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Open access Original research

Prevalence and incidence of

microvascular and macrovascular
complications over 15 years among
patients with incident type 2 diabetes
Jaejin An ‍ ‍,1,2 Gregory A Nichols ‍ ‍,3 Lei Qian,1 Mercedes A Munis,1
Teresa N Harrison,1 Zhuoxin Li,1 Rong Wei,1 Tracey Weiss,4 Swapnil Rajpathak ‍ ‍,4
Kristi Reynolds ‍ ‍1,2

To cite: An J, Nichols GA, ABSTRACT

Qian L, et al. Prevalence and Introduction Type 2 diabetes (T2D) is a common
Significance of this study
incidence of microvascular and condition that, if left untreated or poorly managed,
macrovascular complications
can lead to adverse microvascular and macrovascular
What is already known about this subject?
over 15 years among patients ►► Type 2 diabetes (T2D) is a very common condition
complications. We estimated the prevalence and incidence
with incident type 2 diabetes. that, if left untreated or with no proper care, can
BMJ Open Diab Res Care of microvascular and macrovascular complications among
patients newly diagnosed with T2D within a US integrated contribute to the development of microvascular
2021;9:e001847. doi:10.1136/
healthcare system. and macrovascular complications. Previous studies
bmjdrc-2020-001847
Research design and methods We conducted a suggest that some T2D complications are preva-
retrospective cohort study among patients newly lent even at the time of diabetes diagnosis, such as
►► Supplemental material is diagnosed with T2D between 2003 and 2014. We chronic kidney disease (CKD).
published online only. To view, evaluated 13 complications, including chronic kidney ►► While there has been a decreasing trend of T2D
please visit the journal online disease (CKD), cardiovascular disease (CVD), and all-­cause complications, including large reductions in cardio-
(http://​dx.​doi.​org/​10.​1136/​ vascular disease (CVD), the development of micro-
mortality through 2018. Multivariable Cox proportional
bmjdrc-​2020-​001847). vascular and macrovascular complications remains
hazards models were used to study factors associated with
complications. a significant clinical concern for patients with T2D.
Some study results were Results We identified 135 199 patients with incident T2D. Peripheral arterial disease, heart failure, and stable
presented as a poster at The mean age was 58 years, and 48% were women. The angina are suggested as early cardiovascular mani-
the American Diabetes prevalence of CKD was the highest of the complications festations in patients with T2D.
Association’s 79th Scientific at the time of T2D diagnosis (prevalence=12.3%, 95%
Sessions; June 7–11, 2019; What are the new findings?
CI 12.2% to 12.5%), while the prevalence of CVD was
San Francisco, California, ►► Our findings show that a substantial proportion of
among the lowest at 3.3% (95% CI 3.2% to 3.3%). The
and at the American Diabetes patients had existing complications including CKD,
median time to incidence of a T2D complication ranged
Association 80th Scientific stable angina, and peripheral neuropathy at the time
from 3.0 to 5.2 years. High incidence rates (95% CI) of T2D
Sessions–Virtual; June 12–16, of T2D diagnosis. Results also show that among
complications included peripheral neuropathy (26.9, 95%
2020. those newly diagnosed with T2D, the highest inci-
CI 26.5 to 27.3 per 1000 person-­years (PY)), CKD (21.2,
95% CI 20.9 to 21.6 per 1000 PY), and CVD (11.9, 95% CI dence rates of complications included peripheral
Received 21 August 2020
11.7 to 12.2 per 1000 PY). The trend of 5-­year incidence neuropathy, CKD, and CVD (myocardial infarction,
Revised 6 November 2020
Accepted 29 November 2020 rates of T2D complications by diagnosis year decreased unstable angina, and stroke).
over time (p value<0.001). Older age, non-­Hispanic white ►► Time to incidence of microvascular and macrovas-
race/ethnicity, sex, higher A1C, smoking, and hypertension cular complications was only a few years; peripheral
were associated with increased CKD and CVD incidence. vascular disease, stable angina, CKD, and peripheral
Conclusion Though incidence rates of T2D complications neuropathy developed earlier in the disease course.
were lower in more recent years (2010–2014), a
significant proportion of patients had complications at T2D
© Author(s) (or their is associated with many adverse microvas-
diagnosis. Earlier preventive therapies as well as managing
employer(s)) 2021. Re-­use
modifiable factors may help delay the development and cular and macrovascular complications.2
permitted under CC BY-­NC. No
commercial re-­use. See rights progression of T2D complications. Recent changes in diabetes treatment guide-
and permissions. Published lines highlight the importance of assessing
by BMJ. common comorbidities that affect people
For numbered affiliations see INTRODUCTION with diabetes and how these may impact their
end of article. Type 2 diabetes (T2D) is a common condition diabetes treatment choices.3 4 With newer
Correspondence to
affecting approximately 463 million adults treatment options, patients with T2D may be
Dr Jaejin An; globally in 2019.1 Treatment and manage- able to slow the development and progres-
​jaejin.​x.​an@​kp.​org ment of T2D is critical since the condition sion of microvascular or macrovascular

BMJ Open Diab Res Care 2021;9:e001847. doi:10.1136/bmjdrc-2020-001847 1

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Epidemiology/Health services research

METHODS
Significance of this study
Study setting
How might these results change the focus of research or We conducted an observational retrospective cohort
clinical practice? study using data obtained from administrative and elec-
►► Understanding when complications develop following diagnosis tronic health records (EHRs) of Kaiser Permanente
and the prevalence of common diabetes complications and risk Southern California (KPSC), a large US-­ integrated
factors at the time of diagnosis may further guide screening and healthcare delivery system. KPSC currently serves approx-
treatment decisions. imately 4.6 million members. KPSC provides medical
►► Findings also support the changes to the American Diabetes services to its members through its own facilities, which
Association and the European Society Cardiology treatment guide- include 15 hospitals, more than 200 outpatient facilities
lines, which emphasize the importance of ongoing risk assessment and a centralized laboratory. All clinical care and interac-
and comprehensive medical evaluations of comorbidities and com- tions with the healthcare delivery system are captured in
plications to best decide on the appropriate treatment plan. comprehensive EHRs.

Study population and study period

complications, such as chronic kidney disease (CKD) and We identified KPSC members aged ≥20 years with incident
cardiovascular disease (CVD).5 T2D between January 1, 2003 and December 31, 2014,
Despite the importance of comorbidities of T2D, using a validated algorithm14 that incorporated inpatient,
there is a lack of evidence describing the natural emergency, ambulatory care, laboratory and pharmacy
progression of T2D, the prevalence and the long-­term data in EHRs. We defined the first date the algorithm
development of diabetes complications over time in a criteria were met as the date of diagnosis (index date).
large contemporary cohort of T2D. A few US studies We required patients to have a minimum of 2 years of
continuous KPSC membership and a prescription drug
showed a decreasing trend of T2D complications over
benefit prior to the index date to minimize the likeli-
the last few decades with large reductions in myocar-
hood that patients with pre-­existing diabetes entered the
dial infarction (MI) and stroke in older adults.6–8
cohort. We excluded patients who had a prior history of
Recent studies from Europe reported a similar trend,9
any form of diabetes, had a missing date of birth, or who
and heart failure and peripheral arterial disease were were in hospice or a skilled nursing facility in the 1 year
suggested as the most common early cardiovascular prior to the index date.
manifestations.10 11 We used the baseline period of 2 years before and
In addition to the development of new diabetes 6 months after the index date (a total of 2.5 years) to
complications, recent studies suggest that a substantial collect baseline patient demographic and clinical char-
proportion of patients with T2D already have diabetes acteristics. We included 6 months after the index date
complications at the time of diabetes diagnosis. Gatwood in the baseline period to allow for screening of diabetes
et al reported that more than 30% of veterans had CKD complications. Patients were followed from 6 months
prior to being diagnosed with diabetes.12 While previous after the index date until the outcome of interest, study
studies from various countries investigated the preva- end date (June 30, 2018), end of membership, or death,
lence of T2D complications,13 many studies investigated whichever occurred first. The incidence of each micro-
the prevalence of complications cross-­ sectionally and vascular or macrovascular complication was evaluated
reported only a limited number of complications, or the among patients at risk.
timing of prevalence was not specifically at or from the
time of T2D diagnosis. Demographics and clinical characteristics
An understanding of when complications develop Age, sex, race/ethnicity, insurance type, body mass index
following diagnosis during a long-­term follow-­up and the (BMI), and smoking history were extracted from the
prevalence of common diabetes complications and risk EHR. Baseline laboratory measures (A1C, fasting plasma
glucose (FPG), and lipid levels), medication use (anti-
factors at the time of diagnosis in a large contemporary
hyperglycemic agents, antihypertensive agents, other
T2D cohort may further guide screening and treatment
cardiovascular medications, and other concomitant
decisions.
medications), comorbidities (hypertension, hyperlipid-
Accordingly, in this study, we aimed to (1) estimate emia, and the Charlson Comorbidity score), and health-
the prevalence of microvascular and macrovascular care use (inpatient stays and outpatient and emergency
complications among patients with incident T2D at the department visits) were obtained from EHRs.
time of diabetes diagnosis, (2) estimate the incidence of
microvascular and macrovascular complications over 15 Microvascular and macrovascular complications
years stratified by age, sex, race/ethnicity, and diabetes We evaluated 13 microvascular and macrovascular
diagnosis year, and (3) investigate modifiable risk complications commonly associated with T2D: MI,
factors associated with microvascular and macrovascular unstable angina, stroke, composite CVD (including MI,
complications. unstable angina, and stroke), heart failure, stable angina,

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Epidemiology/Health services research

peripheral vascular disease, lower extremity amputa- (index date), 44.3% initiated monotherapy and 3.3%
tion, CKD, end-­ stage kidney disease (ESKD), prolifer- initiated dual therapy, while 52.3% did not initiate any
ative diabetic retinopathy, peripheral neuropathy, and antihyperglycemic agents. Use of other cardiovascular
all-­cause mortality. All outcomes were identified from a medication, such as statins, increased over time from
combination of primary inpatient, outpatient, and emer- 28.3% in 2003–2005 to 36.1% in 2012–2014. A higher
gency department diagnosis codes using the International percentage of patients had comorbidities other than T2D
Classification of Diseases 9th Revision and 10th Revision codes in earlier years than in later years (≥2 Charlson Comor-
or procedure codes (Current Procedural Technology, Fourth bidity score: 67.0% in 2003–2005 vs 51.1% in 2012–2014).
Edition) except for CKD, ESKD and all-­cause mortality. A higher percentage of patients had one or more inpa-
CKD was defined as two or more estimated glomer- tient and emergency department visits in 2003–2005 than
ular filtration rate (eGFR) levels<60 mL/min/1.73 m2 in 2012–2014.
at least 90 days apart by applying the Chronic Kidney
Disease Epidemiology Collaboration equation to serum Prevalence of microvascular and macrovascular
creatinine values. ESKD was defined as initiation of complications at diagnosis
chronic dialysis or kidney transplant identified from the The prevalence of CKD was the most common compli-
KPSC ESKD registry. Mortality was identified from KPSC cation at the time of T2D diagnosis (prevalence=12.3%,
hospital or administrative records, or state or federal 95% CI 12.2% to 12.5%) followed by stable angina (4.6%,
mortality files.15 A definition of each microvascular and 95% CI 4.4% to 4.7%), peripheral neuropathy (3.8%,
macrovascular complication is listed in online supple- 95% CI 3.7% to 3.9%), and heart failure (3.5% 95% CI
mental table S1. 3.4% to 3.6%) (table 2). At T2D diagnosis, the preva-
Statistical analysis lence of CVD was 3.3% (94% CI 3.2% to 3.3%), while the
Descriptive statistics were used to summarize baseline prevalence of lower extremity amputation, proliferative
patient demographics and clinical characteristics for diabetic retinopathy, and ESKD was less than 1%.
the overall population and to estimate the prevalence
of microvascular and macrovascular complications. The Incidence of microvascular and macrovascular complications
T2D complications identified during the 2.5-­year base- Complications with the highest incidence rates included
line period were defined as prevalent cases. peripheral neuropathy (26.9, 95% CI 26.5 to 27.3 per
All complications identified during the follow-­ up 1000 person-­years), CKD (21.2, 95% CI 20.9 to 21.6 per
period were defined as incident cases. All analyses investi- 1000 person-­years), CVD (11.9, 95% CI 11.7 to 12.2 per
gating incidence of complications were conducted among 1000 person-­years), stable angina (7.1, 95% CI 7.0 to 7.3
patients at risk. The cumulative incidence of microvas- per 1000 person-­years), and heart failure (7.1, 95% CI 6.9
cular and macrovascular complications was estimated to 7.3 per 1000 person-­years) (table 2). The median time
using Kaplan-­Meier survival analysis. The incidence rates to incidence of a diabetes complication ranged from 3.0
per 1000 person-­years were estimated using generalized to 5.2 years. The median time to incidence was shorter
linear regression with Poisson errors. Further stratified for peripheral vascular disease (3.0 years), stable angina
analyses of cumulative incidence were conducted by age, (3.0 years), CKD (3.2 years), and peripheral neuropathy
sex, and race/ethnicity. The yearly trend of incidence (3.3 years) compared with lower extremity amputation
rates of 2 and 5 years were investigated by T2D diagnosis (5.2 years) and ESKD (5.0 years).
year. Multivariable Cox proportional hazards models
were used to investigate baseline factors associated with Incidence of microvascular and macrovascular complications
CKD and CVD outcomes, the major outcomes of T2D stratified by age, sex, and race/ethnicity
clinical trials.5 When stratified by age, a higher cumulative incidence
of CKD was observed in older patients (60.6% for age
RESULTS 80+ years, 45.8% for age 65–79 years at 13 years) versus
We identified 135 199 patients with incident T2D. Mean younger patients (19.6% for age 45–64 years, 5.2% for
(SD) age was 57.8 (13.2) years old; 48% were women; age 20–44 years at 13 years). The findings were consis-
36% were non-­Hispanic white; 35% were Hispanic; 13% tent for CVD (45.6% for age 80+ years, 25.0% for age
were non-­Hispanic Asians; and 12% non-­Hispanic black. 65–79 years, 11.3% for age 45–64 years, 5.3% for age
About 20% of patients were considered extremely obese 20–44 years at 13 years) and all-­cause mortality (86.9%
(BMI≥35 kg/m2), and 21% were obese (BMI 30.0–34.9 for age 80+ years, 41.3% for age 65–79 years, 11.8%
kg/m2) (table 1). for 45–64 years, 3.7% for age 20–44 years at 13 years)
(figure 1). The cumulative incidence of CKD rapidly
Diabetes detection, treatment, and comorbidities over time increased in the years immediately following diagnosis
A higher percentage of patients had documented FPG especially among older patients. Men had a higher
testing at baseline in earlier years (2003–2005), whereas cumulative incidence of CVD than women, whereas
a higher percentage of patients had A1C testing in later women had a higher cumulative incidence of CKD
years (2012–2014) (table 1). Within 6 months of diagnosis compared with men. Non-­Hispanic white patients had

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 BMJ Open Diab Res Care: first published as 10.1136/bmjdrc-2020-001847 on 4 January 2021. Downloaded from http://drc.bmj.com/ on November 13, 2023 by guest. Protected by copyright.
Epidemiology/Health services research

Table 1 Baseline characteristics of incident type 2 diabetes over time

Index years
Total 2003–2005 2006–2008 2009–2011 2012–2014
Characteristics (N=135 199) (n=32 150) (n=33 377) (n=35 980) (n=33 692)

Age at index (years) 57.8 (13.2) 58.3 (13.5) 57.5 (13.3) 57.8 (13.1) 57.5 (13.2)
 20–39 11 387 (8.4) 2568 (8.0) 2851 (8.5) 3018 (8.4) 2950 (8.8)
 40–49 25 372 (18.8) 6079 (18.9) 6558 (19.6) 6582 (18.3) 6153 (18.3)
 50–59 38 999 (28.8) 9007 (28) 9748 (29.2) 10 450 (29.0) 9794 (29.1)
 60–69 32 730 (24.2) 7441 (23.1) 7671 (23.0) 9002 (25.0) 8616 (25.6)
 70–79 19 219 (14.2) 4919 (15.3) 4682 (14.0) 5067 (14.1) 4551 (13.5)
 80+ 7492 (5.5) 2136 (6.6) 1867 (5.6) 1861 (5.2) 1628 (4.8)
Women 64 347 (47.6) 15 007 (46.7) 15 636 (46.8) 17 209 (47.8) 16 495 (49.0)
Race/ethnicity
 Non-­Hispanic white 48 629 (36.0) 12 813 (39.9) 12 699 (38.0) 12 596 (35.0) 10 521 (31.2)
 Hispanic 47 121 (34.9) 9714 (30.2) 11 321 (33.9) 13 164 (36.6) 12 922 (38.4)
 Non-­Hispanic Asian 16 874 (12.5) 3152 (9.8) 3714 (11.1) 4932 (13.7) 5076 (15.1)
 Non-­Hispanic black 16 809 (12.4) 4106 (12.8) 3962 (11.9) 4302 (12.0) 4439 (13.2)
 Other/unknown 5766 (4.3) 2365 (7.4) 1681 (5.0) 986 (2.7) 734 (2.2)
Insurance type
 Commercial 93 367 (69.1) 21 400 (66.6) 23 208 (69.5) 25 051 (69.6) 23 708 (70.4)
 Medicare 36 547 (27) 9412 (29.3) 8730 (26.2) 9599 (26.7) 8806 (26.1)
 Others (Medicaid, private pay) 5285 (3.9) 1338 (4.2) 1439 (4.3) 1330 (3.7) 1178 (3.5)
BMI (kg/m2)* 32.1 (7.0) 31.5 (7.2) 31.9 (7.0) 32.1 (6.9) 32.4 (7.1)
 <25 12 074 (8.9) 371 (1.2) 3442 (10.3) 4342 (12.1) 3919 (11.6)
 25.0–29.9 30 276 (22.4) 732 (2.3) 8193 (24.5) 11 270 (31.3) 10 081 (29.9)
 30.0–34.9 27 667 (20.5) 585 (1.8) 7183 (21.5) 10 351 (28.8) 9548 (28.3)
 35+ 27 580 (20.4) 603 (1.9) 7071 (21.2) 9884 (27.5) 10 022 (29.7)
 Missing 37 602 (27.8) 29 859 (92.9) 7488 (22.4) 133 (0.4) 122 (0.4)
Smoking status*
 Current 12 992 (9.6) 3112 (9.7) 3533 (10.6) 3483 (9.7) 2864 (8.5)
 Former 34 690 (25.7) 6096 (19) 8280 (24.8) 10 627 (29.5) 9687 (28.8)
 Never 82 803 (61.2) 18 742 (58.3) 21 153 (63.4) 21 815 (60.6) 21 093 (62.6)
 Missing 4714 (3.5) 4200 (13.0) 411 (1.2) 55 (0.1) 48 (0.1)
Hemoglobin A1C* 7.7 (2.1) 7.5 (2.2) 7.8 (2.2) 7.7 (2.0) 7.6 (1.9)
 Missing 18 164 (13.4) 5767 (17.9) 5717 (17.1) 4399 (12.2) 2281 (6.8)
Fasting plasma glucose* 150.3 (60.6) 157.3 (62.3) 156.2 (62.6) 149.2 (59.7) 138.2 (55.4)
 Missing 20 421 (15.1) 5229 (16.3) 4196 (12.6) 3998 (11.1) 6998 (20.8)
Number of antihyperglycemic agent†
 None 70 746 (52.3) 17 614 (54.8) 16 213 (48.6) 18 253 (50.7) 18 666 (55.4)
 1 59 850 (44.3) 13 548 (42.1) 15 655 (46.9) 16 581 (46.1) 14 066 (41.7)
 2 4449 (3.3) 953 (3) 1461 (4.4) 1110 (3.1) 925 (2.7)
 3+ 154 (0.1) 35 (0.1) 48 (0.1) 36 (0.1) 35 (0.1)
Other cardiovascular medications‡ 44 772 (33.1) 9101 (28.3) 10 608 (31.8) 12 907 (35.9) 12 156 (36.1)
Hypertension 84 565 (62.5) 19 700 (61.3) 22 021 (66) 22 830 (63.5) 20 014 (59.4)
Hyperlipidemia 90 541 (67.0) 17 951 (55.8) 22 625 (67.8) 26 243 (72.9) 23 722 (70.4)
Lipid levels (mg/dL)*
 Total cholesterol 200.4 (49.5) 210.3 (50.4) 204.1 (51.0) 197.7 (48.2) 190.4 (46.4)
 LDL-­C 116.8 (37.7) 123.1 (37.8) 119.0 (37.4) 114.8 (37.5) 111.0 (37.0)
 HDL-­C 45.4 (12.1) 45.8 (13.0) 44.5 (11.8) 45.9 (11.9) 45.6 (11.7)
 Triglycerides 205.9 (224.1) 225.8 (257.2) 211.1 (244.3) 198.3 (201.6) 191.4 (191.1)

Continued

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Epidemiology/Health services research

Table 1 Continued
Index years
Total 2003–2005 2006–2008 2009–2011 2012–2014
Characteristics (N=135 199) (n=32 150) (n=33 377) (n=35 980) (n=33 692)
2
eGFR (mL/min/1.73 m )* 84.5 (22.4) 84.5 (23.8) 82.6 (22.6) 84.8 (21.6) 86.1 (21.3)
 <60 18 072 (13.4) 4598 (14.3) 5128 (15.4) 4520 (12.6) 3826 (11.4)
 60–89 54 209 (40.1) 12 226 (38) 13 752 (41.2) 14 836 (41.2) 13 395 (39.8)
 90+ 59 277 (43.8) 13 982 (43.5) 13 603 (40.8) 15 854 (44.1) 15 838 (47)
 Missing 3641 (2.7) 1344 (4.2) 894 (2.7%) 770 (2.1%) 633 (1.9%)
Charlson Comorbidity Score
 1 55 609 (41.1) 10 628 (33.1) 10 668 (32) 17 824 (49.5) 16 489 (48.9)
 2 37 848 (28.0) 10 888 (33.9) 9132 (27.4) 9143 (25.4) 8685 (25.8)
 3+ 41 742 (30.9) 10 634 (33.1) 13 577 (40.7) 9013 (25.1) 8518 (25.3)
Healthcare use
Inpatient visits§
 None 118 870 (87.9) 27 787 (86.4) 29 237 (87.6) 31 768 (88.3) 30 078 (89.3)
 1–2 14 187 (10.5) 3734 (11.6) 3559 (10.7) 3709 (10.3) 3185 (9.5)
 3+ 2142 (1.6) 629 (2.0) 581 (1.7) 503 (1.4) 429 (1.3)
Outpatient visits§
 None 7226 (5.3) 1770 (5.5) 1954 (5.9) 1846 (5.1) 1656 (4.9)
 1–4 37 037 (27.4) 8403 (26.1) 9335 (28.0) 9956 (27.7) 9343 (27.7)
 5–11 44 125 (32.6) 11 339 (35.3) 11 201 (33.6) 12 369 (34.4) 11 902 (35.3)
 12+ 46 811 (34.6) 10 638 (33.1) 10 887 (32.6) 11 809 (32.8) 10 791 (32.0)
Emergency department visits§
 None 96 747 (71.6) 21 869 (68) 24 220 (72.6) 26 109 (72.6) 24 549 (72.9)
 1–2 32 303 (23.9) 8466 (26.3) 7750 (23.2) 8477 (23.6) 7610 (22.6)
 3+ 6149 (4.5) 1815 (5.6) 1407 (4.2) 1394 (3.9) 1533 (4.6)

Data is either n (%) or mean (SD).

*Closest to the index date.
†On or 6 months after the index date.
‡6 months before index date.
§2 years prior to the index date; other variables were determined using the 2.5 years of baseline data.
BMI, body mass index; eGFR, estimated glomerular filtration rate; HDL-­C, high-­density lipoprotein cholesterol; LDL-­C, low-­density lipoprotein cholesterol.

the highest cumulative incidence of CVD and CKD, and Trends of incidence rates of microvascular and
the highest all-­cause mortality followed by non-­Hispanic macrovascular complications by diagnosis year
black patients. The incidence rates of complications of 2 and 5 years were
The cumulative incidence of other complications aside investigated by diabetes diagnosis year. Lower incidence rates
from CKD, CVD, and all-­cause mortality is shown in online of CKD and CVD were observed among patients diagnosed
supplemental table S2. The cumulative incidence of the with diabetes in later years (2013–2014) compared with
other complications was higher in older patients versus earlier years (2003–2004), and the mortality rates were lower
younger patients; however, the differences between age in later years as well (figures 2 and 3). These lower trends
groups were smaller for lower extremity amputation, of event rates in later diagnosis years were observed for all
ESKD, and peripheral neuropathy. The cumulative inci- complications (online supplemental table S3).
dence of proliferative diabetic retinopathy was higher in
younger patients compared with older patients. Men had Modifiable factors associated with microvascular and
higher cumulative incidence of most of the complications, macrovascular complications
including stroke and ESKD than women, but the differ- Several modifiable factors were associated with CKD and/or
ences were less than 0.5% for these two complications. CVD (online supplemental table S4). Smoking status (HR of
The cumulative incidence of ESKD was highest among current smoker vs never smoked=1.17, 95% CI 1.10 to 1.24),
non-­Hispanic black patients followed by non-­Hispanic a higher number of comorbidities (HR of 4 or more comor-
Asian patients. The cumulative incidence of proliferative bidities vs diabetes alone=1.55, 95% CI 1.47 to 1.64), hyper-
diabetic retinopathy was the highest among Hispanic tension (HR of hypertension vs no hypertension=1.60, 95%
patients followed by non-­Hispanic black patients. CI 1.53 to 1.67), and a higher baseline A1C (HR of A1C≥8%

BMJ Open Diab Res Care 2021;9:e001847. doi:10.1136/bmjdrc-2020-001847 5

 6
Table 2 Prevalence and incidence of microvascular and macrovascular complications (N=135 199)
(A) Microvascular
complications and Chronic kidney End-­stage kidney Proliferative diabetic Lower extremity
all-­cause mortality disease disease retinopathy Peripheral neuropathy amputation All-­cause mortality

Prevalent cases, N 16 659 259 444 5115 155 –

Prevalence (%) (95% CI) 12.3 (12.2 to 12.5) 0.5 (0.5 to 0.6) 0.3 (0.3 to 0.4) 3.8 (3.7 to 3.9) 0.1 (0.1 to 0.1) –
Patients at risk,* N 118 540 134 940 134 755 130 084 135 044 135 199
Incident cases, N 14 609 870 1353 19 957 554 16 401
Total person-­years 688 542 860 683 859 390 741 744 865 641 866 591
Incidence rate per 1000 person-­ 21.2 (20.9 to 21.6) 1.0 (1.0 to 1.1) 1.6 (1.5 to 1.7) 26.9 (26.5 to 27.3) 0.6 (0.6 to 0.7) 18.9 (18.6 to 19.2)
years (95% CI)
Median time to incidence 3.2 5.0 3.8 3.3 5.2 4.5
Median time to follow-­up 5.3 5.9 5.9 5.2 6.0 6.0
Cumulative incidence (%) (95% CI)          
 Time (years)            
 2 4.6 (4.5 to 4.7) 0.2 (0.1 to 0.2) 0.3 (0.3 to 0.4) 5.6 (5.4 to 5.7) 0.1 (0.1 to 0.1) 3.3 (3.2 to 3.4)
Epidemiology/Health services research

 5 10.1 (9.9 to 10.3) 0.4 (0.4 to 0.4) 0.73 (0.7 to 0.8) 12.6 (12.4 to 12.8) 0.2 (0.2 to 0.3) 7.9 (7.7 to 8.0)
 10 19.0 (18.7 to 19.4) 1.1 (1.0 to 1.1) 1.5 (1.5 to 1.6) 23.4 (23.0 to 23.7) 0.7 (0.6 to 0.8) 17.7 (17.4 to 18.0)
 13 24.0 (23.5 to 24.5) 1.7 (1.5 to 1.8) 2.2 (2.0 to 2.4) 29.9 (29.4 to 30.4) 1.0 (0.9 to 1.1) 24.7 (24.2 to 25.1)
 15 25.4 (24.9 to 26.0) 2.0 (1.8 to 2.2) 2.9 (2.3 to 3.6) 33.4 (32.6 to 34.1) 1.3 (1.0 to 1.6) 30.0 (29.1 to 30.8)
(B) Macrovascular Myocardial infarction Unstable angina Stroke Composite cardiovascular Heart failure Stable angina Peripheral vascular
complications disease disease
Prevalent cases, N 1713 1504 1635 4388 4717 6150 2958
Prevalence, % (95% CI) 1.3 (1.2 to 1.3) 1.1 (1.1 to 1.2) 1.2 (1.2 to 1.3) 3.3 (3.2 to 3.3) 3.5 (3.4 to 3.6) 4.6 (4.4 to 4.7) 2.2 (2.1 to 2.3)
Patients at-­risk,* N 133 486 133 695 133 564 130 811 130 482 129 049 132 241
Incident cases, N 3519 2597 5578 9645 5846 5714 3967
Total person-­years 846 149 846 776 843 872 809 482 823 805 801 065 830 215
Incidence rate per 1000 person-­ 4.2 (4.0 to 4.3) 3.1 (3.0 to 3.2) 6.6 (6.4 to 6.8) 11.9 (11.7 to 12.2) 7.1 (6.9 to 7.3) 7.1 (7.0 to 7.3) 4.8 (4.6 to 4.9)
years (95% CI)
Median time to incidence 4.0 3.3 4.4 3.9 4.3 3.0 3.0
Median time to follow-­up 5.9 5.9 5.9 5.7 5.9 5.7 5.8
Cumulative Incidence (%) (95%            
CI)
 Time (years)            
 2 0.8 (0.8 to 0.9) 0.7 (0.7 to 0.8) 1.1 (1.1 to 1.2) 2.4 (2.3 to 2.5) 1.3 (1.3 to 1.4) 1.9 (1.8 to 1.9) 1.2 (1.1 to 1.3)
 5 1.9 (1.8 to 2.0) 1.6 (1.5 to 1.7) 2.9 (2.8 to 3.0) 5.4 (5.3 to 5.6) 3.1 (3.0 to 3.2) 3.6 (3.5 to 3.7) 2.6 (2.5 to 2.7)
 10 4.0 (3.9 to 4.2) 2.9 (2.8 to 3.0) 6.5 (6.3 to 6.7) 11.2 (11.0 to 11.5) 7.0 (6.8 to 7.2) 6.4 (6.2 to 6.6) 4.6 (4.4 to 4.8)

 13 5.8 (5.6 to 6.1) 3.8 (3.7 to 4.0) 9.4 (9.0 to 9.7) 15.5 (15.1 to 15.9) 9.9 (9.5 to 10.2) 8.6 (8.3 to 8.9) 5.2 (5.0 to 5.4)
 15 7.6 (6.9 to 8.3) 4.3 (4.0 to 4.6) 11.2 (10.7 to 11.8) 18.6 (17.8 to 19.5) 11.5 (11.0 to 12.0) 10.6 (9.8 to 11.4) 5.4 (5.2 to 5.7)

*Patients after excluding each prevalent complication.

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Epidemiology/Health services research

Figure 1 Cumulative incidence of type 2 diabetes complications stratified by age, sex, and race/ethnicity.

vs <8%=1.46, 95% CI 1.40 to 1.53) were associated with a and high baseline A1C (HR of A1C≥8% vs <8%=1.19, 95%
higher risk of CKD. These factors were also associated with CI 1.13 to 1.26).
CVD outcomes: smoking status (HR of current smoker vs
never smoked=1.60, 95% CI 1.50 to 1.72), a higher number
of comorbidities (HR of 4 or more comorbidities vs diabetes DISCUSSION
alone=2.30, 95% CI 2.16 to 2.46), hypertension (HR of Using data from a large US integrated healthcare system,
hypertension vs no hypertension=1.33, 95% CI 1.26 to 1.41), this study estimated the prevalence and incidence of

Figure 2 2 Year incidence rates by type 2 diabetes diagnosis year. CKD, chronic kidney disease; CVD, cardiovascular
disease.

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Epidemiology/Health services research

Figure 3 5-­Year incidence rates by type 2 diabetes diagnosis year. CKD, chronic kidney disease; CVD, cardiovascular

microvascular and macrovascular complications over 15 and consistent with previous US and European studies
years among patients with newly diagnosed T2D. This showing a decreasing trend of diabetes complications
study demonstrated that a substantial proportion of in patients with T2D.6–9 Improvements in risk factor
patients had existing complications, especially CKD, at control, including better blood pressure control with
the time of T2D diagnosis. Although the incidence of more ACE inhibitor use, better lipid control with more
microvascular and macrovascular complications signifi- statin use, and more stringent glycemic control, may be
cantly decreased among patients diagnosed with T2D responsible.16
more recently, the time to incidence of these complica- The study results provide further insights into the
tions was still only a few years, suggesting the need for timing of microvascular and macrovascular complica-
earlier preventive therapies.3 tions among patients with incident T2D. Among patients
The current study showed that about 12% of patients at risk, the median time to incidence of diabetes compli-
had CKD at the time of T2D diagnosis. In addition, 40% cations was only 3–5 years. These findings are consistent
had mild reduction in eGFR (60–89 mL/min/1.73 m2). with recent multinational and UK studies investigating a
The prevalence of stable angina, peripheral neuropathy, large cohort of patients with T2D. Some of the earlier
heart failure, and CVD was high, with 3%–4% for each complications included peripheral vascular disease,
compared with other conditions. This high prevalence of stable angina, CKD, and peripheral neuropathy. These
microvascular and macrovascular complications can be a findings suggest the need for at least annual screening
result of hyperglycemia progression even before the clin- for these complications beginning at T2D diagnosis.
ical diagnosis of diabetes, but organ damage caused by These are in line with guideline recommendations from
the presence of other comorbidities may also play a role. the American Diabetes Association and the European
To help delay the progression of diabetes complications Society Cardiology, which emphasize the importance
further, the study findings suggest some patients may of ongoing risk assessment and comprehensive medical
benefit from earlier introduction of therapies that have evaluations of comorbidities and complications to
been shown to reduce complication risk. For example, achieve patient health goals.3 4 In addition, earlier initi-
newer treatment options for T2D such as sodium– ation of preventive therapies with individualized treat-
glucose transport protein 2 inhibitors and glucagon-­like ment options based on the risk of diabetes complications
peptide 1 receptor agonists have been shown to reduce may help further delay the progression of microvascular
CVD risk and to slow the progression of kidney disease.5 and macrovascular complications for high-­risk patients,
These agents may be appropriate first-­ line therapies such as those aged >65 years or with comorbidities. For
among those with prevalent diabetes complications or in lower-­risk groups such as those aged <65 years or without
older populations (>65 years) due to the relatively rapid comorbidities at diagnosis, it may be appropriate to save
increase in incidence of these complications in that newer treatment options for later use in the disease
population. course as our data show that these complications develop
The current study showed that patients diagnosed with gradually over time.
T2D in more recent years (2012–2014) were at lower The current study results confirm that the cumulative
risk of microvascular and macrovascular complications incidence of diabetes complications differed by age, sex,
compared with patients diagnosed with diabetes in earlier and race/ethnicity. Consistent with other literature,17 18
years (2003–2005). These findings are encouraging the incidence of CVD and CKD was significantly higher

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Epidemiology/Health services research

in older adults than young adults. However, younger This study has several strengths and limitations. The
patients with T2D had similar cumulative incidence current study used a large and ethnically diverse contem-
of lower extremity amputation, ESKD, and peripheral porary population of patients with T2D with long-­term
neuropathy, and had a higher cumulative incidence of follow-­up up to 15 years. We investigated a comprehen-
proliferative diabetic retinopathy compared with older sive list of diabetes complications using EHRs. However,
patients. This may be due to higher baseline A1C levels, we investigated each complication in a separate at-­risk
poor glycemic control over time, and poor adherence population to estimate the incidence of diabetes compli-
to regular eye exams in younger patients.12–14 Treating cations. Patients may have multiple complications or
younger patients earlier and more intensively may be may have developed multiple complications over time,
important to reduce lifetime risk for these complications. but we did not investigate the natural progression of
Moreover, this study showed that women with T2D are at multiple diabetes complications or how they may relate
higher risk of CKD than men, whereas men are at higher to one another. Although the treatment of T2D may have
risk of CVD than women. These findings are generally in affected the incidence rates of diabetes complications,
line with other study findings from various countries.19–21 we did not account for diabetes therapy in our analyses.
The role of sex in the development of CKD is complex,22 As in other observational studies, there may be poten-
and limited evidence currently exists for sex differences tial measurement bias to estimate the incidence rates of
in CKD among patients with T2D. Future studies of the diabetes complications. Although this study used previ-
comparative impact of risk factors on CKD among men ously validated algorithms to identify incident T2D and
and women are needed. to define a comprehensive list of diabetes complications,
We found racial/ethnic disparities of diabetes compli- validation studies for some complications such as stable
cations. Consistent with previous studies, we found angina were not available. Lastly, this study was conducted
racial/ethnic minorities are disproportionately affected in a single healthcare system among insured population,
by microvascular complications associated with T2D. The therefore, the incidence rates of diabetes complications
cumulative incidence of ESKD was the highest among in other populations may be different.
non-­Hispanic black patients followed by non-­Hispanic
Asian patients.23 Also, the cumulative incidence of prolif-
erative diabetic retinopathy was the highest among CONCLUSION
Hispanic patients followed by non-­ Hispanic blacks Patients with T2D diagnosed in recent years are at lower
patients, again similar to a previous study.24 For macrovas- risk of diabetes complications; however, a significant
cular complications, non-­Hispanic whites patients are at proportion of patients already have microvascular and
a higher risk of CVD than other race/ethnicities, consis- macrovascular complications at the time of diagnosis.
tent with other study findings.23 While the consistency of The time to incidence of these complications was only
these study findings relative to other published data is a few years, suggesting the need for earlier and strategic
reassuring, some of our study findings are not necessarily initiation of T2D therapy. Modifiable factors associated
the same as those of previous studies, such as a higher with T2D complications, such as higher A1C, smoking,
mortality among non-­Hispanic white patients compared and hypertension, should be a focus of care management.
with other race/ethnicities.25 It is important to note that
our study shows cumulative incidence of diabetes compli- Author affiliations
1
Research and Evaluation, Kaiser Permanente Southern California, Pasadena,
cations by race/ethnicity not adjusting for other demo- California, USA
graphic, biological, behavior, and socioeconomic factors; 2
Department of Health Systems Science, Kaiser Permanente Bernard J. Tyson
therefore, the results should be interpreted with caution. School of Medicine, Pasadena, California, USA
3
Aside from older age, race/ethnicity, and sex, several 4
Center for Health Research, Kaiser Permanente Northwest, Portland, Oregon, USA
modifiable factors were associated with both CKD and Center for Observational and Real World Evidence, Merck & Co., Inc, Kenilworth,
New Jersey, USA
CVD outcomes, including smoking status and hyperten-
sion. Our study findings also showed the increased risk of Contributors JA contributed to the study design and interpretation of study
diabetes complications associated with higher A1C levels findings, and drafted the manuscript for publication. GAN, LQ, TNH, and MAM
at the time of T2D, which are consistent with recent find- contributed to the conception, study design, and interpretation of study findings,
ings.26 Our results underscore the importance of earlier and significantly revised the manuscript. ZL and RW performed all data extraction
and analyses and participated in data analysis planning, interpretation of study
identification of T2D and aggressive A1C control earlier findings, and revising the manuscript. TW and SR contributed to the conception
in the disease course. Somewhat alarmingly, less than and interpretation of data, and revised the manuscript. KR contributed to the
50% of the study population initiated antihyperglycemic conception and oversaw the study design, interpretation of data, and revision of the
agents within 6 months of their T2D diagnosis. Previous manuscript. All authors read and approved the final manuscript. JA is the guarantor
of this work and, as such, had full access to all the data in the study and takes
studies have demonstrated that delays in therapy initia- responsibility for the integrity of the data and the accuracy of the data analysis.
tion are associated with poorer glycemic control, reduced
Funding Funding for this research was provided by Merck Sharp & Dohme Corp.,
therapy durability, and greater complication risk inde- a subsidiary of Merck & Co., Inc., Kenilworth, New Jersey, USA.
pendent of baseline A1C.27 28 Future studies identifying Competing interests JA and KR are employees of Kaiser Permanente Southern
barriers of early treatment initiation may help to better California, and GAN is an employee of Kaiser Permanente Northwest, who received
address these gaps. funding through their institutions from Merck & Co., Inc., for the conduct of this

BMJ Open Diab Res Care 2021;9:e001847. doi:10.1136/bmjdrc-2020-001847 9

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Epidemiology/Health services research

study. TW and SR are employees of Merck Sharp & Dohme Corp., a subsidiary of 8 Bethel MA, Sloan FA, Belsky D, et al. Longitudinal incidence and
Merck & Co., Inc., Kenilworth, New Jersey, USA. prevalence of adverse outcomes of diabetes mellitus in elderly
patients. Arch Intern Med 2007;167:921–7.
Patient consent for publication Not required. 9 McAllister DA, Read SH, Kerssens J, et al. Incidence of
Ethics approval The study was approved by the Kaiser Permanente Southern hospitalization for heart failure and case-­fatality among 3.25
million people with and without diabetes mellitus. Circulation
California institutional review committee (#11616) and informed consent was
2018;138:2774–86.
waived. 10 Shah AD, Langenberg C, Rapsomaniki E, et al. Type 2 diabetes and
Provenance and peer review Not commissioned; externally peer reviewed. incidence of cardiovascular diseases: a cohort study in 1·9 million
people. Lancet Diabetes Endocrinol 2015;3:105–13.
Data availability statement Data are available upon reasonable request. Due to 11 Birkeland KI, Bodegard J, Eriksson JW, et al. Heart failure and
sensitive nature of data, anonymized data that support the findings of this study chronic kidney disease manifestation and mortality risk associations
are made available from the corresponding author after the legal and ethical in type 2 diabetes: a large multinational cohort study. Diabetes Obes
reviews on reasonable request from qualified researchers with documented Metab 2020;22:1607–18.
12 Gatwood J, Chisholm-­Burns M, Davis R, et al. Evidence of chronic
evidence of training for human subjects protections.
kidney disease in veterans with incident diabetes mellitus. PLoS One
Supplemental material This content has been supplied by the author(s). It has 2018;13:e0192712.
not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been 13 Einarson TR, Acs A, Ludwig C, et al. Prevalence of cardiovascular
peer-­reviewed. Any opinions or recommendations discussed are solely those disease in type 2 diabetes: a systematic literature review of scientific
evidence from across the world in 2007-2017. Cardiovasc Diabetol
of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and
2018;17:83.
responsibility arising from any reliance placed on the content. Where the content 14 Nichols GA, Schroeder EB, Karter AJ, et al. Trends in diabetes
includes any translated material, BMJ does not warrant the accuracy and reliability incidence among 7 million insured adults, 2006-2011: the
of the translations (including but not limited to local regulations, clinical guidelines, SUPREME-­DM project. Am J Epidemiol 2015;181:32–9.
terminology, drug names and drug dosages), and is not responsible for any error 15 Chen W, Yao J, Liang Z, et al. Temporal trends in mortality rates
and/or omissions arising from translation and adaptation or otherwise. among Kaiser Permanente southern California health plan enrollees,
2001-2016. Perm J 2019;23:18–213. doi:10.7812/TPP/18-213
Open access This is an open access article distributed in accordance with the 16 Gregg EW, Cheng YJ, Saydah S, et al. Trends in death rates among
Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which U.S. adults with and without diabetes between 1997 and 2006:
permits others to distribute, remix, adapt, build upon this work non-­commercially, findings from the National health interview survey. Diabetes Care
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