI 53 and
DECLARE-TIMI 58 studies were supported by AstraZeneca.
Disclosures
Dr Berg has nothing to disclose. Dr Wiviott has received grants from AstraZeneca,
Bristol Myers Squibb, Sanofi Aventis, and Amgen; grants and personal fees from
Arena, Daiichi Sankyo, Eisai, Eli Lilly, and Janssen; grants and consulting fees from
Merck (additionally, his spouse is employed by Merck); and personal fees from
Aegerion, Allergan, AngelMed, Boehringer Ingelheim, Boston Clinical Research
Institute, Icon Clinical, Lexicon, St Jude Medical, Xoma, Servier, AstraZeneca, and
Bristol Myers Squibb. Dr Scirica has received research grants from AstraZeneca,
Eisai, Novartis, and Merck and consulting fees from AstraZeneca, Biogen Idec,
Boehringer Ingelheim, Covance, Dr Reddy’s Laboratories, Eisai, Elsevier Practice
Update Cardiology, GlaxoSmithKline, Lexicon, Merck, Novo Nordisk, Sanofi, and
St Jude’s Medical; and has equity in Health [at] Scale. Dr Gurmu has received grant
support from Novartis. Dr Mosenzon has received grants and personal fees from
AstraZeneca, Bristol Myers Squibb, and Novo Nordisk and personal fees from Eli
Lilly, Sanofi, Merck Sharp & Dohme, Boehringer Ingelheim, Johnson & Johnson,
and Novartis. S.A. Murphy has received grant support from Abbott Laboratories,
Amgen, AstraZeneca, Critical Diagnostics, Daiichi-Sankyo, Eisai, Genzyme, Gilead,
GlaxoSmithKline, Intarcia, Janssen Research and Development, The Medicines
Company, MedImmune, Merck, Novartis, Poxel, Pfizer, Roche Diagnostics, and
Takeda and has received an  honorarium from Amgen. Dr Bhatt has served on
advisory boards for Cardax, Cereno Scientific, Elsevier Practice Update Cardiol-
ogy, Medscape Cardiology, PhaseBio, and Regado Biosciences; on the board of
directors for Boston Veterans Affairs Research Institute, Society of Cardiovascular
Patient Care, and TobeSoft; as chair of the American Heart Association Quality
Oversight Committee; and on data monitoring committees for Baim Institute for
Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO
trial (Portico Re-sheathable Transcatheter Aortic Valve System US IDE trial), fund-
xxx xxx, 2019 7
 Berg et al
ed by St Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED
trial [CENTERA THV System in Intermediate Risk Patients Who Have Symptomatic,
ORIGINAL RESEARCH
Severe, Calcific, Aortic Stenosis Requiring Aortic Valve Replacement], funded by
Edwards), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of
ARTICLE
Medicine (for the ENVISAGE-TAVI AF trial [Edoxaban Compared to Standard Care
After Heart Valve Replacement Using a Catheter in Patients With Atrial Fibrilla-
tion], funded by Daiichi Sankyo), and Population Health Research Institute. Dr
Bhatt has received honoraria from the American College of Cardiology (senior
associate editor, Clinical Trials and News, ACC.org; vice chair, American College
of Cardiology Accreditation Committee), Baim Institute for Clinical Research (for-
merly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial (Evaluation of
Dual Therapy With Dabigatran vs. Triple Therapy With Warfarin in Patients With
Atrial Fibrillation That Undergo a Percutaneous Coronary Intervention With Stent-
ing) steering committee funded by Boehringer Ingelheim; AEGIS-II (Study to Inves-
tigate CSL112 in Subjects With Acute Coronary Syndrome) executive committee
funded by CSL Behring), Belvoir Publications (editor-in-chief, Harvard Heart Letter),
Duke Clinical Research Institute (clinical trial steering committees), HMP Global
(editor-in-chief, Journal of Invasive Cardiology), Journal of the American College of
Cardiology (guest editor; associate editor), Medtelligence/ReachMD (Continuing
Medical Education steering committees), Population Health Research Institute (for
the COMPASS [Rivaroxaban for the Prevention of Major Cardiovascular Events in
Coronary or Peripheral Artery Disease] operations committee, publications com-
mittee, steering committee, and US national coleader, funded by Bayer), Slack
Publications (chief medical editor, Cardiology Today’s Intervention), Society of Car-
diovascular Patient Care (secretary/treasurer), and WebMD (Continuing Medical
Education steering committees). Dr Bhatt has also reported the following rela-
tionships: Clinical Cardiology (deputy editor), National Cardiovascular Data Reg-
istry (NCDR)-ACTION Registry Steering Committee (chair), and Veterans Affairs
Clinical Assessment Reporting and Tracking (VA CART) Research and Publications
Committee (chair). Dr Bhatt has received research funding from Abbott, Amarin,
Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi,
CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Idorsia,
Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi
Aventis, Synaptic, and The Medicines Company and royalties from Elsevier (editor,
Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); he has
also served as site coinvestigator for Biotronik, Boston Scientific, St Jude Medical
(now Abbott), and Svelte and as trustee for the American College of Cardiology
and has conducted unfunded research for FlowCo, Fractyl, Merck, Novo Nordisk,
Downloaded from http://ahajournals.org by on August 31, 2019
PLx Pharma, and Takeda. Dr Leiter has received grants and personal fees from
AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk, and Sanofi;
personal fees from Merck and Servier; and grants from GlaxoSmithKline. Dr Mc-
Guire has received personal fees from AstraZeneca, Boehringer Ingelheim, Janssen
Research and Development, Sanofi US, Merck Sharp & Dohme, Lilly USA, Novo
Nordisk, GlaxoSmithKline, Lexicon, Eisai, Esperion, Metavant, Pfizer, and Applied
Therapeutics. Dr Wilding has received grants, personal fees, and consultancy fees
(paid to his institution) from AstraZeneca, Novo Nordisk, and Takeda; personal fees
and consultancy fees (paid to his institution) from Boehringer Ingelheim, Lilly, Jans-
sen, Napp, Mundipharma, and Sanofi; and consultancy fees (paid to his institu-
tion) from Wilmington Healthcare, outside the submitted work. Dr Johanson, P.A.
Johansson, and Dr Langkilde are employees of AstraZeneca. Dr Raz has received
personal fees from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Con-
center BioPharma and Silkim, Eli Lilly, Merck Sharp & Dohme, Novo Nordisk, Or-
genesis, Pfizer, Sanofi, SmartZyme Innovation, Panaxia, FutuRx, Insuline Medical,
Medial EarlySign, CameraEyes, Exscopia, Dermal Biomics, Johnson & Johnson, No-
vartis, Teva, GlucoMe, and DarioHealth. Dr Braunwald has received research grants
through his institution from AstraZeneca, Bristol Myers Squibb,  Daiichi Sankyo,
GlaxoSmithKline, Merck, and Novartis; personal fees for consultancy from Carduri-
on, MyoKardia, Sanofi, and Verve; and fees for lectures from Medscape; he also has
reported uncompensated consultancies and lectures from Merck, Novartis, and The
Medicines Company. Dr Sabatine has received institutional research grants to the
TIMI Study Group at Brigham and Women’s Hospital from Amgen, AstraZeneca,
Bayer, Daiichi-Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen Research and Devel-
opment, Medicines Company, MedImmune, Merck, Novartis, Poxel, Pfizer, Quark
Pharmaceuticals, and Takeda; consulting fees from Amgen, Anthos Therapeutics,
AstraZeneca, Bristol Myers Squibb, CVS Caremark, DalCor, Dyrnamix, Esperion,
IFM Therapeutics, Intarcia, Ionis, Janssen Research and Development, The Medi-
cines Company, MedImmune, Merck, and Novartis; and is a member of the TIMI
Study Group, which has also received research grant support through Brigham and
Women’s Hospital from Abbott, Aralez, BRAHMS, Roche, and Zora Biosciences.
REFERENCES
1. Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U,
Shaw JE. Global estimates of diabetes prevalence for 2013 and projections
8 xxx xxx, 2019
Heart Failure Risk Stratification in Diabetes
for 2035. Diabetes Res Clin Pract. 2014;103:137–149. doi: 10.1016/j.
diabres.2013.11.002
2. Scirica BM, Braunwald E, Raz I, Cavender MA, Morrow DA, Jarolim P,
Udell JA, Mosenzon O, Im K, Umez-Eronini AA, et al; SAVOR-TIMI 53 Steer-
ing Committee and Investigators. Heart failure, saxagliptin, and diabetes
mellitus: observations from the SAVOR-TIMI 53 randomized trial. Circula-
tion. 2014;130:1579–1588. doi: 10.1161/CIRCULATIONAHA.114.010389
3. Cavender MA, Steg PG, Smith SC Jr, Eagle K, Ohman EM, Goto S, Kuder J,
Im K, Wilson PW, Bhatt DL; REACH Registry Investigators. Impact of diabe-
tes mellitus on hospitalization for heart failure, cardiovascular events, and
death: outcomes at 4 years from the Reduction of Atherothrombosis for
Continued Health (REACH) Registry. Circulation. 2015;132:923–931. doi:
10.1161/CIRCULATIONAHA.114.014796
4. Benjamin EJ, Muntner P, Alonso A, Bittencourt MS, Callaway CW,
Carson AP, Chamberlain AM, Chang AR, Cheng S, Das SR, et al; Ameri-
can Heart Association Council on Epidemiology and Prevention Statistics
Committee and Stroke Statistics Subcommittee. Heart disease and stroke
statistics–2019 update: a report from the American Heart Association. Cir-
culation. 2019;139:e56–e528. doi: 10.1161/CIR.0000000000000659
5. Boudina S, Abel ED. Diabetic cardiomyopathy revisited. Circulation.
2007;115:3213–3223.
6. McMurray JJ, Gerstein HC, Holman RR, Pfeffer MA. Heart failure: a cardio-
vascular outcome in diabetes that can no longer be ignored. Lancet Diabe-
tes Endocrinol. 2014;2:843–851. doi: 10.1016/S2213-8587(14)70031-2
7. MacDonald MR, Petrie MC, Varyani F, Ostergren J, Michelson EL, Young JB,
Solomon SD, Granger CB, Swedberg K, Yusuf S, et al; CHARM Investiga-
tors. Impact of diabetes on outcomes in patients with low and preserved
ejection fraction heart failure: an analysis of the Candesartan in Heart fail-
ure: Assessment of Reduction in Mortality and morbidity (CHARM) pro-
gramme. Eur Heart J. 2008;29:1377–1385. doi: 10.1093/eurheartj/ehn153
8. Rawshani A, Rawshani A, Franzén S, Sattar N, Eliasson B, Svensson AM,
Zethelius B, Miftaraj M, McGuire DK, Rosengren A, et al. Risk factors,
mortality, and cardiovascular outcomes in patients with type 2 diabetes. N
Engl J Med. 2018;379:633–644. doi: 10.1056/NEJMoa1800256
9. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S,
Mattheus M, Devins T, Johansen OE, Woerle HJ, et al; EMPA-REG OUT-
COME Investigators. Empagliflozin, cardiovascular outcomes, and mor-
tality in type 2 diabetes. N Engl J Med. 2015;373:2117–2128. doi:
10.1056/NEJMoa1504720
10. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N,
Shaw W, Law G, Desai M, Matthews DR; CANVAS Program Collaborative
Group. Canagliflozin and cardiovascular and renal events in type 2 diabe-
tes. N Engl J Med. 2017;377:644–657. doi: 10.1056/NEJMoa1611925
11. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Silverman
MG, Zelniker TA, Kuder JF, Murphy SA, et al; DECLARE–TIMI 58 Investiga-
tors. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl
J Med. 2019;380:347–357. doi: 10.1056/NEJMoa1812389
12. Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP, Mosenzon O,
Kato ET, Cahn A, Furtado RHM, et al. SGLT2 inhibitors for primary and
secondary prevention of cardiovascular and renal outcomes in type 2 dia-
betes: a systematic review and meta-analysis of cardiovascular outcome
trials. Lancet. 2019;393:31–39. doi: 10.1016/S0140-6736(18)32590-X
13. Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B,
Ohman P, Frederich R, Wiviott SD, Hoffman EB, et al; SAVOR-TIMI 53 Steer-
ing Committee and Investigators. Saxagliptin and cardiovascular outcomes
in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369:1317–
1326. doi: 10.1056/NEJMoa1307684
14. Bertoni AG, Hundley WG, Massing MW, Bonds DE, Burke GL, Goff DC Jr.
Heart failure prevalence, incidence, and mortality in the elderly with dia-
betes. Diabetes Care. 2004;27:699–703. doi: 10.2337/diacare.27.3.699
15. Carr AA, Kowey PR, Devereux RB, Brenner BM, Dahlöf B, Ibsen H, Lindholm
LH, Lyle PA, Snapinn SM, Zhang Z, et al. Hospitalizations for new heart failure
among subjects with diabetes mellitus in the RENAAL and LIFE studies.
Am J Cardiol. 2005;96:1530–1536. doi: 10.1016/j.amjcard.2005.07.061
16. Rodrigues B, Cam MC, McNeill JH. Myocardial substrate metabolism: impli-
cations for diabetic cardiomyopathy. J Mol Cell Cardiol. 1995;27:169–179.
17. Bahrami H, Bluemke DA, Kronmal R, Bertoni AG, Lloyd-Jones DM,
Shahar E, Szklo M, Lima JA. Novel metabolic risk factors for incident heart
failure and their relationship with obesity: the MESA (Multi-Ethnic Study
of Atherosclerosis) study. J Am Coll Cardiol. 2008;51:1775–1783. doi:
10.1016/j.jacc.2007.12.048
18. Masoudi FA, Inzucchi SE, Wang Y, Havranek EP, Foody JM, Krumholz HM.
Thiazolidinediones, metformin, and outcomes in older patients with diabe-
tes and heart failure: an observational study. Circulation. 2005;111:583–
590. doi: 10.1161/01.CIR.0000154542.13412.B1
Circulation. 2019;140:00–00. DOI: 10.1161/CIRCULATIONAHA.119.042685
 Berg et al Heart Failure Risk Stratification in Diabetes

19. Lago RM, Singh PP, Nesto RW. Congestive heart failure and cardiovas- peptide receptor agonists and sodium-glucose cotransporter 2 inhibitors for
cular death in patients with prediabetes and type 2 diabetes given

ORIGINAL RESEARCH
prevention of major adverse cardiovascular and renal outcomes in type 2 diabetes
thiazolidinediones: a meta-analysis of randomised clinical trials. Lancet. mellitus. Circulation. 2019;139:2022–2031. doi: 10.1161/CIRCULATIONAHA.
2007;370:1129–1136. doi: 10.1016/S0140-6736(07)61514-1 118.038868

ARTICLE
20. Scirica BM. The safety of dipeptidyl peptidase 4 inhibitors and
22. From AM, Scott CG, Chen HH. The development of heart failure in
the risk for heart failure. JAMA Cardiol. 2016;1:123–125. doi:
patients with diabetes mellitus and pre-clinical diastolic dysfunction
10.1001/jamacardio.2016.0184
21. Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Furtado RHM, Bonaca MP, a population-based study. J Am Coll Cardiol. 2010;55:300–305. doi:
Mosenzon O, Kato ET, Cahn A, et al. Comparison of the effects of glucagon-like 10.1016/j.jacc.2009.12.003
Downloaded from http://ahajournals.org by on August 31, 2019

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