Can J Diabetes xxx (2021) 1e9

Contents lists available at ScienceDirect

Canadian Journal of Diabetes

journal homepage:
www.canadianjournalofdiabetes.com

Original Research

Quantifying the Risk Continuum for Cardiovascular Death in Adults

with Type 2 Diabetes
Brent A. Williams PhD a, *; James C. Blankenship MD a; Stephen Voyce MD a;
Jeanine M. Cordova PhD b; Pranav Gandhi PhD b; Sharash S. Shetty PhD b
a
Geisinger Health System, Danville, Pennsylvania, United States
b
Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut, United States

Key Messages

Identifying patients with type 2 diabetes (T2D) at highest risk for cardiovascular events enables prioritization of cardioprotective
antidiabetes therapies.

The risk continuum for cardiovascular (CV) death in T2D was quantified using a prediction model that enables ranking of individuals
with respect to CV death risk.

The 10% highest-risk patients according to prediction model elements had an annual CV death risk of w5%.

a r t i c l e i n f o a b s t r a c t

Article history: Objectives: In type 2 diabetes (T2D), the most common causes of death are cardiovascular (CV) related,
Received 28 August 2020 accounting for >50% of deaths in some reports. As novel diabetes therapies reduce CV death risk,
Received in revised form
identifying patients with T2D at highest CV death risk allows for cost-effective prioritization of these
12 January 2021
Accepted 16 January 2021
therapies. Accordingly, the primary goal of this study was to quantify the risk continuum for CV death in
a real-world T2D population as a means to identify patients with the greatest expected benefit from
cardioprotective antidiabetes therapies.
Keywords:
cardiovascular death Methods: This retrospective study included T2D patients receiving services through an integrated health-
diabetes care system and used data generated through electronic medical records (EMRs). Quantifying the risk
prediction model continuum entailed developing a prediction model for CV death, creating an integer risk score based on
the final prediction model and estimating future CV death risk according to risk score ranking.
Results: Among 59,180 patients with T2D followed for an average of 7.5 years, 15,691 deaths occurred,
6,033 (38%) of which were CV related. The EMR-based prediction model included age, established CV
disease and risk factors and glycemic indices (c statistic ¼ 0.819). The 10% highest-risk patients according
to prediction model elements had an annual CV death risk of w5%; the 25% highest-risk patients had an
annual risk of w2%.
Conclusions: This study incorporated a prediction modelling approach to quantify the risk continuum for
CV death in T2D. Prospective application allows us to rank individuals with T2D according to their CV
death risk, and may guide prioritization of novel diabetes therapies with cardioprotective properties.
Ó 2021 Canadian Diabetes Association.

r é s u m é
Mots clés:
décès d’origine cardiovasculaire
Objectifs : Les causes les plus fréquentes de décès en présence du diabète sucré de type 2 (DST2) sont les
diabète
décès d’origine cardiovasculaire (CV), et comptent pour > 50 % des décès selon certaines données
modèle prédictif
recueillies. Puisque les nouveaux traitements contre le diabète contribuent à la réduction du risque de
décès d’origine CV, le repérage des patients atteints du DST2 qui sont les plus exposés au risque de décès
d’origine CV permet de donner la priorité à ces traitements rentables. En conséquence, le principal

* Address for correspondence: Brent A. Williams PhD, Geisinger Health System, 100 North Academy Avenue, Danville, Pennsylvania 17822, United States.
E-mail address: bawilliams2@geisinger.edu

1499-2671/Ó 2021 Canadian Diabetes Association.

The Canadian Diabetes Association is the registered owner of the name Diabetes Canada.
https://doi.org/10.1016/j.jcjd.2021.01.009
2 B.A. Williams et al. / Can J Diabetes xxx (2021) 1e9

objectif de la présente étude était de quantifier le continuum de risque de décès d’origine CV dans une
population atteinte du DST2 en contexte réel pour déterminer les patients qui devraient tirer le plus
grand avantage des thérapies antidiabétiques cardioprotectrices.
Méthodes : Cette étude rétrospective portait sur des patients atteints du DST2 qui recevaient des services
grâce à un système de soins de santé intégrés et utilisait des données issues des dossiers médicaux
électroniques (DMÉ). La quantification du continuum de risque implique l’élaboration d’un modèle de
prédiction des décès d’origine CV, la création d’un score de risque de coefficients entiers fondé sur le
modèle prédictif final et l’estimation du risque futur de décès d’origine CV selon la classification du score
de risque.
Résultats : Parmi les 59 180 patients atteints du DST2 suivis en moyenne durant 7,5 ans, il y a eu 15 691
décès, dont 6033 (38 %) étaient d’origine CV. Selon les données des DMÉ utilisées pour élaborer le
modèle prédictif étaient les suivantes : l’âge, la maladie CV avérée, les facteurs de risque et les indices
glycémiques (statistique C ¼ 0,819). Les 10 % des patients exposés au risque le plus élevé selon les
éléments du modèle prédictif avaient un risque annuel de décès d’origine CV de w 5 %; les 25 % des
patients exposés au risque le plus élevé avaient un risque annuel de w 2 %.
Conclusions : Dans le cadre de cette étude, nous avons utilisé une approche de modélisation prédictive
pour quantifier le continuum de risque de décès d’origine CV lors de DST2. L’application prospective nous
permet de classer les individus atteints du DST2 selon leur risque de décès d’origine CV, et peut conduire
à la priorisation des nouvelles thérapies antidiabétiques qui présentent des propriétés cardioprotectrices.
Ó 2021 Canadian Diabetes Association.

Introduction population with T2D. Specifically, we aimed to quantify the risk

Type 2 diabetes (T2D) is a common chronic condition affecting
approximately 10% of adults in the United States (1). T2D is
recognized as a strong risk factor for cardiovascular (CV) disease,
and is frequently accompanied by cardiometabolic disorders, such
as obesity, dyslipidemia and hypertension; accordingly, T2D
portends an increased likelihood of CV events, including myocar-
dial infarction, stroke and heart failure (2e9). The most commonly
reported causes of death among individuals with T2D are CV
related, with some reports attributing >50% of deaths to an
underlying CV cause, a figure well above the population norm
(w33%) (1,10e15). Although epidemiologic and laboratory evidence
collectively supports a causal link between dysglycemia and CV
events, randomized clinical trials testing the effect of glucose-
lowering strategies on CV events have provided little evidence of
clinical benefit (13e19). However, 2 new classes of diabetes
therapies—sodium-glucose cotransporter-2 inhibitors (SGLT2is)
and glucagon-like peptide-1 receptor agonists (GLP-1 RAs)—have
demonstrated benefits on multiple CV outcomes, including CV
death, and both classes have been recognized prominently by the
American Diabetes Association (20e22).
Providing novel therapeutics, such as SGLT2i and GLP-1 RA,
to patient populations with common chronic conditions (like
T2D) in a value-based manner can be challenging. Cost consid-
erations often prohibit provision of novel therapies to all eligible
patients, so efficient strategies must be devised that optimize
the risk- and cost-benefit balances of such therapies. Risk-
prediction models may be valuable in this context by identi-
fying the highest-risk patients most likely to have events averted
with new therapies while minimizing the number needed to
treat for benefit which helps control cost (23). Multiple risk-
prediction models for CV endpoints applicable to T2D have
been developed and validated over the last few decades
(24e37). Application of these models to contemporary T2D
populations is challenged by a predominance of models devel-
oped strictly for primary prevention, development of models in
highly selected clinical trial populations and the inclusion of
specialized predictors seldom measured in clinical practice.
Furthermore, guidance on proper application of such models in
clinical practice is also sparse. Accordingly, the ultimate goal of
the current study was to provide a method for quantifying and
ranking CV death risk in a real-world, all-comers patient
continuum for CV death by: 1) developing a risk-prediction
model for CV death in a real-world T2D patient population
using predictors drawn from electronic medical records
(EMRs), 2) creating a scoring tool to facilitate model application
in practice and 3) estimating future CV death risk according to
risk ranking, which may facilitate prioritization of novel,
cardioprotective antidiabetes therapies.
Methods
Study population
In this retrospective cohort study, we have incorporated the
patient population and EMR data of the Geisinger Health System
(Geisinger), an integrated health-care delivery network serving
central and northeast Pennsylvania in the United States. The base
study population included patients receiving primary care and
other health-care services through Geisinger with a minimum
2-year interval between the first and last EMR-documented
encounters during the time period from January 1, 2001 to
November 10, 2015. Among patients in the base study population,
diagnostic criteria for T2D were defined according to the ninth and
tenth editions of the International Classification of Diseases (ICD-9/
10) codes and EMR documentation of diabetes-specific medication
as follows: a) when the appropriate ICD-9/10 codes were observed
at 1 inpatient or 2 outpatient encounters >30 days but <1 year
apart or b) when medication orders or reconciliation lists docu-
mented any oral antidiabetic medication other than metformin, or
metformin in the absence of an accompanying prediabetes or
polycystic ovary syndrome diagnosis. Patients meeting diagnostic
criteria within 2 years of the first EMR-documented encounter
were considered pre-existing T2D cases, and after 2 years as newly
diagnosed cases. An index date was assigned to all study patients
corresponding to the first office visit where diagnostic criteria were
met 2 years after the first EMR-documented encounter. Thus, all
study patients had an index date between January 1, 2003 and
November 10, 2015, with at least 2 years of preindex date encounter
information for determining baseline characteristics. The study was
approved by the Institutional Review Board of Geisinger, which
granted a waiver of patient consent due to the retrospective nature
of the study.
 B.A. Williams et al. / Can J Diabetes xxx (2021) 1e9 3

Table 1
Baseline characteristics of patients with T2D overall, and stratified by CV death, non-CV death and alive

All (n¼59,180) CV death (n¼6,033) Non-CV death (n¼9,658) Alive (n¼43,489) p Value *

Incident T2D (vs pre-existing) 20,663, 35% 1,132, 19% 2,129, 22% 17,402, 40% <0.001
Demographics and vital signs
Age (at index date), years 61 (51‒72) 74 (65‒80) 72 (63‒79) 58 (48‒67) <0.001
Male 29,275, 49% 3,188, 53% 4,999, 52% 21,088, 48% 0.19
White 57,172, 97% 5,960, 99% 9,521, 99% 41,691, 96% 0.27
Smoking <0.001
Current 9,627, 16% 677, 11% 1,493, 15% 7,457, 17%
Former 17,729, 30% 1,865, 31% 3,098, 32% 12,766, 29%
Never 31,824, 54% 3,491, 58% 5,067, 52% 23,266, 54%
Body mass index, kg/m2 33 (29‒39) 31 (27‒36) 31 (27‒36) 34 (30, 40) 0.59
Systolic blood pressure, mmHg 130 (120‒140) 132 (120‒146) 130 (120‒144) 128 (120‒140) 0.02
Diastolic blood pressure, mmHg 74 (68e80) 70 (64e80) 72 (64e80) 76 (70e82) 0.18
Pulse pressure, mmHg 54 (46e64) 60 (50e72) 60 (50e70) 52 (44e62) 0.002
Mean arterial pressure, mmHg 93 (86e100) 93 (85e100) 93 (85e100) 93 (87e100) 0.50
Heart rate, bpm 76 (68e84) 72 (64e80) 76 (68e84) 76 (68e84) <0.001
Medical history
Anemia 10,922, 18% 1,585, 26% 2,590, 27% 6,747, 16% 0.45
Arrhythmia (non-AF) 5,509, 9% 994, 16% 1,102, 11% 3,413, 8% <0.001
Atrial fibrillation 4,702, 8% 1,330, 22% 1,257, 13% 2,115, 5% <0.001
Cancer 8,871, 15% 1,187, 20% 2,612, 27% 5,072, 12% <0.001
Cardiomyopathy (non-HF) 1,576, 3% 392, 6% 338, 4% 846, 2% <0.001
Cerebrovascular disease 5,485, 9% 1,265, 21% 1,559, 16% 2,661, 6% <0.001
Conduction disorder 1,739, 3% 396, 7% 438, 5% 905, 2% <0.001
CABG 3,132, 5% 808, 13% 774, 8% 1,550, 4% <0.001
Coronary artery disease 14,573, 25% 3,139, 52% 3,530, 37% 7,904, 18% <0.001
Dementia 1,040, 2% 254, 4% 476, 5% 310, 1% 0.04
Depression 16,177, 27% 1,406, 23% 2,550, 26% 12,221, 28% <0.001
Family history of CVD 2,885, 5% 115, 2% 208, 2% 2,562, 6% 0.29
Gout 4,297, 7% 663, 11% 947, 10% 2,687, 6% 0.02
Heart failure 6,022, 10% 1,866, 31% 1,833, 19% 2,323, 5% <0.001
Hyperlipidemia 42,136, 71% 4,309, 71% 6631, 69% 31,196, 72% <0.001
Hypertension 43,576, 74% 5,120, 85% 7,754, 80% 30,702, 71% <0.001
Hyperthyroidism 822, 1% 71, 1% 138, 1% 613, 1% 0.18
Hypothyroidism 10,263, 17% 1130, 19% 1829, 19% 7,304, 17% 0.75
Implantable cardioverter-defibrillator 410, <1% 124, 2% 59, 1% 227, 1% <0.001
Kidney disease (chronic) 6,746, 11% 1,208, 20% 1,710, 18% 3,828, 9% <0.001
Liver disease (chronic) 3,352, 6% 183, 3% 526, 5% 2,643, 6% <0.001
Lung disease (chronic) 12,923, 22% 1635, 27% 2845, 29% 8,443, 19% 0.002
Myocardial infarction 4,147, 7% 871, 14% 914, 9% 2,362, 5% <0.001
Pacemaker 1,215, 2% 380, 6% 308, 3% 527, 1% <0.001
PCI 2,574, 4% 322, 5% 437, 5% 1815, 4% 0.021
Peripheral artery disease 4,458, 8% 906, 15% 1,103, 11% 2,449, 6% <0.001
Pulmonary embolism 916, 2% 132, 2% 196, 2% 588, 1% 0.50
Sleep apnea 6,918, 12% 444, 7% 789, 8% 5,685, 13% 0.07
Stroke/TIA 3,853, 7% 754, 12% 939, 10% 2,160, 5% <0.001
Thrombocytopenia 1,277, 2% 196, 3% 400, 4% 681, 2% 0.004
Valve disease 4,179, 7% 1058, 18% 1,023, 11% 2,098, 5% <0.001
Venous thromboembolism 1,660, 3% 221, 4% 379, 4% 1,060, 2% 0.41
Cardiovascular symptoms
Angina/chest pain 15,146, 26% 1,555, 26% 2,383, 25% 11,208, 26% 0.12
Dyspnea 9,658, 16% 1,120, 19% 1,744, 18% 6,794, 16% 0.42
Edema 9,989, 17% 1,380, 23% 2,216, 23% 6,393, 15% 0.92
Fatigue 11,578, 20% 1,027, 17% 1,751, 18% 8,800, 20% 0.08
Cardiovascular medications
Statin 29,252, 49% 3,075, 51% 4,427, 46% 21,750, 50% <0.001
ACE inhibitor 27,513, 46% 3,312, 55% 4,677, 48% 19,524, 45% <0.001
Diuretic 26,031, 44% 3,670, 61% 5,165, 53% 17,196, 40% <0.001
Beta blocker 21,863, 37% 3,156, 52% 4,269, 44% 14,438, 33% <0.001
Antiplatelet (including aspirin) 19,380, 33% 2,064, 34% 2,948, 31% 14,368, 33% <0.001
Calcium channel blocker 11,848, 20% 1,764, 29% 2,452, 25% 7,632, 18% <0.001
Nitrate 8,555, 14% 1,768, 29% 1,955, 20% 4,832, 11% <0.001
Angiotensin receptor blocker 7,907, 13% 962, 16% 1,315, 14% 5,630, 13% <0.001
Warfarin 4,749, 8% 1,140, 19% 1,174, 12% 2,435, 6% <0.001
Fibrate 3,925, 7% 371, 6% 540, 6% 3,014, 7% 0.15
Antiadrenergic antihypertensive 3,594, 6% 585, 10% 889, 9% 2,120, 5% 0.30
Digoxin 2,773, 5% 923, 15% 860, 9% 990, 2% <0.001
Alpha-beta blocker 2,344, 4% 392, 6% 357, 4% 1,595, 4% <0.001
Intestinal cholesterol absorption inhibitors 1,790, 3% 136, 2% 238, 2% 1,416, 3% 0.40
Antiarrhythmic 1,652, 3% 323, 5% 301, 3% 1,028, 2% <0.001
Nicotinic acid 1,062, 2% 109, 2% 127, 1% 826, 2% 0.01
Bile acid sequestrants 1,015, 2% 110, 2% 176, 2% 729, 2% 0.99
Diabetes medications
Biguanides 28,300, 48% 2,049, 34% 3,471, 36% 22,780, 52% 0.01
Sulfonylureas 16,821, 28% 2,420, 40% 3,515, 36% 10,886, 25% <0.001
Insulin 11,063, 19% 1,379, 23% 2,090, 22% 7,594, 17% 0.07
(continued on next page)
4 B.A. Williams et al. / Can J Diabetes xxx (2021) 1e9

Table 1 (continued )

All (n¼59,180) CV death (n¼6,033) Non-CV death (n¼9,658) Alive (n¼43,489) p Value *

Thiazolidinedione 5,999, 10% 903, 15% 1272, 13% 3,824, 9% 0.002

DPP-4 inhibitors 2,378, 4% 117, 2% 183, 2% 2,078, 5% 0.84
Glitinides 1,387, 2% 202, 3% 312, 3% 873, 2% 0.69
Laboratory tests
A1C, % 6.9 (6.3‒8.0) 7.0 (6.3‒7.9) 6.8 (6.2‒7.8) 6.9 (6.3‒8.1) <0.001
<7% 30,145, 51% 3,015, 50% 5,205, 54% 21,916, 50% <0.001
Basic metabolic panel
Blood urea nitrogen, mg/dL 16 (13e21) 21 (16e27) 19 (15e25) 16 (12e19) <0.001
Calcium, mg/dL 9.4 (9.1e9.7) 9.4 (9.0e9.7) 9.4 (9.0e9.7) 9.5 (9.2e9.8) 0.52
Carbon dioxide, mEq/L 27 (25e29) 27 (25e29) 27 (25e29) 27 (25e29) 0.06
Chloride, mmol/L 102 (100e104) 102 (99e104) 102 (99e104) 102 (100e104) 0.17
Glomerular filtration rate, mL/min <0.001
<30 634, 1% 269, 5% 319, 3% 52, <1%
30e50 2,267, 4% 861, 14% 975, 10% 448, 1%
>50 56,279, 95% 4,903, 81% 8,364, 87% 42,989, 99%
Glucose, mg/dL 137 (112e176) 136 (109e177) 136 (110e176) 138 (113e176) 0.82
Potassium, mEq/L 4.3 (4.0e4.6) 4.4 (4.1e4.7) 4.3 (4.0e4.6) 4.3 (4.0e4.5) <0.001
Sodium, mmol/L 139 (137e141) 139 (137e141) 139 (137e141) 139 (137e141) 0.15
Liver function tests
Alanine aminotransferase, IU/L 25 (18e37) 20 (15e28) 21 (15e30) 27 (19e40) 0.001
Albumin, g/dL 4.2 (4.0e4.4) 4.0 (3.8e4.3) 4.0 (3.8e4.3) 4.2 (4.0e4.4) 0.37
Alkaline phosphatase, U/L 79 (64e97) 80 (65e100) 82 (66e104) 78 (64e96) <0.001
Aspartate aminotransferase, U/L 24 (19e31) 23 (19e29) 23 (19e30) 24 (19e32) 0.02
Bilirubin, mg/dL 0.5 (0.3e0.6) 0.5 (0.3e0.7) 0.5 (0.3e0.6) 0.4 (0.3e0.6) 0.007
Protein, g/dL 7.1 (6.8e7.5) 7.1 (6.7e7.5) 7.1 (6.7e7.5) 7.1 (6.8e7.4) 0.96
Complete blood count
Hematocrit, % 41.2 (38.3e44.0) 40.0 (36.8e43.0) 40.2 (36.7e43.3) 41.6 (38.8e44.2) 0.05
Hemoglobin, g/dL 14.0 (12.8e15.0) 13.4 (12.2e14.5) 13.6 (12.2e14.7) 14.1 (13.1e15.1) 0.005
Lymphocyte, % of total WBC 26 (19e32) 22 (16e29) 23 (16e29) 27 (21e33) 0.03
MCHC, g/dL 33.9 (33.1e34.6) 33.6 (32.8e34.3) 33.7 (32.9e34.4) 34.0 (33.3e34.7) <0.001
MCH, pg 30.3 (29.1e31.5) 30.5 (29.3e31.6) 30.6 (29.3e31.8) 30.3 (29.1e31.4) 0.05
Mean corpuscular volume, mm3 89.5 (86.4e92.6) 90.8 (87.6e94.0) 90.8 (87.5e94.2) 89.0 (85.9e92.0) 0.90
Mean platelet volume, fL 10.0 (8.8e10.9) 10.3 (9.3e11.2) 10.2 (9.1e11.1) 9.9 (8.7e10.8) <0.001
Neutrophil, % of total WBC 63 (56e70) 66 (59e73) 66 (58e73) 62 (56e69) 0.12
Platelet count,  103/mL 239 (196e287) 225 (182e275) 225 (181e277) 243 (202e291) 0.73
Red blood cell count,  106/mL 4.6 (4.3e5.0) 4.4 (4.0e4.8) 4.4 (4.0e4.8) 4.7 (4.4e5.0) 0.12
Red cell distribution width, % 13.4 (12.9e14.2) 13.8 (13.2e14.7) 13.7 (13.1e14.7) 13.3 (12.8e14.0) 0.11
White blood cell count,  103/mL 7.7 (6.3e9.4) 7.8 (6.4e9.5) 7.7 (6.3e9.5) 7.6 (6.3e9.3) 0.003
Lipid panel
Cholesterol, mg/dL 183 (158e212) 179 (154e208) 180 (154e208) 185 (159e214) 0.91
HDL cholesterol, mg/dL 44 (37e52) 43 (36e52) 44 (37e53) 44 (37e52) <0.001
LDL cholesterol, mg/dL 101 (80e126) 96 (76e120) 97 (76e120) 102 (81e127) 0.79
Triglyceride, mg/dL 166 (117e238) 170 (119e244) 165 (116e238) 166 (117e238) 0.004
Total cholesterol:HDL 4.1 (3.4e5.1) 4.1 (3.3e5.0) 4.0 (3.2e4.9) 4.2 (3.4e5.2) <0.001
LDL: HDL 2.3 (1.7e3.0) 2.2 (1.6e2.9) 2.1 (1.6e2.8) 2.3 (1.7e3.0) 0.04
Non-HDL 137 (112e166) 133 (109e162) 133 (108e161) 139 (113e168) 0.26

ACE, angiotensin-converting enzyme; AF, atrial fibrillation; CABG, coronary artery bypass graft; CVD, cardiovascular disease; DPP, dipeptidyl peptidase-4; HDL, high-density
lipoprotein; HF, heart failure; LDL, low-density lipoprotein; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; PCI, percutaneous
coronary intervention; T2D, type 2 diabetes; TIA, transient ischemic attack; WBC, white blood cell.
Note: Continuous variables reported as median (interquartile range), and categorical variables as frequency, %.
* Comparing cardiovascular deaths vs noncardiovascular deaths only.

Quantifying the risk continuum
The approach to quantifying the risk continuum for CV death in
T2D included 3 steps: 1) develop a CV death-prediction model
using variables from the EMR, 2) create an integer-based risk score
from the final prediction model created in step 1 and 3) quantify CV
death risk by risk score ranking (i.e. percentile).
lipid profiles. When vital signs and laboratory test results were not
recorded on the index date, the first measurement before the index
date was chosen. CV- and diabetes-related medications docu-
mented via orders and medication reconciliations within 1 year
prior to or 90 days after the index date were noted, although
medications were not considered as candidate predictors given
concern about confounding by indication.

Candidate predictors for CV death-prediction model Study outcome

Eighty-one candidate predictors for the CV death-prediction
model were assembled from EMR documentation on or before
the index date from the following EMR domains (Table 1): demo-
graphics, vital signs, medical history including diagnoses and pro-
cedures performed, CV signs and symptoms and laboratory tests.
Historic diagnoses and procedures were determined through
ICD-9/10 and Current Procedural Terminology codes. Laboratory
test results considered included glycated hemoglobin (A1C), basic
metabolic panels, liver function tests, complete blood counts and
The sole study outcome was CV-related death. Death indicators
and dates were documented in structured EMR fields when appli-
cable. Death dates were documented by Geisinger providers when
known, and further retrieved through government data sources on
a monthly basis. Cause-of-death attribution was not available
through structured EMR data fields and was determined primarily
through the National Death Index (NDI) and, secondarily, via
manual review of patient EMRs (38). The NDI is a national,
centralized repository of death record information derived from
 B.A. Williams et al. / Can J Diabetes xxx (2021) 1e9
state vital statistics offices. A list of study patients (with appropriate
identifying information) with documented death in 2016 or earlier
was sent to the NDI. At the time of the NDI data request, only deaths
occurring in 2016 or before were available through the NDI. The
2 most salient data elements returned by the NDI included a
numerical index quantifying the degree of confidence that the best-
matched NDI record truly represented the Geisinger patient, and
the underlying cause of death for the match classified by ICD-10
codes. Among correctly matched individuals, cause of death was
labelled cardiovascular when the ICD-10 code for underlying cause
of death had a (letter) “I” prefix (e.g. ICD-10 code I21 for myocardial
infarction). When NDI records could not confidently match the
deceased Geisinger patient or an indeterminate ICD-10 code for
underlying cause of death was provided, manual chart review was
employed to determine cause of death (CV vs non-CV). All known
deaths that could not confidently be assigned an underlying CV
cause by chart review were considered non-CV deaths. Among
15,691 total deaths in the study cohort, 870 (5.5%) were assigned a
non-CV cause of death due to inconclusive chart review.
Statistical analyses
Baseline characteristics as of the index date are presented across
3 strata—CV death, non-CV death and alive (i.e. no known death
before January 1, 2017)—as median (interquartile range) for
continuous variables and frequency (percentage) for categorical
variables. Differences between baseline characteristics restricted to
CV/non-CV death comparisons were tested for statistical signifi-
cance by Wilcoxon rank sum test for continuous variables and chi-
square test for categorical variables. The primary outcome was time
to CV death, defined as the number of days from the index date to
CV death. Non-CV deaths were censored at the death date, and
individuals presumed alive were censored at December 31, 2016—
the last day of available information through the NDI. The cumu-
lative incidence of CV death, non-CV death and all-cause death
were estimated separately by the Kaplan-Meier method and
plotted over 10 years of follow up.
The strongest independent predictors of CV death were identi-
fied via Cox proportional hazards regression. Before model devel-
opment, continuously distributed covariates were separated into
clinically relevant categories before assessing their associations
with CV death. Missing data for continuous covariates were
conservatively imputed via random draw from the empirical dis-
tributions of nonmissing values given the nonrandom nature of
missing data. Starting from the initial list of 81 candidate pre-
dictors, a model was fit using a forward stepwise variable selection
procedure with a restrictive p-value threshold of 0.0001 for model
inclusion/exclusion. The discriminatory capacity of the model was
quantified by the c statistic as appropriate for censored data (39).
All statistically significant predictors (at p<0.0001) were listed in
descending order of predictive strength according to the Wald chi-
square statistic from the full model. Hazard ratios (HRs) and 95%
confidence intervals (CIs) are reported for all significant predictors.
No internal validation was performed given the large size of the
patient cohort. To propose a more parsimonious final model for
clinical use that preserves the majority of the predictive power
from the original set of significant predictors, the weakest of the
significant predictors were removed sequentially and the resulting
decrements in c statistic quantified. As a sensitivity analysis, the
final set of predictors was refit in a Cox regression model with
all-cause death as the outcome. Furthermore, the discriminatory
performance of the proposed model was compared with that of
3 previously published, simpler (i.e. fewer predictor) models with
CV or all-cause death included in the outcome definition (34e36).
Two of these models were chosen based on inclusion of
pre-existing CV conditions among their predictors.
5
The final reduced CV death model was reparameterized so all
regression coefficients were >0 to facilitate creation of an integer-
based risk score. Individual variable risk points were assigned by
scaling each variable’s regression coefficient to the regression
coefficient of the weakest 1-degree-of-freedom predictor
(beta¼0.243, HR¼1.275) and rounding to the nearest integer.
Regression coefficients <0.243 were not assigned risk points.
Thereafter, for each study patient, a total risk score was calculated
as the sum of risk points for all predictors in the final model.
Risk continuum
The total risk score point distribution was tabulated with the
highest set of risk points pooled (28) due to small counts. From
this distribution, cumulative percentiles were determined where
percentile x is interpreted as the x% highest-risk patients according
to the prediction model. For example, risk scores at or above the
10th percentile reflect the 10% highest-risk patients according to
the prediction model. For each risk score value, Kaplan-Meier
cumulative incidence estimates at 1, 3 and 5 years are reported,
as are the number of CV deaths per 100 person years of follow up,
which accounts for the entire duration of the follow-up period.
Results
Study population
Among 484,338 patients meeting base study population criteria,
59,180 (12%) met the T2D diagnostic definition. Study participants
were followed for a cumulative total of 441,344 person years, an
average per-person postindex date follow up of 7.5 years.
Maximum follow-up time was 14 years. New T2DM diagnoses at
the index date accounted for 35% of study patients, whereas 65%
had pre-existing T2DM as of the index date. Among the 15,691
deaths occurring over the follow up, 6,033 (38%) were determined
to have an underlying CV cause. Cumulative incidence across
10 years of postindex date follow up for all-cause, CV and non-CV
death are shown in Figure 1.
Baseline characteristics of T2DM patients
Several notable differences in baseline characteristics were
observed between CV and non-CV deaths (Table 1). Compared with
non-CV deaths, individuals with CV death were slightly at the older
index date (median, 74 vs 72 years; p<0.001), but there was no
difference for gender. A slightly greater percentage of CV deaths
had pre-existing T2DM (81% vs 78%; p<0.001). CV deaths were less
likely to have a smoking history (42% vs 47%; p<0.001). CV deaths
Figure 1. Cumulative incidence of all-cause, cardiovascular- and noncardiovascular-
related death among patients with type 2 diabetes. CV, cardiovascular.
6 B.A. Williams et al. / Can J Diabetes xxx (2021) 1e9

were more likely to have a history of CV conditions including atrial
fibrillation, coronary artery disease, heart failure and myocardial
infarction, but less likely to have a history of cancer, depression,
chronic liver disease and chronic lung disease. CV deaths had a
higher median A1C at the index date (7.0% vs 6.8%; p<0.001), but no
difference in blood glucose was observed (median, 136 vs 136 mg/
dL; p¼0.82).
Per-variable risk score point assignments are shown in the last
column of Table 2 (only variable categories assigned 1þ risk points
are shown). The Spearman correlation coefficient comparing the
total risk points with the linear predictor from the corresponding
Cox model was 0.95, suggesting the total risk score is a strong
surrogate for the more mathematically detailed Cox model.
Supplementary Table 2 reports the HRs and 95% CIs for the final Cox
model when re-fit using all-cause death as the outcome.

Risk-prediction model for CV death CV death risk continuum

Among the original 81 candidate predictors considered in the Quantification of the risk continuum is displayed in Table 3,
variable selection procedure (Table 1, excluding medications), showing the estimated 1-, 3- and 5-year CV death rates across all
27 were independently associated with CV death at a p-value risk score values. Also, the last column shows the estimated num-
threshold of 0.0001 (Supplementary Table 1). Supplementary ber of CV deaths per 100 person years of follow up (equivalently
Table 1 lists the significant predictors in descending order of pre- interpreted as the percentage of patients dying of CV cause per
dictive strength. The c statistic for this model was 0.824. Upon year). Risk point totals of 18 identify the 10% highest-risk patients
removing the 12 weakest, although statistically significant, pre- (10th percentile) according to model predictors. For risk point totals
dictors, the c statistic decreased to 0.819 for the 15-predictor model at or above this threshold, the estimated 5-year risk of CV death
(Table 2). Age was the strongest predictor of CV death, with was 18.3% and the number of CV deaths per 100 person years was
established CV diagnoses among the strongest predictors, including 4.7. The comparable numbers for the 25% highest-risk patients
heart failure, coronary artery disease, atrial fibrillation and cere- (25th percentile) were 5.9% and 1.9, respectively.
brovascular disease. Seven laboratory tests remained among the
top 15 predictors, most notably blood urea nitrogen as the fourth Discussion
strongest predictor overall, and A1C. The c statistics from the
3 external models applied to the current cohort were 0.774, 0.792 The primary goal of this study was to quantify the CV death risk
and 0.803. continuum in a real-world, all-comers patient population with T2D.
This goal was achieved by developing a prediction model for CV
Table 2
death, then translating the model accordingly such that an indi-
The 15 strongest predictors of cardiovascular death among patients with type 2 vidual patient’s percentile ranking of CV death risk could be
diabetes determined, and subsequent risk of 1-, 3- and 5-year CV death
Predictors Hazard ratios Regression Risk
quantified. Model predictors were derived from the EMR of a large
(95% CI) coefficients points integrated health-care delivery network—a feature that facilitates
broad application of the model to many health-care delivery set-
Age, years (vs <40)
40e49 1.91 (1.41e2.59) 0.648 3 tings. Not unexpectedly, age and pre-existing CV diagnoses at the
50e59 3.12 (2.36e4.14) 1.139 5 index date were the strongest predictors of CV death. Furthermore,
60e69 5.06 (3.83e6.68) 1.621 7 among 33 laboratory tests measured during the course of usual
70e79 9.80 (7.42e12.93) 2.282 9 clinical care, 7 were among the top 15 predictors of CV death,
80 21.20 (16.01e28.06) 3.054 13
Heart failure 1.96 (1.84e2.09) 0.674 3
including A1C. The proposed 15-variable model had a strong c
Coronary artery disease 1.65 (1.56e1.75) 0.503 2 statistic of 0.819, higher than those produced when applying
Blood urea nitrogen, mg/dL 3 external models to our study cohort. The practical value of the
(vs 13‒16) model lies in its ability to place patients with T2D in their proper
22‒28 1.37 (1.26e1.49) 0.316 1
location along the CV death risk continuum, allowing cost-efficient,
29 2.00 (1.84e2.18) 0.694 3
Atrial fibrillation 1.56 (1.45e1.66) 0.441 2 judicious allocation of cardioprotective diabetes therapies.
Cerebrovascular disease 1.50 (1.41e1.60) 0.405 2
A1C, % (vs 6.0‒6.9) Diabetes as a risk factor for CV disease
8.0‒8.9 1.36 (1.25e1.48) 0.309 1
9.0‒9.9 1.35 (1.20e1.53) 0.303 1
10.0 1.51 (1.35e1.68) 0.409 2
T2D has been recognized as a risk factor for CV disease since the
Albumin, g/dL (vs 4.5) original work from the Framingham Heart Study (40). However, the
<3.5 1.68 (1.50e1.88) 0.518 2 initial randomized clinical trials testing the effects of glucose-
3.5‒3.9 1.39 (1.27e1.51) 0.326 1 lowering strategies on CV outcomes were largely disappointing
Pre-existing T2D (vs newly 1.39 (1.30e1.48) 0.329 1
(13e19). Indeed, given the array of nonglycemic CV risk factors,
diagnosed)
Chloride, mmol/L (vs 104) which often accompany T2D (e.g. dyslipidemia, hypertension), the
<100 1.37 (1.28e1.47) 0.317 1 direct impact of glycemic control on CV outcomes was unclear. In
Red cell distribution width, % fact, some diabetes therapies showed evidence of CV harm,
(vs <13.0) prompting the United States Food and Drug Administration to
15.0 1.48 (1.36e1.61) 0.390 2
Male (vs female) 1.28 (1.21e1.34) 0.243 1
require inclusion of CV safety endpoints in subsequent diabetes
Alanine aminotransferase, IU/L trials (41). Thereafter, 2 new classes of diabetes therapies, SGLT2is
(vs 55) and GLP-1 RAs, demonstrated positive effects on CV outcomes, and
<13 1.41 (1.23e1.61) 0.342 1 these therapies have quickly gained prominence in guidelines and
13‒16 1.34 (1.18e1.52) 0.291 1
consensus reports as appropriate second-line therapy among
Systolic blood pressure, mmHg
(vs 110‒119) individuals with suboptimally controlled type 2 diabetes at high CV
<110 1.29 (1.15e1.44) 0.252 1 risk (42e44). Both drug classes have demonstrated benefit with
Lymphocyte, % (vs 31 to <37) respect to CV death (22,45). Notably, evidence suggests the car-
12 to <18 1.34 (1.23e1.48) 0.297 1 dioprotective properties of these drugs are unlikely due to
A1C, glycated hemoglobin; CI, confidence interval; T2D, type 2 diabetes. improved glycemic control (46,47).
 B.A. Williams et al. / Can J Diabetes xxx (2021) 1e9 7

Table 3
The cardiovascular death risk continuum

Risk points Number, % Cumulative percentile * CI 1 year CI 3 years CI 5 years CV deaths / py CV deaths per 100 py

28þ 168, 0.3% 0.3% 17.4 47.2 61.7 80 / 415 19.3

27 133, 0.2% 0.5% 11.7 38.0 57.4 71 / 384 18.5
26 174, 0.3% 0.8% 13.5 46.0 60.4 97 / 548 17.7
25 278, 0.5% 1.3% 16.5 33.4 50.7 127 / 873 14.5
24 326, 0.6% 1.8% 8.5 29.7 42.6 137 / 1,121 12.2
23 481, 0.8% 2.6% 7.2 23.2 37.5 185 / 1,899 9.7
22 539, 0.9% 3.6% 6.9 22.6 38.7 227 / 2,286 9.9
21 709, 1.2% 4.7% 5.1 14.9 29.0 257 / 3,300 7.8
20 929, 1.6% 6.3% 5.2 15.2 29.0 327 / 4,580 7.1
19 1,123, 1.9% 8.2% 3.6 11.2 20.0 337 / 6,090 5.5
18 1,283, 2.2% 10.4% 3.0 10.0 18.3 343 / 7,327 4.7
10th percentile
17 1,577, 2.7% 13.0% 2.1 7.3 12.0 398 / 10,040 4.0
16 2,022, 3.4% 16.5% 1.4 6.7 12.3 441 / 12,906 3.4
15 2,239, 3.8% 20.2% 1.0 4.0 9.3 447 / 15,523 2.9
14 2,727, 4.6% 24.8% 1.0 3.4 7.3 463 / 19,826 2.3
13 3,113, 5.3% 30.1% 0.8 2.6 5.9 455 / 23,748 1.9
25th percentile
12 3,677, 6.2% 36.3% 0.5 1.9 4.0 419 / 28,997 1.4
11 4,653, 7.9% 44.2% 0.3 1.3 2.6 374 / 37,440 1.0
10 4,970, 8.4% 52.6% 0.3 1.2 2.0 287 / 40,077 0.7
50th percentile
9 5,214, 8.8% 61.4% 0.2 0.8 1.3 176 / 41,982 0.4
8 5,209, 8.8% 70.2% 0.2 0.6 0.9 132 / 42,629 0.3
7 4,810, 8.1% 78.3% 0.1 0.5 0.9 104 / 38,412 0.3
6 4,007, 6.8% 85.1% 0.1 0.3 0.5 64 / 31,937 0.2
5 3,003, 5.1% 90.2% 0.1 0.3 0.6 46 / 23,658 0.2
4 2,064, 3.5% 93.7% 0 0.1 0.2 14 / 16,136 <0.1
3 1,353, 2.3% 96.0% 0 <0.1 0.3 11 / 10,777 0.1
2 1,187, 2.0% 98.0% 0 <0.1 0.2 10 / 9,483 0.1
1 898, 1.5% 99.5% 0 0.1 0.1 4 / 6,664 <0.1
0 314, 0.5% 100% 0 0 0 0 / 2,289 0.0

CI, cumulative incidence; py, person years.

* Percentage of patients at this risk score or higher.

Predictors of CV death Applying the CV death risk continuum

Our primary motivation for focusing exclusively on CV death
lies in its primacy as the ultimate end consequence of multiple
antecedent CV conditions, including myocardial infarction, heart
failure and stroke. Importantly, certain SGLT2is and GLP-1 RAs
have shown benefit on multiple fatal and nonfatal CV outcomes
(21,22,41). As our prediction model and risk continuum were
intentionally designed to be applicable to an “all-comers” T2D
population with no exclusions according to pre-existing condi-
tions, it is not surprising that existing CV disorders at the index
date were among the strongest predictors of CV death. The
inclusion of both primary and secondary prevention patients with
T2D creates a more heterogeneous risk distribution compared
with either alone, which partially explains the generally higher c
statistic observed in this study compared with previous
T2D-prediction models, which typically focused on primary CV
prevention (24e37). Importantly, 2 measures of glycemic burden
remained associated with CV death in the final proposed model:
pre-existing T2D and A1C. Pre-existing T2D serves as an imperfect
surrogate for diabetes duration, which was shown to be a strong
predictor of CV outcomes in earlier studies (48,49). A1C has also
been shown to be a strong predictor of CV death in a recent
study (2). More generally, our study was unique in its ability to
evaluate 33 laboratory tests that were measured in the majority of
study patients as part of usual clinical care. Notably, 7 of these
were among the top 15 predictors of CV death. Importantly, these
tests should be readily available to model implementors—either
through historic records or by new, low-cost test orders. Indeed,
more generally, development of our model using data drawn from
the EMRs of a health-care system allows straightforward transport
of the model to external organizations.
A novel contribution of this study is the mapping of the pre-
diction model’s quantitative output (i.e. the total risk score) to the
CV death risk continuum (Table 3). By developing the model in an
all-comers T2D population, the mapping allows for estimation of
the CV death risk and associated percentile ranking for any patient
with T2D. Indeed, any action provoked by the model’s output is
based on the estimated risk exceeding some “high-risk”
threshold, with the assumption that higher-risk patients receive
greater absolute benefit from risk-lowering interventions than
lower-risk patients (50). However, what constitutes as high-risk is
subject to inter-rater variability and may be context specific, thus
requiring the entire risk continuum accomodates various
high-risk definitions. A possible application of the model and risk
continuum may involve shared decision-making for prescribing
an SGLT2i or GLP-1 RA when risk is “high enough” according to the
prediction model. To provide context for our proposed risk con-
tinuum, CV death rates from recently published trials can be
referenced to Table 3. For example, in the EMPA-REG OUTCOME
(Empagliflozin Cardiovascular Outcome Event Trial in Type 2
Diabetes Mellitus Patients—Removing Excess Glucose) trial,
which enrolled patients with established CV disease, the CV death
rate in the placebo arm was 2.02 per 100 person years, an event
rate corresponding approximately to the 25th percentile (i.e. 25%
highest-risk patients) of our CV death risk continuum (45). In
contrast, the DECLARE-TIMI 58 (Dapagliflozin Effect on Cardio-
vascular Events—Thrombolysis in Myocardial Infarction 58) trial,
which enrolled patients at lower CV risk compared with EMPA-
REG, reported a CV death rate with placebo of 0.71 per 100 per-
son years, an event rate corresponding approximately to the 50th
percentile of our risk continuum (51).
8 B.A. Williams et al. / Can J Diabetes xxx (2021) 1e9
Limitations
Some limitations of our study are worth noting. EMR data,
having been collected outside the context of a research protocol, are
prone to measurement error and misclassification. CV/non-CV
death classification frequently relied on death certificates, which
are often incorrect (52). Furthermore, in many cases, determining
cause of death by chart review was hindered by absent or insuffi-
cient documentation of salient health events immediately pre-
ceding death. External validation of the proposed model would be
valuable to determine its predictive properties in an independent
data set.
In conclusion, in this study we have proposed a CV death risk
continuum applicable to an all-comers, real-world patient popu-
lation with T2D. The prediction model generating the risk contin-
uum showed strong discriminative capacity with predictors drawn
from the EMR—a feature that makes the model readily transferable
to other health-care institutions. The risk continuum enables esti-
mating the percentile rank of CV death risk across all patients with
T2D, allowing proper identification of T2D patients at highest risk
for CV death. Thus, practical application of the risk continuum may
allow for targeting of new and expensive diabetes therapies to
patients who will benefit most.
Supplementary Material
To access the supplementary material accompanying this article,
visit the online version of the Canadian Journal of Diabetes at www.
canadianjournalofdiabetes.com.
Acknowledgments
This study was funded by Boehringer Ingelheim Pharmaceuti-
cals, Inc.
Author Disclosures
B.A.W. receives research funding from Biosense Webster, Gilead,
Roche, Janssen, Novo Nordisk and Merck. S.S. and J.C. are current
employees of Boehringer Ingelheim Pharmaceuticals. P.G. is a
former employee of Boehringer Ingelheim.
Author Contributions
B.A.W. was the primary author and biostatistician. J.C.B., S.V.,
J.M.C., P.G. and S.S.S. provided valuable feedback during the various
phases of study execution. All authors reviewed and provided
comments during manuscript development.
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Supplementary Table 1 Supplementary Table 1 (continued )

Strongest predictors of cardiovascular death among patients with T2D
Predictors Hazard ratio (95% CI)
Predictors Hazard ratio (95% CI)
170‒199 1.14 (1.04e1.26)
Age, years 200‒229 1.09 (0.97e1.23)
<40 1.00 (reference) 230 1.26 (1.14e1.39)
40e49 2.05 (1.52e2.77) Heart rate, bpm
50e59 3.51 (2.65e4.66) <60 1.00 (reference)
60e69 5.90 (4.46e7.81) 60e69 1.04 (0.93e1.16)
70e79 11.50 (8.70e15.22) 70e79 1.05 (0.94e1.18)
80 24.02 (18.09e31.88) 80e89 1.15 (1.02e1.29)
Coronary artery disease 1.74 (1.64e1.85) 90 1.29 (1.13e1.48)
Heart failure 1.81 (1.69e1.94) Implantable cardioverter-defibrillator 1.65 (1.37e1.98)
Blood urea nitrogen, mg/dL Total:HDL cholesterol
<11 1.20 (1.05e1.37) <3.0 1.00 (reference)
11e12 1.16 (1.04e1.31) 3.0 to <4.0 1.02 (0.94e1.10)
13e16 1.00 (reference) 4.0 to <5.0 1.09 (1.01e1.19)
17e21 1.16 (1.07e1.25) 5.0 to <6.0 1.14 (1.04e1.25)
22e28 1.31 (1.21e1.43) 6.0 1.25 (1.13e1.38)
29 1.84 (1.68e2.01) Chest pain 0.85 (0.80e0.91)
Cerebrovascular disease 1.49 (1.39e1.58) Carbon dioxide, mEq/L
Atrial fibrillation 1.51 (1.41e1.62) <25 1.12 (1.04e1.21)
Albumin, g/dL 25e27 1.00 (reference)
<3.5 1.62 (1.44e1.81) 28e30 1.01 (0.95e1.08)
3.5e3.9 1.34 (1.23e1.46) 31 1.19 (1.10e1.29)
4.0e4.4 1.21 (1.12e1.31) Edema 1.17 (1.10e1.24)
4.5 1.00 (reference) eGFR<60 mL/min 1.17 (1.09e1.26)
Male (vs female) 1.28 (1.21e1.35)
A1C, glycated hemoglobin; CI, confidence interval; eGFR, estimated glomerular
Pre-existing T2D (vs newly diagnosed) 1.35 (1.26e1.44)
filtration rate; HDL, high-density lipoprotein; T2D, type 2 diabetes.
Red cell distribution width, %
<13.0 1.00 (ref)
13.0e13.9 1.13 (1.05e1.21)
14.0e14.9 1.22 (1.12e1.32)
15.0 1.43 (1.31e1.56)
Alanine aminotransferase, IU/L
<13 1.39 (1.22e1.59)
13e16 1.36 (1.20e1.54)
17e23 1.20 (1.06e1.35)
24e35 1.13 (1.00e1.28)
36e54 1.04 (0.91e1.19)
55 1.00 (reference)
A1C, %
<6.0 1.01 (0.93e1.10)
6.0e6.9 1.00 (reference)
7.0e7.9 1.10 (1.03e1.17)
8.0e8.9 1.32 (1.21e1.44)
9.0e9.9 1.26 (1.11e1.42)
10.0 1.34 (1.20e1.51)
Chloride, mmol/L
<100 1.29 (1.20e1.40)
100e101 1.11 (1.03e1.19)
102e103 1.03 (0.96e1.11)
104 1.00 (ref)
Systolic blood pressure, mmHg
<110 1.28 (1.14e1.43)
110e119 1.00 (ref)
120e129 1.04 (0.95e1.14)
130e139 1.05 (0.95e1.15)
140e149 1.16 (1.06e1.28)
150 1.25 (1.14e1.37)
Lymphocyte, %
<12 1.07 (0.96e1.19)
12 to <18 1.33 (1.21e1.45)
18 to <24 1.10 (1.00e1.19)
24 to <31 1.06 (0.98e1.16)
31 to <37 1.00 (reference)
37 1.07 (0.96e1.18)
Smoking status (vs never)
Current 1.31 (1.20e1.42)
Former 0.99 (0.93e1.05)
Dementia 1.48 (1.30e1.68)
Valve disease 1.23 (1.14e1.32)
Hyperlipidemia 0.85 (0.80e0.90)
Glucose, mg/dL
<110 1.16 (1.08e1.24)
110‒139 1.00 (ref)
140‒169 1.06 (0.98e1.14)
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Supplementary Table 2
Final model re-fit with all-cause mortality as outcome

Predictors Hazard ratios (95% CI)

Age, years (vs <40)

40e49 1.55 (1.33e1.81)
50e59 2.67 (2.32e3.08)
60e69 4.61 (4.02e5.30)
70e79 8.39 (7.30e9.63)
80 16.50 (14.32e19.00)
Heart failure 1.61 (1.54e1.68)
Coronary artery disease 1.26 (1.22e1.30)
Blood urea nitrogen, mg/dL (vs 13‒16)
22‒28 1.20 (1.14e1.26)
29 1.76 (1.67e1.86)
Atrial fibrillation 1.25 (1.19e1.31)
Cerebrovascular disease 1.41 (1.35e1.47)
A1C, % (vs 6.0‒6.9)
8.0‒8.9 1.21 (1.14e1.27)
9.0‒9.9 1.28 (1.18e1.38)
10.0 1.41 (1.32e1.50)
Albumin, g/dL (vs 4.5)
<3.5 1.78 (1.66e1.91)
3.5‒3.9 1.38 (1.30e1.45)
Pre-existing T2D (vs newly diagnosed) 1.28 (1.23e1.33)
Chloride, mmol/L (vs 104)
<100 1.32 (1.26e1.38)
Red cell distribution width, % (vs <13.0)
15.0 1.62 (1.53e1.70)
Male (vs female) 1.30 (1.26e1.34)
Alanine aminotransferase, IU/L (vs 55)
<13 1.32 (1.22e1.42)
13‒16 1.16 (1.08e1.25)
Systolic blood pressure, mmHg (vs 110‒119)
<110 1.25 (1.16e1.34)
Lymphocyte, % (vs 31 to <37)
12 to <18 1.28 (1.21e1.36)

A1C, glycated hemoglobin; CI, confidence interval; T2D, type 2 diabetes.