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Cardiovascular risk factors early in the course of treatment in people with type 2 diabetes without established cardiovascular disease: A population‐based observational retrospective cohort study

Abstract Aims To characterise the cardiovascular risk of people with type 2 diabetes without established cardiovascular disease but with risk factors, relative to those with established cardiovascular disease, to provide information on which patients could benefit from early use of glucose‐lowering therapies that also reduce cardiovascular risk. Methods Data from people with type 2 diabetes initiating second‐line glucose‐lowering medication were retrieved from the UK Clinical Practice Research Datalink GOLD database and linked with Hospital Episode Statistics and Office for National Statistics (2001–2016). Cox proportional hazards models were used to estimate relative risks of major adverse cardiovascular events within groups defined by the presence of selected risk factors in people without versus with established cardiovascular disease. Results Of 53,182 individuals, 19.4% had established cardiovascular disease (i.e. a prior cardiovascular event). Over 5–7 years’ follow‐up, the rate of major adverse cardiovascular events was 14.0 and 49.6 events/1000 person‐years without and with established cardiovascular disease, respectively (hazard ratio [HR] 0.28, 95% confidence interval [CI] 0.26, 0.29). Compared with a reference HR 1.0 for participants with established cardiovascular disease, estimated glomerular filtration rate <60 mL/min was the single factor associated with the highest risk of major adverse cardiovascular events (HR 0.75, 95% CI 0.70, 0.81) and mortality (HR 1.12, 95% CI 1.07, 1.18) in people with type 2 diabetes without established cardiovascular disease. The combination of chronic kidney disease with older age, smoking and/or dyslipidaemia was associated with a similarly high risk of cardiovascular events in people with type 2 diabetes and without cardiovascular disease compared with those having established cardiovascular disease. Conclusions These analyses provide important information to identify people who may benefit from primary prevention of cardiovascular disease. Modifiable cardiovascular risk factors should be controlled early in all individuals with type 2 diabetes (as well as in all individuals with cardiovascular disease).

95% confidence interval [CI] 0.26, 0.29). Compared with a reference HR 1.0 for participants with established cardiovascular disease, estimated glomerular filtration rate <60 mL/min was the single factor associated with the highest risk of major adverse cardiovascular events (HR 0.75, 95% CI 0.70, 0.81) and mortality (HR 1.12, 95% CI 1.07, 1.18) in people with type 2 diabetes without established cardiovascular disease. The combination of chronic kidney disease with older age, smoking and/or dyslipidaemia was associated with a similarly high risk of cardiovascular events in people with type 2 diabetes and without cardiovascular disease compared with those having established cardiovascular disease.

| INTRODUCTION
Atherosclerotic cardiovascular disease is the leading cause of death in people with type 2 diabetes. 1 Diabetes confers a substantial independent risk for cardiovascular disease, and many people with type 2 diabetes have coexisting conditions and cardiovascular disease risk factors, such as hypertension, dyslipidaemia, obesity, chronic kidney disease and smoking. 1 Premature mortality is similar in people with type 2 diabetes, previous stroke, or previous myocardial infarction and any combination of these conditions is associated with multiplicative mortality risk. 2 In people with type 2 diabetes and established cardiovascular disease or with risk factors for cardiovascular disease, a glucagon-like peptide-1 receptor agonist (GLP-1RA) or sodium-glucose cotransporter 2 inhibitor (SGLT2i) with proven cardiovascular benefit is recommended, added to metformin, 3,4 independent of glycaemic targets. 5 This is based on large cardiovascular outcome trials. [6][7][8][9][10][11][12][13] However, important knowledge gaps exist regarding people with type 2 diabetes and cardiovascular risk factors, but without established cardiovascular disease, early in their treatment course. Here, we describe the cardiovascular risk profile of people with type 2 diabetes who initiated second-line glucoselowering medication (added to first-line pharmacotherapy) in a large UK primary care cohort. We compared outcomes in people without established cardiovascular disease (i.e. no prior cardiovascular event) to those in people with established cardiovascular disease (who had a previous event) to evaluate the effect of numbers and combinations of selected cardiovascular risk factors on the risk of major adverse cardiovascular events (MACE). The aim was to characterise the cardiovascular risk of subpopulations without established cardiovascular disease, relative to those with established cardiovascular disease, to provide information on which patients could benefit from receiving glucose-lowering therapies that reduce cardiovascular risk early in their type 2 diabetes treatment course.
Conclusions: These analyses provide important information to identify people who may benefit from primary prevention of cardiovascular disease. Modifiable cardiovascular risk factors should be controlled early in all individuals with type 2 diabetes (as well as in all individuals with cardiovascular disease).

K E Y W O R D S
cardiovascular disease, cardiovascular disease risk, risk factors, type 2 diabetes Novelty statement What is already known?
• People with established cardiovascular disease and type 2 diabetes are known to be a highrisk population, but few studies have evaluated cardiovascular risk and risk factors early in the course of diabetes treatment.
What has this study found?
• In this retrospective observational cohort study, people with type 2 diabetes and cardiovascular risk factors who were initiating second-line glucose-lowering medication had a high incidence of cardiovascular events. The risk of a major cardiovascular adverse event or death from any cause was greatest in people without established cardiovascular disease in the presence of moderate-to-severe chronic kidney disease. The combination of chronic kidney disease plus two other risk factors was associated with a risk for cardiovascular events that was not significantly different from that for people with established cardiovascular disease.
What are the clinical implications of the study?
• These findings highlight that modifiable cardiovascular risk factors, particularly chronic kidney disease, smoking and dyslipidaemia, should be controlled early in all individuals with type 2 diabetes (as well as in all individuals with cardiovascular disease).

| Data sources and population
A retrospective observational study was conducted using individual record data from the Clinical Practice Research Datalink GOLD database, derived from a UK-wide network of primary care practices. 14 Eligible participants had type 2 diabetes and were receiving both first-and secondline glucose-lowering pharmacotherapy during the followup period from 2001 to 2016 (Table S1). Outcomes data that could be linked to individuals were retrieved from Hospital Episode Statistics and the Office for National Statistics during the follow-up period.

| CVD risk determination and clinical characteristics at the index date
The index date was defined as that of the first prescription of second-line glucose-lowering therapy. This was chosen to capture the early type 2 diabetes population.
Established cardiovascular disease was defined as any record prior to the index date of a cardiovascular diseaserelated Read Code in the GOLD database (including codes for acute myocardial infarction, acute coronary syndrome, coronary revascularisation and other arterial revascularisation procedures, stroke and transient ischemic attack, heart failure, aortic aneurysm and peripheral artery disease) (Table S2). Information on clinical characteristics was collected from participant records at the index date. Cardiovascular risk factor values included the last value in the year prior to the index date. To identify people with type 2 diabetes at high cardiovascular risk, the presence of nine selected risk factors was assessed based on known risk levels and modified guideline recommendations: sex (male), 15  The type and total number of different types of cardiovascular medication and first-and second-line glucoselowering medication prescribed before the index date were calculated and categorised by class to further characterise the population.

| Endpoints assessed during follow-up
The following cardiovascular-related endpoints were assessed over the follow-up period: (1) 3-point MACE, a composite of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke; (2) expanded MACE, 3-point MACE plus hospitalisation for angina, hospitalisation for HF or coronary revascularisation (also evaluation of individual expanded MACE components); and (3) all-cause mortality. International Classification of Diseases, 10th Revision codes and Office of Population Censuses and Surveys Classification of Surgical Operations and Procedures version 4 codes from Hospital Episode Statistics and the Office for National Statistics were used to identify the following: cardiovascular mortality, acute myocardial infarction, stroke, hospitalisation for unstable angina, hospitalisation for heart failure, coronary revascularisation and all-cause mortality (Table S3).

| Statistical analyses
Demographics and clinical characteristics were reported as n (%) and mean ± standard deviation for participants with/without cardiovascular disease, respectively.
Statistical analyses were performed using SAS version 7.1. Time to first in-study event of 3-point MACE, expanded MACE and all-cause mortality were analysed by a Cox proportional hazards model comparing outcomes in participants without established cardiovascular disease to those in participants with established cardiovascular disease. MACE outcomes were recorded from the time of first prescription of second-line glucose-lowering therapy. Individuals were censored at the first occurrence of either the end of their personal follow-up, end of follow-up of their primary care practice, end of Hospital Episode Statistics coverage, end of Office for National Statistics coverage or death. All analyses were adjusted for the calendar year at index date by including this as a continuous variable in the model. Effect estimates for participants without established cardiovascular disease were reported as hazard ratios (HR) with 95% CI against a reference value of 1.0 for participants with established cardiovascular disease. Similar analyses were performed comparing outcomes in participants without cardiovascular disease versus with cardiovascular disease, categorising participants without cardiovascular disease according to baseline risk defined by the following (Table S4): 1. According to the actual number of the nine selected risk factors 2. As high risk according to the respective nine selected individual risk factors 3. As high risk according to two-and three-way combinations of the nine selected individual risk factors.
Participants with missing values on one or more of the nine selected risk factors were excluded from these analyses. However, to explore the effect of missing data, an analysis of outcomes according to individual risk factors was also performed via multiple imputation using fully conditional specification (also known as imputation by chained equations or sequential generalised regression). The variables included were the nine selected risk factors (male sex, age >65 years, body mass index ≥30 kg/m 2 , hypertension, dyslipidaemia, current smoking, hyperglycaemia, diabetes duration ≥5 years and chronic kidney disease) plus history of cardiovascular disease, calendar year, and incidence of and time to 3-point MACE, expanded MACE and all-cause mortality. Twenty datasets were imputed using PROC MI in SAS. Results were combined by PROC MIANALYZE.

| RESULTS
Of 464,253 patients in the GOLD database with type 2 diabetes-related codes, 17,057 were excluded to avoid alternative diabetes diagnoses (Table S1). Between 2001 and 2016, 90,838 type 2 diabetes patients in the database had at least one prescription of second-line glucose-lowering therapy within 120 days of the last prescription of first-line glucose-lowering therapy. Of these, 53,182 were people aged ≥18 years with sufficient follow-up data that could be cross-linked in Hospital Episode Statistics and the Office for National Statistics. There was a high rate of missing data for cholesterol, body mass index, HbA 1c and estimated glomerular filtration rate (Table 1).
Most participants (99% with and 85% without cardiovascular disease) were receiving at least one cardiovascular medication at index date, mostly lipid-lowering drugs, hypertension/heart failure medication and/or antiplatelet drugs (Table 1). Of those with cardiovascular disease, 88% were receiving at least three cardiovascular medications compared with 42% of those without cardiovascular disease. The most common first-line glucose-lowering treatment for both groups was metformin (68%-78%), with sulphonylureas (48%-51%) most frequently added as second-line treatment (Table 1). Second-line treatment with GLP-1RA (0.5%-0.8%) and SGLT2i (0.3%-0.7%) was uncommon.
Compared with those with cardiovascular disease, the cardiovascular-related endpoints occurred at around one-quarter to one-third of the rate in individuals without cardiovascular disease. Over the follow-up period, the incidence rate of 3-point MACE was 14.0 events per 1000 person-years in those without cardiovascular disease (mean follow-up 6.6 years) compared with 49.6 events per 1000 person-years in people with cardiovascular disease (mean follow-up 5.6 years) (HR for people without cardiovascular disease vs. with cardiovascular disease: 0.28, 95% CI 0.26, 0.29; Table S6). The incidence rate of the expanded MACE endpoint was 22.6 events per 1000 personyears in people without cardiovascular disease (mean follow-up 6.4 years) compared with 93.1 events per 1000 person-years in those with cardiovascular disease (mean follow-up 4.8 years) (HR 0.24, 95% CI 0.23, 0.25), with hospitalisation for heart failure the most common individual component (10.2 and 50.7 events per 1000 person-years, respectively; HR 0.20, 95% CI 0.19, 0.21; Table S6). In total, 16.9% of people without cardiovascular disease died (mean follow-up 6.8 years), while 41.0% of those with cardiovascular disease died (mean follow-up 6.0 years) (HR 0.35, 95% CI 0.34, 0.37; Table S6).
Compared with those with cardiovascular disease, the risk of 3-point MACE in those without cardiovascular disease increased with an increasing number of risk factors (Figure 1). People without cardiovascular disease had a median (range) of 3 (0-8) of the selected nine cardiovascular risk factors. The risk of 3-point MACE associated with the presence of a minimum number and T A B L E 1 Demographic and clinical characteristics of individuals with type 2 diabetes without and with established cardiovascular disease prior to index date (first prescription of second-line glucose-lowering therapy) an actual number of selected cardiovascular risk factors is shown in Figure 1, and for expanded MACE and allcause mortality in Tables S7 and S8. Demographic and clinical characteristics were generally similar for people without cardiovascular disease and complete data (included in the analyses), and those with missing data (excluded from the analyses), except for hypertension and dyslipidaemia (higher among people with missing data) and diabetes duration ≥5 years (higher among people with complete data) ( Table S9). The risks of 3-point MACE, expanded MACE and all-cause mortality by selected risk factors are shown in Table 2 (using multiple imputation to account for missing data) and  Table 2). Chronic kidney disease was also the single selected risk factor associated with the highest all-cause mortality; the HR of 1.12 (95% CI 1.07, 1.18) indicates that risk of death in people with type 2 diabetes and chronic kidney disease is potentially greater than for those with cardiovascular disease ( Table 2). The second highest risk factor for death was older age (crude HR 0.78, 95% CI 0.75, 0.81). Exclusion rather than imputation of missing data had little effect on the three main adverse endpoints (Table S10, Figure 2). However, the association with adverse outcomes in people with chronic kidney disease was somewhat weaker for 3-point MACE and all-cause mortality.
For combinations of two selected risk factors associated with a risk of 3-point MACE in people without versus with cardiovascular disease, chronic kidney disease plus one other risk factor gave HRs of approximately 0.8, comparable to the reference risk of 1.0 in the cardiovascular disease group when missing data were excluded ( Figure 2). This was similar for all-cause mortality (data not shown). Other combinations of two risk factors, such as obesity plus hyperglycaemia or obesity plus male sex, were associated with the lowest risk of adverse endpoints (data not shown).
For risk factors other than chronic kidney disease in people without cardiovascular disease, the double combination of risk factors associated with the highest HR for 3-point MACE compared with participants with cardiovascular disease (reference HR 1.0), were older age and dyslipidaemia (crude HR 0.70, 95% CI 0.59, 0.83), and older age and smoking (crude HR 0.55, 95% CI 0.47, 0.65) (data not shown). Similarly, in the absence of chronic kidney disease, the double combinations associated with the highest HR for all-cause mortality were older age plus smoking (crude HR 0.88, 95% CI 0.80, 0.98), and older age plus dyslipidaemia (crude HR 0.87, 95% CI 0.76, 0.99) (data not shown). In the absence of chronic kidney disease, the triple risk factor combinations associated with the highest HR for 3-point MACE and all-cause mortality were older age, dyslipidaemia, plus smoking; and older age, male sex, plus dyslipidaemia (data not shown).

| DISCUSSION
A large proportion of people with type 2 diabetes without established cardiovascular disease were at high cardiovascular risk and a large proportion (17%) died over the 6.4 years of follow-up. When missing data were accounted for by multiple imputation, the risk of death in people with chronic kidney disease was similar or even greater than for those with established cardiovascular disease (mean follow-up 4.8 years). Additionally, risk factors such as obesity, hypertension and dyslipidaemia were more common in those without cardiovascular disease than those with cardiovascular disease, possibly due to a greater focus on prevention in people with previous events. These findings highlight the need to control cardiovascular risk factors early in the course of type 2 diabetes in all individuals, and emphasise the need to identify people who may particularly benefit from treatments known to reduce cardiovascular risk.
Even relatively early in the treatment course of type 2 diabetes, approximately one-fifth of people had established cardiovascular disease. Many of these were receiving at least three cardiovascular medications, almost half were hypertensive and half had obesity. Furthermore, mean HbA 1c levels were 74 mmol/mol [8.9%] at secondline glucose-lowering therapy initiation, indicating delayed treatment intensification. Current guidelines recommend modifying treatment regularly (3-6 months) if HbA 1c remains above target. 3,14 Sulphonylureas were the most-prescribed second-line treatment, whereas GLP-1RA or SGLT2i use was low. As the study retrieved records from 2001 to 2016, infrequent use of newer agents is not unexpected. Were the study to be extended up to the present, we might anticipate an increase in the use of GLP-1RAs and SGLT2is with proven cardiovascular benefit as second-line therapy, in line with recent recommendations. [3][4][5] The current study showed high post-index rates of 3-point MACE, expanded MACE, and all-cause mortality (50-93 events per 1000 person-years) in people with cardiovascular disease, demonstrating the need for glucose-lowering treatments that reduce cardiovascular risk and approaches to reduce cardiovascular risk factors, such as hypertension, dyslipidaemia and obesity.
Assessment of cardiovascular disease risk according to the actual number of risk factors in people without cardiovascular disease showed that risk increased with the number of risk factors present, with people having seven or more risk factors having a risk of 3-point MACE and all-cause mortality similar to that of the reference group. The risk of cardiovascular disease in people without previous cardiovascular disease was also assessed according to the presence of the minimum number of selected cardiovascular risk factors present and showed a similar pattern. Some single risk factors were associated with T A B L E 2 Risk of endpoints associated with selected risk factors after multiple imputation to account for missing data Note: HRs and associated CIs calculated via multiple imputation using fully conditional specification. Twenty multiply imputed datasets were analysed for each of the nine selected risk factors.
a No data were missing so no imputation was done.
substantially higher risk of adverse outcomes than others. Chronic kidney disease (estimated glomerular filtration rate <60 mL/min) was the single selected risk factor associated with the highest risk of adverse outcomes, and was common with or without established cardiovascular disease (31% and 13%, respectively). These findings are in line with another Clinical Practice Research Datalink analysis showing that nephropathy and other microvascular diseases significantly affect future cardiovascular disease risk in people with type 2 diabetes in a cumulative manner. 20 International recommendations state that for individuals with type 2 diabetes and chronic kidney disease, with or without cardiovascular disease, the use of an SGLT2i shown to reduce the progression of chronic kidney disease should be considered. 3 If SGLT2is are contraindicated or not preferred, a GLP-1RA shown to reduce the progression of chronic kidney disease should be considered. For people without chronic kidney disease, combinations of older age, dyslipidaemia, smoking and male sex appeared to be associated with a risk of MACE and all-cause mortality nearing that of those with cardiovascular disease. Strategies for smoking cessation and intensification of lipid-lowering drugs should be encouraged in these high-risk populations. However, it should be noted that patients with established cardiovascular disease were on average 9 years older than those without. Given that the risk of stroke doubles each decade after the age of 55, 21,22 age would have had a potentially disproportionate (and unavoidable) effect on the event rates in people with established cardiovascular disease.
A strength of the present study is that it provides a comprehensive representation of the cardiovascular risk profile of people with type 2 diabetes initiating secondline glucose-lowering treatment who are likely to be largely managed in primary care. Around the time of the analysis, Clinical Practice Research Datalink GOLD included approximately 4.4 million currently registered individuals, around 6.9% of the UK population, who are broadly representative of the UK general population in terms of age, sex and ethnicity. 14 F I G U R E 2 Risk of 3-point MACE by selected risk factors and combinations of selected risk factors associated with the highest risk (top 5) among people with type 2 diabetes without established CVD (patients with missing data were excluded). People with missing data for one or more risk factors were excluded. HR adjusted for calendar year of first prescription of second-line glucose-lowering therapy (index date). Abbreviations: CKD, chronic kidney disease; CVD, cardiovascular disease; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HbA1c, glycated haemoglobin; HR, hazard ratio; MACE, major adverse cardiovascular events; SBP, systolic blood pressure  .  0  2  1  n  i  m  /  L  m  0  6  <  R  F  G  e  :  D  K  C  e  t  a  r  e  d  o  m  t  s  a  e  l  t  A  )  3  5  .  0  ,  7  4  .  0  (  0  5  .  0  6  3  s  r  a  e  y  5  6  >  :  e  g  a  r  e  d  l  O   )  3  3  .  0  ,  9  2  .  0  (  1  3  .  0  4  4  g  H  m  m  0  9  ≥  P  B  D  r  o  g  H  m  m  0  4  1  ≥  P  B  S  :  n  o  i  s  n  e  t  r  e  p  y  H  )  A potentially major limitation is that an appreciable amount of data for selected risk factors were missing, particularly for measurements of total cholesterol, body mass index, HbA 1c and estimated glomerular filtration rate, which are known to be predictors of poor outcomes in cardiovascular and other diseases. Although individuals with missing data were excluded from the association analyses, a sensitivity analysis using multiple imputation suggested that missing data did not appear to greatly affect the overall findings. In the UK, the Quality and Outcomes Framework that was initiated in 2004 has greatly reduced the amount of missing data in general practice databases and, had we only included patients from 2004 onwards, it is likely that this would have reduced the amount of missing data.
Of note, the Chronic Kidney Disease Epidemiology Collaboration and Modification of Diet in Renal Disease equations are increasingly preferred to the Cockcroft-Gault formula used here to calculate estimated glomerular filtration, 23 but the former is not widely used in the UK (or at least was not during the timeframe of data collection). It includes the variable of race, which was sparsely recorded in the current dataset.
Some risk factors may have been measured more accurately than others and this may have impacted the findings. The most frequent event in the established cardiovascular disease group was hospitalisation for heart failure, which is consistent with other observations. 24 Heart failure may occur due to causes other than cardiovascular disease, 25 but people with heart failure were included in the established cardiovascular disease group to avoid overestimation of overall cardiovascular disease risk in those without cardiovascular disease. Although the definition of established cardiovascular disease in this study was based on people who had experienced a cardiovascular event, people without a previous cardiovascular event can also have increased cardiovascular risk. Some misclassification may have occurred due to undiagnosed cardiovascular disease event in the group without established cardiovascular disease. Although total cholesterol was chosen as a risk factor because it is routinely measured in UK primary care, many guidelines and cardiovascular risk trials focus on low-density lipoprotein cholesterol, and this may have provided a better risk assessment.
In total, 42,805 of the 53,182 participants identified were included in the analysis. The aim was not to examine causal relationships, but rather which risk factors and risk factor combinations were most strongly associated with cardiovascular disease on its own. The selected risk factors were chosen based on their known causal relationship with cardiovascular disease. We acknowledge that chance associations are likely, which is a limitation of analyses of the type reported here.
Approximately 70% of participants were taking sulfonylureas either as first-or second-line treatment. Since the time the data were collected, sulfonylureas have been associated with an increased risk of cardiovascular events and mortality. 26 However, the randomised CAROLINA trial showed no increase in cardiovascular risk with the sulfonylurea glimepiride compared with the dipeptidyl peptidase-4 inhibitor linagliptin. 27 Dipeptidyl peptidase-4 inhibitors are considered neutral with respect to cardiovascular effect. [3][4][5] Current recommendations advocate the use of a GLP-1RA or SGLT2i with proven cardiovascular benefit in patients with type 2 diabetes who are at increased cardiovascular risk. [3][4][5] In the current analysis, the time that participants remained on their prescribed second-line glucose-lowering therapy was not considered.
Although the study required a minimum of 1 year of data, the established cardiovascular disease definition covered any record of a cardiovascular disease-related Read Code in the database prior to the index date and therefore minimised bias in terms of overestimating risk assessment of the risk factor only group. Most participants had long-term data available, but there remains the possibility of overestimation of risk for those with a short disease history.
In conclusion, we found a high prevalence of cardiovascular disease among people with type 2 diabetes relatively early during their treatment course, and there is a high level of unmet need with regard to risk factor management. We identified risk factors (chronic kidney disease, older age, smoking and dyslipidaemia) that may help stratify those with type 2 diabetes without cardiovascular disease who are at particularly high risk of cardiovascular events, so that efforts to control modifiable risk factors and glucose-lowering therapies that reduce cardiovascular risk can be targeted appropriately. Modifiable cardiovascular risk factors should be controlled early in all individuals with type 2 diabetes (as well as in all individuals with cardiovascular disease).