Incidence of cardiovascular events and vascular interventions in patients with type 2 diabetes

    Incidence of cardiovascular events and vascular interventions in patients with type 2 diabetes Suzanne E. Engelen, Yolanda van der Graaf, Manon C. Stam-Slob, Diederick E. Grobbee, Maarten J. Cramer, L. Jaap Kappelle, Gert J. de Borst, Frank L.J. Visseren, Jan Westerink PII: DOI: Reference:

S0167-5273(17)32587-1 doi:10.1016/j.ijcard.2017.07.081 IJCA 25302

To appear in:

International Journal of Cardiology

Received date: Revised date: Accepted date:

30 April 2017 2 July 2017 13 July 2017

Please cite this article as: Engelen Suzanne E., van der Graaf Yolanda, Stam-Slob Manon C., Grobbee Diederick E., Cramer Maarten J., Jaap Kappelle L, de Borst Gert J., Visseren Frank L.J., Westerink Jan, Incidence of cardiovascular events and vascular interventions in patients with type 2 diabetes, International Journal of Cardiology (2017), doi:10.1016/j.ijcard.2017.07.081

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ACCEPTED MANUSCRIPT Incidence of cardiovascular events and vascular interventions in patients with type 2

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diabetes

Suzanne E. Engelen, BSc1; Yolanda van der Graaf MD PhD5; Manon C. Stam-Slob MD

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Msc1; Diederick E. Grobbee5; Maarten J. Cramer MD PhD2; L. Jaap Kappelle MD PhD3; Gert J. de Borst MD PhD4; Frank LJ Visseren MD PhD1; Jan Westerink MD

Department of Vascular Medicine, University Medical Center Utrecht, Heidelberglaan

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PhD1, on behalf of the SMART study group.

100, 3584 CX, Utrecht, The Netherlands. 2

Department of Cardiology, University Medical Center Utrecht, Heidelberglaan 100,

Department of Neurology, Brain Center Rudolf Magnus, University Medical Center

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3584 CX, Utrecht, The Netherlands.

Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, the Netherlands Department of Vascular Surgery, University Medical Center Utrecht, Utrecht, the

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Netherlands

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Julius Center for Health Sciences and Primary Care, University Medical Center

Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands.

Keywords: type 2 diabetes, cardiovascular disease, interventions Short running title: The cardiovascular burden of type 2 diabetes

Contact information corresponding author Jan Westerink, MD PhD Department of Vascular Medicine

ACCEPTED MANUSCRIPT University Medical Center Utrecht Heidelberglaan 100, 3584 CX Utrecht, the Netherlands

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Telephone number: 0031 88 75 555 55

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E-mail adress: [email protected]

Word count: 2985 Number of tables: 4

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Number of figures: 4

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ACCEPTED MANUSCRIPT ABSTRACT Objective: Diabetes mellitus is associated with an increased risk for cardiovascular morbidity

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and mortality. The vascular burden in terms of incidence of cardiovascular events (CVE) and vascular interventions is however poorly quantified. In this study we evaluated the incidence

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rates of CVE and vascular interventions in patients with type 2 diabetes (T2DM) with and without cardiovascular disease (CVD) in comparison to patients without type 2 diabetes.

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Research design and methods: In a cohort of 9.808 high-risk patients with and without

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cardiovascular disease and type 2 diabetes originated from the ongoing, single-center prospective SMART (Second Manifestations of ARTerial disease) cohort, the number and incidence rates of CVE and interventions were calculated. The incidence rates were adjusted

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for confounders using Poisson regression models. CVE were defined as vascular death, stroke

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and myocardial infarction (MI). Interventions were defined as percutaneous coronary intervention, coronary artery bypass grafting, percutaneous transluminal angioplasty or

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stenting of the peripheral arteries and amputation.

Results: Patients with T2DM and CVD had a 4-fold higher incidence rate of CVE and a 8fold higher incidence rate of vascular interventions compared to high-risk patients without T2DM and CVD after adjusting for confounders. The incidence rate for the composit of nonfatal MI, non-fatal stroke and vascular death was 5.8 per 1000 person-years in patients without T2DM or CVD at baseline, 15.2 per 1000 person-years in patients with T2DM but without CVD at baseline, 26.0 per 1000 person-years in patients without T2DM but with CVD and 40.7 per 1000 person-years in patients with both T2DM and CVD at baseline. A similar increasing incidence rate was seen for all vascular interventions from patients without T2DM or CVD to patients with both T2DM and CVD.

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ACCEPTED MANUSCRIPT Conclusions: Patients with type 2 diabetes or CVD are subject to an increased incidence of cardiovascular events and interventions compared to hight-risk patients without type 2

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diabetes or vascular disease. Patients with type 2 diabetes and CVD have the highest incidence of new cardiovascular diseases and vascular interventions when compared to

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patients without type 2 diabetes and CVD. These results underline the need for optimal risk factor treatment as well as the need for new prevention and treatment strategies in this very

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high risk population.

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Introduction

The prevalence of type 2 diabetes mellitus (T2DM) has increased rapidly in the last decades

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from 108 million in 1980 to 422 million in 2014 (1). Diabetes is associated with an increased risk of atherosclerotic cardiovascular complications such as MI, stroke, renal disease and peripheral artery disease (2, 3).

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For example, T2DM is associated with a more than two-fold increase in the rate of MI and

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all-cause mortality (4), while having a poorer outcome after coronary revascularization (5-8) and bypass grafting (9-10). This increased risk associated with T2DM is not limited to coronary artery disease (CAD) but extends to both ischemic and haemorrhagic stroke (11),

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including a poorer functional outcome and cognitive recovery afterwards (12-14). Finally,

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T2DM is also associated with a higher prevalence of peripheral artery disease (PAD) (15), worsens the outcome in patients with PAD, and is associated with a 4-fold increase in

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incidence of critical limb ischaemia and worse outcomes after revascularisation (16, 17).

Although the increased risk for cardiovascular morbidity and mortality in patients with type 2 diabetes and manifest vascular disease is well-known (18), most research has focussed on the increased risk for the first cardiovascular event or the risk for a subsequent event (19). Less is known about the real cardiovascular burden in T2DM patients, defined as the number of CVE and interventions in patients per time unit. Quantifying the risk of total number of CVE in patients with T2DM would better reflect the cardiovascular burden, as well as the socioeconomic strain on the healthcare system. Comparison of the total number of CVE and interventions in patients with and without T2DM and CVD would also help to clarify which patient groups probably need more intensive treatment in terms of stricter and updated

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ACCEPTED MANUSCRIPT treatment goals, as well as new therapeutic options. Lastly, quantifying the incidence of CVE and interventions in these populations might underline the need for prevention of T2DM and

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thus stem the tide of T2DM and subsequent cardiovascular disease. Therefore, we aimed to evaluate the course of vascular disease as defined by incidence rates

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of all CVE and vascular interventions in patients with T2DM with and without vascular

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disease compared to patients without T2DM .

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Research design and methods

Study Population

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For this study, data is used from 9.808 participants originating from the ongoing, single-center

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prospective SMART (Second Manifestations of ARTerial disease) cohort study conducted at the University Medical Center Utrecht (UMCU) in the Netherlands. Patients with clinically

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manifest vascular disease or risk factors for vascular disease, including hyperlipidaemia,

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hypertension and renal insufficiency (20), who were referred to the UMCU were invited to participate. The cohort started in September 1996 and data of patients who were enrolled in the SMART study before March 2014 were used with the written informed consent from all participants. Exclusion criteria were age <18 years, malignancy, dependency in daily activities or lack of sufficient fluency in the Dutch language. The study was approved by the Medical Ethics Committee of the UMCU (20).

Data collection and follow-up At the moment of enrollment a thorough medical assessment was performed to acquire information on the vascular health of the patient. A more detailed description of the precise

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ACCEPTED MANUSCRIPT assessment at inclusion has been described elsewhere (20). During follow-up patients were biannually asked to fill out a standardized questionnaire about new vascular events. When the

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participant recorded a possible event, hospital discharge letters and results of relevant laboratory and radiology examinations were collected. With this information, all events were

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audited by three members of the SMART study End Point Committee, comprising physicians from different departments (20).

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Study definitions

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The study population was divided into four groups depending on the medical history of type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). The first group included patients with T2DM and CVD. The second group included patients with T2DM but without

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CVD. The third group consisted of patients without T2DM but with CVD. As reference group

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patients without T2DM and CVD, but with cardiovascular risk factors were chosen. Type 2 diabetes mellitus was defined as a referral diagnosis of T2DM, self-reported T2DM, a fasting

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serum glucose concentration of 7.0 mmol/L at study inclusion with the initiation of glucose-

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lowering treatment within 1 year, or the use of oral anti-hyperglycemic agents or insulin at baseline. Participants with known type 1 diabetes mellitus were excluded for this analysis. Vascular disease at baseline was defined as a history of or recent diagnosis of symptomatic cerebral vascular disease, peripheral artery disease, abdominal aortic aneurysm or coronary artery disease. Smoking was divided into current or never smoking. At baseline the current use of oral glucose lowering agents, insulin, platelet inhibitors, oral anticoagulant agent, blood pressure lowering agents, lipid lowering agents and statins was self-reported by the patient. Blood pressure was measured twice, manually at the right and left upper arm using the correct cuff size. The mean of the two measurements was taken as the blood pressure. Body Mass Index

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ACCEPTED MANUSCRIPT (BMI) was defined as weight (kg) divided by squared height (m2). Waist circumference was measured halfway between the lowest rib and the iliac crest with the patient standing. HbA1c

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level was measured at baseline in all patients who were enrolled in the SMART study after 2006. If a patient was enrolled before 2006, HbA1c level was determined using stored blood

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samples. Fasting plasma glucose, triglycerides, and total cholesterol were measured using commercial enzymatic dry chemistry kits (Johnson & Johnson), and High-Density Lipoproteins (HDL)-cholesterol was measured using a commercial enzymatic kit (Boehringer

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Mannheim). Low-Density Lipoproteins (LDL)-cholesterol was estimated with the Friedewald

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formula up to a plasma triglyceride level of 4 mmol/L (21). The glomerular filtration rate was assessed using the Modification of Diet in Renal Disease formula (22).

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Cardiovascular events and interventions

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Events of interest for the current study were divided into CVE and vascular interventions. CVE consist of CVE including vascular death, non-fatal stroke, non-fatal MI and non-

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vascular death (webtable 1). Vascular interventions included interventions such as

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percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), percutaneous transluminal angioplasty (PTA) or stenting (including carotid-, renal-, iliacarteries and aorta) and amputation. In addition, we were interested in cardiovascular mortality and nonvascular death.

Data analyses The incidence rates of the different CVE and interventions were calculated by dividing the total number of events by the total duration of follow-up and were expressed as number of events per 1000 person-years.

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ACCEPTED MANUSCRIPT The effect of T2DM on the incidence rate of both CVE and interventions was estimated using Poisson regression models, with the number of events as dependent variable and individual

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follow-up time included as an offset in the model. We adjusted for the confounders age, sex, smoking status, renal function (MDRD), LDL-cholesterol, BMI and systolic blood pressure.

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Continuous variables were transformed if they were not linearly related to the number of events. Model assumptions were checked with Q-Q plots and plots of residuals versus fitted values for normality and homoscedasticity of the residual distribution. Influential

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observations were detected with Leverage values and the Cook’s distance (23). Results were

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corrected for under- or overdispersion (i.e. less or more spread in the individual count observations than expected on the basis of the Poisson distribution) if present. Statistical

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analyses were performed using SPSS v.23 and computing environment R.

Baseline characteristics

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Results

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The study population consisted of 9.808 patients with a median follow-up of 7 years (IQR

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3.7-10.7) of whom 1835 (17.6%) had T2DM at baseline (Table 1). The median duration of follow-up was 8.1 (4.0-11.5) years in patients without T2DM or CVD, 8.9 (4.7-11.5) years in patients with T2DM but without CVD, 7.1 (3.9-10.6) years in patients without T2DM but with CVD and 6.5 (3.7-9.6) years in patients with T2DM and CVD. When comparing patients with T2DM and CVD to patients without T2DM and CVD the percentage of males was higher (75% vs. 50%), patients were older (63 vs. 49 years) and more patients had ever smoked (53% vs. 35%). Plasma LDL-cholesterol was lowest in patients with T2DM and CVD (2.6±1.0 mmol/L) and highest in patients without T2DM or CVD (3.8±1.4 mmol/L) (Table 1).

Incidence of cardiovascular events

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ACCEPTED MANUSCRIPT The incidence rate for the composit of non-fatal MI, non-fatal stroke and vascular death was 5.8 per 1000 person-years in patients without T2DM or CVD at baseline, 15.2 per 1000

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person-years in patients with T2DM but without CVD at baseline, 26.0 per 1000 person-years in patients without T2DM but with CVD and 40.7 per 1000 person-years in patients with

between groups is seen for all-cause mortality.

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T2DM and CVD at baseline (Table 2 + Figure 1A). A similar difference in incidence rates

In addition, patients with T2DM and CVD were more likely than other patients to develop

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multiple events during the follow-up period (Figure 2A).

After adjusting for potential confounders, patients with T2DM and CVD at baseline had a 3.9 (95%CI 3.1-5.0) higher incidence rate of CVE during the follow-up period than patients

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without T2DM or CVD at baseline (Table 3). Slightly lower but still markedly increased

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incidence rates of CVE were observed in patients with T2DM but without CVD (IRR 2.1 (95%CI 1.5-2.9)) and in patients with CVD but without T2DM (IRR 2.7 (95%CI 2.2-3.4)),

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both when compared to patients without T2DM or CVD at baseline. The effect of diabetes on

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the incidence of cardiovascular events was greater in patients without a history of vascular disease than in patients with a history of vascular disease (Table 3, p-value for interaction = 0.03).

Incidence of vascular interventions Patients with T2DM and CVD at baseline were found to have the highest incidence of vascular interventions during the follow-up period. The incidence of vascular interventions increased from patients without T2DM or CVD (IR 4.8 percutaneous coronary interventions per 1000 person-years, 1.6 coronary artery bypass grafting per 1000 person-years, 7.7 percutaneous transluminal angioplasty or stenting per 1000 person-years and 0.3 amputations

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ACCEPTED MANUSCRIPT per 1000 person-years) through patients with either T2DM or CVD, to patients with both T2DM and CVD (IR 37.8 percutaneous coronary interventions per 1000 person-years, 11.8

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coronary artery bypass grafting per 1000 person-years, 59.4 percutaneous transluminal angioplasty or stenting per 1000 person-years and 11.8 amputations per 1000 person-years)

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(Table 2 + Figure 1 B).

After adjusting for potential confounders, patients with T2DM and CVD at baseline had a 7.8 (95% CI 6.5-9.4) higher incidence rate than patients without TD2M or CVD (Table 3).

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Patients with T2DM and CVD at baseline were also more likely to have multiple

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interventions during follow-up (Figure 2B). The effect of diabetes on the incidence of cardiovascular interventions was greater in patients without a history of vascular disease than

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in patients with a history of vascular disease (Table 3, p-value for interaction <0.001).

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Discussion

The current study shows that patients with T2DM and CVD at baseline have a high incidence

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of new CVE and interventions. It is well known that both T2DM and the presence of CVD at

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baseline are associated with an increased risk of developing new cardiovascular disease (24). Our study shows that this holds true for both the incidence of CVE and interventions during follow-up, while also quantifying the total event rate in this very high risk population, including those with both type 2 diabetes and cardiovascular disease.

In a previous study, the excess risks of cardiovascular death among patients with type 2 diabetes with a mean follow-up of 4.6 years is increased by 14% (18). We expand on the data from this study by showing the incidence rate of different cardiovascular events including cardiovascular death while also showing the occurrence of different cardiovascular interventions in patients with type 2 diabetes with or without cardiovascular disease (18).

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The incidence rates of recurrent CVE in patients with type 2 diabetes are higher in male

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patients and increase with age, high triglyceride levels, and use of insulin (24). We were able to quantify the total number of different sorts of events and interventions, and in such show

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the total burden of macrovascular disease associated with a diagnosis of T2DM or CVD, or both. Furthermore, our study shows the percentage of patients having 1, 2 and 3 or more

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recurrent cardiovascular events or interventions which can be very useful in the clinic.

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We expand on earlier research from the SMART study group (25) by showing the incidence rate of CVE and interventions in patients with type 2 diabetes with and without vascular disease during maximum follow-up time. In addition, we were able to distinguish between

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different CVE and interventions in separate subpopulations of patients with diabetes,

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comparing the cardiovascular burden between these populations.

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We studied a specific patient group which consists of patients with cardiovascular disease. By specifically studying this group we provide new information about the incidence rate of cardiovascular events and interventions in patients with cardiovascular disease with or without type 2 diabetes .

The current study shows that patients with T2DM, and especially those with concurrent cardiovascular disease are at a very high risk for developing new CVE and are also more likely to undergo vascular interventions. High healthcosts of CVE and interventions and the rising trend of the incidence of type 2 diabetes worldwide calls for action to improve prevention and treatment of type 2 diabetes to reduce the cardiovascular and socioeconomic

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ACCEPTED MANUSCRIPT burden of type 2 diabetes (27). Despite extensive research into lipid- (27), blood pressure(28) and glycemic management (29-31) and susequent delinealition in international guidelines

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(32), the high risk for, and burden of, macrovascular disease in this high risk population remains daunting. Further research is needed to develop more individualized treatment targets

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for lipids, blood pressure and glycemic control, especially in patients with T2DM and CVD who have not been shown to benefit from stringent glycemic control (29-31). Apart from treatment goals, new treatment options have been shown to be beneficial in reducing

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cardiovascular complications and mortality in patients with T2DM and CVD (33, 34).

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Implementing new treatment options in guidelines however takes time due to unfamiliarity with the new options, high costs and limited data on long term sequelae. In addition, preventing the development of T2DM in patients with CVD may prove a viable option in

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reducing the risk for CVE and intervention in patients with CVD (35). Partly shifting our

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focus from preventing a first cardiovascular event or limiting its consequences in patients with T2DM to developing new strategies to reduce the risk for new CVE and interventions in

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patients with T2DM and CVD may benefit this steadily increasing patient group.

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Strenghts of our study include the large cohort of patients with or without diabetes and/or vascular disease who were monitored for a long period. Type 2 diabetes mellitus and cardiovascular disease at baseline and during follow-up were clearly defined and reported in a standardized manner. Medical care was given according to current guidelines and thereby reflected current clinical practice. In addition, all endpoints were reviewed by a committee following standardized protocols.

Study limitations also need to be considered. The patients in our reference group are not healthy patients. The patients are included in the cohort because they have cardiovascular risk factors. We expect that the difference of the incidence rates of cardiovascular events and

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ACCEPTED MANUSCRIPT interventions in patients with T2DM and CVD compared to healthy patients will probably be bigger than when comparing to our reference group. Patients characteristics were only

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measured at baseline and therefore knowledge on important confounders in our models were not available during follow-up. Moreover, we did not take into account the possible

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development of T2DM during follow-up. Since the start of our study in 1996 treatment strategies for type 2 diabetes and cardiovascular disease have changed. These changes are mainly in the field of cardiovascular risk factor treatment. In our Poisson analyses we adjust for these

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risk factors (age, sex, smoking status, renal function, LDL-cholesterol, BMI and systolic blood pressure) which reduces the effect of changes in treatment strategies. As shown in table 3, these

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patients characteristics are not important confounders. Because of the large duration and design of the SMART study it is not possible to show changes of these patient characteristics as we only

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have data on baseline. Finally, we did not have access to the clinical reasoning or indications

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for intervention, but we expect that the effect of it is balanced accross the four groups.

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In conclusion, patients with type 2 diabetes and cardiovascular disease have the highest incidence of new cardiovascular diseases and vascular interventions when compared to

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patients without type 2 diabetes and cardiovascular disease. These results underline the need for optimal risk factor treatment as well as the need for new prevention and treatment strategies in this very high risk population.

Author contributions Suzanne E. Engelen BSc: researched data, performed data analysis, wrote manuscript Yolanda van der Graaf MD PhD: reviewed manuscript Manon C. Stam-Slob MD Msc: assisted and performed data analysis Diederick E. Grobbee: revieweded manuscript Maarten J. Cramer MD PhD: reviewed manuscript 14

ACCEPTED MANUSCRIPT L. Jaap Kappelle MD PhD: reviewed manuscript Gert J. de Borst MD PhD: reviewed manuscript

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Frank LJ Visseren MD PhD: reviewed manuscript Jan Westerink MD PhD: contributed to manuscript, reviewed and supervised work of first

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author

Acknowledgements

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We gratefully acknowledge the contribution of the SMART research nurses; R. van Petersen

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(data-manager); B. G. F. Dinther (vascular manager) and the participants of the SMART Study Group: A. Algra MD, PhD; Y. van der Graaf, MD, PhD; D. E. Grobbee, MD, PhD; G. E. H. M. Rutten, MD, PhD, Julius Center for Health Sciences and Primary care; F. L. J.

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Visseren, MD, PhD, Department of Internal Medicine; G. J. de Borst, MD, PhD, Department

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of Vascular Surgery; L. J. Kappelle, MD, PhD, Department of Neurology; T. Leiner, MD, PhD, Department of Radiology; P. A. Doevendans, MD, PhD, Department of Cardiology. No

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compensation was received for these contributions. This work was financially supported by

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ZonMw, the Netherlands Organization for Health Research and Development (Grant No. 836011027).

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Diabetes and Prediabetes: A Call for Action! Diabetes Care 2014 Dec; 37(12): 31373138

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cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative

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ACCEPTED MANUSCRIPT Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled

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trial. Lancet 2004 21-27;364(9435):885-98

The ACCORD Study Group. Effects of Intensive Blood-Pressure Control in

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Type 2 Diabetes Mellitus N Engl J Med 2010; 362:1575-1585

The ACCORD Study Group. Effects of Intensive Glucose Lowering in Type 2

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Diabetes. N Engl J Med 2008; 358:2545-2559

Duckworth W, Abraira C, Moritz T et al. VADT Investigators. Glucose control

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2009;360:129–139

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and vascular complications in veterans with type 2 diabetes. N Engl J Med

Patel A, MacMahon S, Chalmers J et al. ADVANCE Collaborative Group.

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Intensive blood glucose control and vascular outcomes in patients with type 2

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diabetes. N Engl J Med 2008;358:2560–2572

American Diabetes Association. Standards of medical care in diabetes 2016.

Diabetes Care 2016;34(1): 3-21

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cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016

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Zinman B, Wanner C, Lachin JM et al. Empagliflozin, cardiovascular

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outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117–28.

Knowler WC, Barrett-Connor E, Fowler SE et al. Reduction in the incidence of

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ACCEPTED MANUSCRIPT Table 1: Baseline characteristics of 9808 patients with or without type 2 diabetes and vascular disease

CVD

No CVD No Diabetes

Type 2 diabetes

No Diabetes

n=1209

n=5959

n=549

n=2091

SC RI

Patient characteristics

PT

Type 2 diabetes

63 (8.8)

4380 (74%) 60 (11)

Diabetes duration (years)

4 [1.0-10]

0

3.0 [0.0-7.0]

0

Duration of vascular disease (years)

1 [0.0-9.0]

0

0

Smoking, current n(%)

310 (26%)

125 (23%)

497 (24%)

Smoking, ever n(%)

644 (53%)

3.2 (6.6) 1964 (33%) 2739 (46%)

224 (41%)

736 (35%)

0

0

0

0

0

0

0

0

908 (75%)

Age (years)

MA

Medical history, n (%)

805 (67%)

Cerebrovascular disease

350 (29%)

3533 (59%) 1761 (30%) 1094 (18%) 470 (8.0%)

ED

Coronary disease

Peripheral arterial disease

264 (22%) 75 (6.2%)

PT

Abdominal aortic aneurysm Medication, n(%)

NU

Male sex, n(%)

327 (60%)

1139 (50%)

55 (11)

49 (13)

779 (65%)

0

369 (67%)

0

Use of insulin

288 (24%)

0 4524 (76%) 632 (11%) 4287 (72%) 3898 (65%)

124 (23%)

0

81 (15%)

201 (10%)

23 (4.0%)

43 (2.0%)

351 (64%)

1177 (56%)

226 (41%)

633 (30%)

Platelet inhibitor

CE

Orale glucose lowering agents

AC

Oral anticoagulant agents

926 (77%) 111 (9%)

Blood pressure-lowering agents

1005 (83%)

Lipid-lowering agents

882 (73%)

Physical examination Blood pressure, systolic (mmHg)

145 (21)

139 (21)

146 (20)

147 (23)

Blood pressure, diastolic (mmHg)

81 (11)

81 (11)

86 (12)

90 (14)

28.4 (4.3)

26.5 (3.9)

30 (6.1)

26.6 (4.6)

8.5 [7.0-10.8]

5.5 [5.1-5.9]

7.1 [6.4-8.2]

5.5 [5.3-5.8] 5.8 [5.0-6.9] 1.3 [1.031.60] 4.6 (1.6)

2

BMI (kg/m ) Laboratory measurements

HbA1c (%)

7.0 (1.1)

5.6 [5.36.1] 5.6 (0.4)

Total Cholesterol (mmol/L)

4.6 (1.2)

4.9 (1.2)

5.0 [4.4-6.0]

HDL-cholesterol (mmol/L)

1.1 (0.3)

1.3 (0.4)

1.1 (0.37)

Non-HDL cholesterol (mmol/L)

3.5 (1.2)

3.7 (1.2)

4.1 (1.7)

LDL-cholesterol (mmol/L)

2.6 (1.0)

2.9 (1.0) 1.4 [1.01.9]

3.1 (1.1)

Plasma glucose (mmol/L)

Triglycerides (mmol/L)

7.9 [6.8-9.6]

1.6 [1.2-2.4] 27

1.8 [1.2-2.7]

3.8 (1.4) 1.4 [0.982.25]

ACCEPTED MANUSCRIPT Creatinine (µmol/L)

89 [72108] 77 (18)

85 [75.1-110]

eGFR (MDRD) (ml/min/1,73 m2)

75 (21)

98 [79-122]

84 (22.4)

81 (17.9)

PT

Legenda

97 [77-130]

CVD = Cardiovascular disease T2DM = Type 2 diabetes mellitus

AC

CE

PT

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MA

MDRD = Modification of Diet in Renal Disease

NU

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BMI = Body Mass Index HDL-cholesterol = High-density-lipoprotein cholesterol LDL- cholesterol = Low-density-lipoprotein cholesterol eGFR = Estimated glomerual filtration rate

28

ACCEPTED MANUSCRIPT

CVD

Type 2 diabetes

N

IR (/1000py)

N

IR (/1000py)

IR (/1000py)

N

IR (/1000py)

Non-fatal myocardinfarction

99

11.9

435

9.9

19

4.1

43

2.6

Non-fatal stroke

62

7.5

285

6.5

18

3.9

20

1.2

Cardiovascular death

177

21.3

514

11.7

33

7.1

33

2.1

Non-vascular death

95

11.4

456

10.4

44

9.5

47

2.9

Composite vascular endpoint

338

40.7

1146

26

70

15.2

96

5.8

All cause mortality

292

35.2

1029

23.4

84

18.2

87

5.3

PCI

314

37.8

1088

24.7

51

11

79

4.8

CABG

98

11.8

340

7.7

11

2.4

26

1.6

PTA or stenting

493

59.4

1777

40.4

78

16.9

127

7.7

Amputation

98

11.8

95

2.2

27

5.8

5

0.3

Legenda N = Number of events IR = Incidence rate CVD = Cardiovascular disease PCI = Percutaneous coronary intervention CABG = Coronary artery bypass grafting PTA = Percutaneous transluminal angioplasty

AC CE

Cardiovascular interventions

MA

Cardiovascular events

N

No diabetes

NU

No diabetes

No CVD

PT ED

Type 2 diabetes

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Table 2: The number and incidence rate of cardiovascular events in patients with or without type 2 diabetes and vascular disease

ACCEPTED MANUSCRIPT

Type 2 diabetes

No Diabetes

IRR (95%CI)

IRR (95%CI)

Type 2 diabetes IRR (95%CI)

Model I

3.9 (2.7-4.3)

2.7 (2.0-3.0)

2.1 (1.4-2.5)

Model II

3.9 (3.1-5.0)

2.7 (2.2-3.4)

2.1 (1.5-2.9)

Model I

7.9 (6.6-9.5)

4.9 (4.2-5.8)

2.6 (2.0-3.3)

Model II

7.8 (6.5-9.4)

4.9 (4.1-5.8)

IRR = Incidence rate ratio I: Adjusted for age and sex

IRR (95%CI)

interaction

2.6 (2.0-3.3)

Ref

0.07

Ref

0.03

Ref

<0.001

Ref

<0.001

AC CE

CVD = Cardiovascular disease

P-value for

PT ED

Cardiovascular interventions

Legenda

No Diabetes

MA

Cardiovascular events

SC RI

No CVD

NU

CVD

PT

Table 3: Adjusted incidence rate ratio of cardiovascular events and interventions

II: Adjusted for age, sex, current smoking, Estimated glomerular filtration rate, Low-density-lipoprotein cholesterol, Body Mass Index and Systolic Blood Pressure p-value for interactions shows that the effect of diabetes on the incidence of cardiovascular events is much greater in patients with a history of cardiovascular disease than in patients without vascular disease

30