Chinese expert consensus on the risk assessment and management of panvascular disease inpatients with type 2 diabetes mellitus (2022 edition) : Cardiology Plus

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Chinese expert consensus on the risk assessment and management of panvascular disease inpatients with type 2 diabetes mellitus (2022 edition)

Chu, Xi1; Feng, Bo2; Ge, Junbo3,4,*; Guo, Lixin5; Huo, Yong6; Ji, Linong7; Jia, Qian8; Jiang, Song9; Li, Yong10; Liu, Fang11; Liu, Xinfeng12; Liu, Yuping13; Lu, Bin10; Lv, Ankang14; Wang, Yongjun8; Weng, Jianping15,*; Zeng, Qiang16,*; Zhang, Yingmei3,*; Zhou, Jingmin3;  Chinese Physicians Association Cardiovascular Medicine Physicians Branch, Chinese Expert Consensus on the Risk Assessment and Management of Panvascular Disease in Patients with Type 2 Diabetes Mellitus Expert Panel

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Cardiology Plus 7(4):p 162-177, October-December 2022. | DOI: 10.1097/CP9.0000000000000029
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Abstract

INTRODUCTION

Panvascular disease is a class of systemic vascular diseases that can involve large, medium-sized, and micro vessels. The primary target organs affected include the heart, brain, peripheral blood vessels, kidney, and retina[1,2]. Cardiovascular diseases (CVDs) are the leading cause of death among the Chinese population[3]. In 2019, CVD accounted for 46.74% and 44.26% of causes of death in rural and urban areas in China, respectively, and two of every five deaths were due to CVD. The current number of CVD patients in China is projected to be approximately 330 million, including 13 million cases of stroke, 11.39 million cases of coronary heart disease, and 45.3 million cases of lower extremity arterial disease[4]. In addition, the number of patients with chronic kidney disease (CKD) in China has reached 132.3 million, and CVD deaths caused by CKD and kidney dysfunction account for 4.6% of all deaths[5]. China is facing the simultaneous pressure of an aging population and the continued prevalence of metabolic risk factors. Hence, the burden of panvascular disease will continue to increase.

Type 2 diabetes mellitus (T2DM) is an important independent risk factor for panvascular disease and is closely associated with its development[6]. In China, approximately 141 million people have diabetes mellitus[7], and those with T2DM often have concomitant hypertension, dyslipidemia, obesity, and other significant metabolic risk factors for panvascular disease[8]. Compared with the non-diabetic population, panvascular disease in T2DM patients usually develops at a younger age and has an insidious onset, and vascular lesions have been observed in these patients at the time of detection, which may have caused myocardial infarction and stroke. The vascular lesions in T2DM patients are more extensive, severe, and likely to involve multiple sites[9–15]. Although subclinical atherosclerotic lesions are prevalent in T2DM patients, the prevention and treatment of vascular lesions are not the clinical focus. Treatment of panvascular disease in T2DM patients involves different disciplines, including cardiology, endocrinology, nephrology, neurology, ophthalmology, vascular surgery, and cardiovascular surgery. However, due to the subdivision of disciplines, each discipline tends to focus more on local lesions and neglects systemic vascular lesions, leading to incomplete prevention and treatment strategies for patients with T2DM. Therefore, early and systematic evaluation of vascular lesions in patients with T2DM and the development of comprehensive management strategies are important for preventing panvascular disease.

To promote multidisciplinary cooperation and integration, standardize the management of panvascular disease in T2DM patients, improve outcomes of T2DM patients with panvascular disease, and respond to the “Health China 2030” planning outline, “14th Five-Year Plan” national health plan, “Health China Action (2019-2030)” plan, and other policies on the prevention and control of vascular disease, a group of Chinese researchers in the fields of cardiovascular disease, endocrinology, nephrology, neurology, and health management led by the Chinese Society of Cardiology and Chinese Medical Association formed a “Chinese Expert Consensus on Risk Assessment and Management of Panvascular Disease in Patients with Type 2 Diabetes” study group to review the latest evidence and major developments in relevant domestic and international disciplines to develop the “2022 Chinese Expert Consensus on Risk Assessment and Management of Panvascular Disease in Patients with Type 2 Diabetes Mellitus” (hereinafter referred to as the Consensus), focusing on the processing and management strategies for risk assessment of panvascular disease in patients with T2DM.

EPIDEMIOLOGY OF PANVASCULAR DISEASE IN PATIENTS WITH T2DM

Large-sample data from epidemiological studies conducted in 31 provinces and cities across China between 2015 and 2017 showed that the standardized prevalence of diabetes in adults aged ≥ 18 years in mainland China was 12.8% (2018 American Diabetes Association criteria) or 11.2% (1999 World Health Organization criteria)[16]. The results of a prospective Chinese study on chronic disease showed that the risk of coronary heart disease and stroke in the diabetic population was approximately 1.5 to 2.5 times higher than that in the non-diabetic population, and CVD mortality was approximately 2 times higher than that in the non-diabetic population[17,18]. The overall prevalence of CVD in T2DM patients in China is 33.9%[19], and approximately 75% of T2DM patients eventually die from CVD.

Cerebral atherosclerosis and microvascular brain disease in T2DM patients can cause cognitive impairment[20]. A meta-analysis of large-sample domestic studies confirmed that the risk of developing cognitive dysfunction in patients with T2DM is significantly higher than in healthy individuals, and their risk of developing Alzheimer’s disease, vascular dementia, and mild cognitive impairment is 1.46, 2.48, and 1.21 times higher than in non-diabetic patients, respectively[21]. Among T2DM patients over 60 years of age, 20% may develop dementia[22]. The prevalence of diabetic kidney disease (DKD) in Chinese T2DM patients is 21.8%[23]. DKD has become a major cause of end-stage renal disease (ESRD)[24] and the leading cause of ESRD in the middle-aged and elderly population in China[25,26].

The prevalence of diabetic retinopathy (DR) among diabetic patients in mainland China is 23%, of which 19.1% of cases are milder non-proliferative DR (NPDR) and 2.8% of cases are proliferative DR (PDR)[27,28]. Among patients with DR, the annual rate of progression to vision-threatening DR ranges from 3.4% to 12.3%[29], making DR one of the leading causes of adult blindness[30,31]. However, there is a lack of large-scale epidemiological evidence from studies of T2DM patients with vascular disease in multiple sites.

PATHOPHYSIOLOGICAL MECHANISMS OF PANVASCULAR DISEASE IN T2DM PATIENTS

Currently, the basic pathological change in macroangiopathy and mesangiopathy in T2DM patients is believed to be atherosclerosis, primarily involving the aorta and coronary arteries. Microangiopathy is the pathological basis and specific manifestation of DKD and DR[32]. Vascular endothelial dysfunction is the initiating factor of panvascular disease in patients with T2DM.

Endothelial dysfunction

The early stage of vasculopathies in T2DM patients is dominated by endothelium-dependent diastolic dysfunction, which is the initiating factor and basic pathophysiological change that causes vasculopathies, with vascular endothelial cell dysfunction at its core. Hyperglycemia and high cholesterol decrease nitric oxide synthase production or activity, decreasing nitric oxide production and endothelium-dependent diastolic function and leading to vascular dysfunction and the development of atherosclerosis. Endothelial cell apoptosis is the initiating event of diabetic macroangiopathy, which not only damages vascular endothelial structure but severely impacts endothelial cells’ normal function and promotes the development of vasculopathies[33]. In addition, metabolic disorders associated with insulin resistance are major causes of vascular endothelial dysfunction and, consequently, results in atherosclerosis[34].

Atherosclerosis

The mechanisms of atherosclerosis in patients with T2DM involve hyperglycemia, abnormal lipid metabolism, insulin resistance, inflammation, hypercoagulable state, and epigenetics[35]. Disorders of lipid metabolism, insulin resistance, hyperinsulinemia, and abnormal fibrinolysis and coagulation can accelerate the progression of atherosclerosis. Furthermore, epigenetic changes in microRNA expression can affect the regulation of atherosclerosis target genes in T2DM patients, which may be a key event in the progression of atherosclerosis[36,37]. In patients with T2DM, atherosclerosis can be secondary to pathological changes, such as intraplaque hemorrhage, plaque rupture, thrombosis, aneurysm rupture, and atherosclerotic stenosis.

Microangiopathies

There is no consensus on the cellular and molecular mechanisms underlying the development of microangiopathy in patients with T2DM. Currently, it is believed that two aspects are involved, namely the formation of glucotoxic products associated with hyperglycemia and their effects on cell signaling pathways. The former primarily involves the activation of the polyol pathway, increased oxidative stress, formation of advanced glycation end products, and activation of the hexose pathway. The latter includes the activation of various signaling pathways, such as the protein kinase C pathway, mitogen-activated protein kinase pathway, and inflammatory signaling cascades. Pathological changes in DKD include glomerular podocyte and endothelial cell damage, mesangial matrix expansion, thickening of the glomerular basement membrane, atherosclerosis, tubular atrophy, and interstitial fibrosis, with clinically detectable proteinuria and/or decreased glomerular filtration rate (GFR)[38,39]. DR is primarily characterized by an imbalance in homeostasis of the retinal vasculature and internal environment of cells. The blood–retina barrier is compromised in the early stages of diabetes, with increased permeability, microvascular leakage, late retinal neovascularization, fibrosis, and eventually structural changes in or even complete loss of retinal microvascular cells[40] and decellularization of capillaries[41–43]. In addition, defects in neurosensory retina function in T2DM patients develop prior to microangiopathy[44,45] and involve all retinal nerve cells[46–49].

MULTIDISCIPLINARY COLLABORATIVE TREATMENT OF PANVASCULAR DISEASE IN PATIENTS WITH T2DM

The risk assessment and management model for panvascular disease in T2DM patients should be a systematic assessment, including the early assessment of risk factors, vascular structure and function, and target organ damage; prediction of risk of long-term cardiovascular and cerebrovascular events; and integrated multidisciplinary management (including the disciplines of cardiology, endocrinology, nephrology, neurology, ophthalmology, and vascular surgery). The management of panvascular disease includes lifestyle adjustments (adjustment of dietary structure, weight reduction for obese patients, exercise, and smoking and alcohol cessation), control of hyperglycemia, hypertension, and lipid metabolism disorders, and use of organ-protecting drugs. In addition, the active promotion of systematic self-management and health education should be performed for T2DM patients regularly so that when risk factors, vasculopathies, or target organ damage are detected, the multidisciplinary collaborative treatment model can help control the disease, reduce costs, and delay disease progression.

All levels of medical institutions are encouraged to establish multidisciplinary collaborative treatment groups for panvascular disease in T2DM, conduct joint consultations for T2DM patients, and develop standardized risk assessment and management pathways. Systemic risk assessment and follow-up of panvascular disease should be conducted at least once a year at diagnosis and follow-up of T2DM to subsequently prevent the development of panvascular disease in T2DM patients.

Recommendation 1: Systematic risk assessment and multidisciplinary follow-up for panvascular disease in T2DM patients should be conducted at diagnosis and at least once annually subsequently.

Risk assessment of panvascular disease in patients with T2DM

Patients with T2DM should be routinely interviewed and undergo a physical examination and general laboratory tests, such as urinalysis, liver function tests, kidney function tests, blood glucose, glycated hemoglobin A1c (HbA1c), insulin, and C-peptide. In addition, systematic risk assessment for panvascular disease (Table 1) should be performed for early detection of subclinical atherosclerosis and target organ damage.

Table 1 - Risk assessment of panvascular disease in T2DM patients
Evaluation parameter Evaluation indicator Evaluation frequency
Risk factors Sex, age, BMI, history of smoking or alcohol, duration of diabetes, dyslipidemia, hypertension, family history of cardiovascular disease, and early-onset cardiovascular disease Baseline* + at least once per year
Vascular structure and function Ankle-brachial index, brachial-ankle pulse wave velocity, carotid ultrasound Baseline* + at least once per year
CT coronary angiography Examination indicated for a long duration of disease (eg, over 10 years) or possible asymptomatic myocardial ischemia or comorbidities of large- or medium-sized vessels
Target organ damage
Heart Cardiac muscle-specific biomarkers (NT-proBNP/BNP and hs-cTn) Baseline* + at least once per year
ECG Baseline* + at least once per year
Transthoracic echocardiography Examination indicated for patients with elevated myocardial markers or comorbid hypertension, abnormal ECG, or abnormal cardiac auscultation findings
Brain Extracranial vessels: carotid ultrasound Examination indicated for patients with risk factors such as a history of smoking, hyperlipidemia, hypertension, or concomitant cerebrovascular diseases such as stroke or transient ischemic attack
Intracranial vessels: transcranial Doppler ultrasound Examination indicated for patients with a history of smoking, hypertension, carotid plaques, and other risk factors for stroke
Cognition function: Mini-Mental State Examination, Montreal Cognitive Assessment T2DM patients aged ≥65 years or who present with difficulty with self-care activities resulting in a significant decline in clinical condition should undergo cognitive function assessment every 1–2 years as appropriate
Small vessels and micro vessels: Head CT or MRI brain structure imaging examination At least once after diagnosis of T2DM, examination indicated for patients with a high likelihood of cognitive dysfunction
Peripheral blood vessels Assessment of clinical symptoms and signs such as intermittent claudication, as well as skin temperature measurement, pulse palpation of the dorsalis pedis artery and the posterior tibial artery, and auscultation for femoral artery bruits. If any of these abnormalities are present, ABI, color Doppler ultrasound of the lower extremity arteries, and other examinations should be performed Patients aged >50 years with risk factors associated with the development of LEAD (cardiovascular disease, dyslipidemia, hypertension, history of smoking) or diabetes mellitus for over 5 years should be evaluated at least once annually
Kidney Urine albumin/creatinine ratio, serum creatinine Baseline* + at least once per year
Retina Eye examination, eg, visual acuity, intraocular pressure, iridocorneal angle, iris, lens, and fundus examination Baseline* + at least once per 1–2 years
*T2DM patients at the time of diagnosis or the first visit.
ABI: ankle-brachial index; BMI: body mass index; CT: computed tomography; ECG: electrocardiography; hs-cTn: high-sensitivity cardiac troponin; LEAD: lower extremity atherosclerotic disease; MRI: magnetic resonance imaging; NT-proBNP/BNP: N-terminal pro-B-type natriuretic peptide; T2DM: type 2 diabetes mellitus.

Recommendation 2: Systematic assessment of panvascular disease in patients with T2DM should include risk factors, vascular structure and function, and target organ damage at minimum.

Risk factors

Patients with T2DM are at high risk of panvascular disease. Therefore, they should be evaluated at least once annually for risk factors of panvascular disease, including sex, age, body mass index, waist circumference, history of smoking and alcohol consumption, duration of diabetes, dyslipidemia, hypertension, history of cardiovascular disease, and family history of early-onset CVD after diagnosis of T2DM and subsequently at follow-up. Among these, dyslipidemia is a major risk factor for the development of cardiovascular complications in patients with T2DM[50,51]. The prevalence of dyslipidemia in patients with T2DM is significantly higher than in the non-diabetic population and is characterized by (1) elevated fasting and postprandial triglyceride (TG) levels; (2) decreased high-density lipoprotein cholesterol (HDL-C) levels; (3) normal or mildly elevated serum total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels, qualitative changes in LDL-C, and elevated small dense low-density lipoprotein (sdLDL-C) levels; and (4) elevated apolipoprotein B (ApoB) and apolipoprotein CIII (ApoCIII) levels[52]. In patients with T2DM, elevated lipoprotein(a) is associated with an increased risk of coronary and cardiovascular events[53]. Based on current routine clinical lipid testing protocols, T2DM patients should be evaluated at least once annually with a lipid panel that includes total cholesterol, TG, LDL-C, HDL-C, and ApoB after diagnosis of T2DM and subsequently at follow-up. Lipoprotein(a) levels should be determined at least once after diagnosis in patients with T2DM. When the TG level is elevated in patients with T2DM, non-HDL-C and ApoB more accurately reflect the number of atherogenic lipoprotein particles[54]; hence, LDL-C, non-HDL-C, and ApoB are recommended as diagnostic and therapeutic targets in patients with T2DM[55].

Recommendation 3: Patients with T2DM should be evaluated at least once annually with a lipid panel that includes total cholesterol, TG, LDL-C, HDL-C, and ApoB after diagnosis of T2DM and subsequently at follow-up. In addition, lipoprotein(a) levels should be determined at least once after diagnosis in patients with T2DM. LDL-C, non-HDL-C, and ApoB are recommended as primary diagnostic and therapeutic targets.

Vascular structure and function

The abnormal glucose metabolism in T2DM patients is closely associated with structural and functional deficits of blood vessels. Therefore, ankle-brachial index (ABI), brachial-ankle pulse wave velocity (baPWV), carotid ultrasound, coronary computed tomography angiography (CCTA), and other tests play important roles in early diagnosis, risk stratification, and prognostic evaluation of vascular diseases involving large- and medium-sized vessels and are essential for the early prevention and treatment of panvascular diseases in patients with T2DM.

  1. ABI: Refers to the ratio of the systolic blood pressure of the posterior tibial artery or dorsalis pedis artery to the systolic blood pressure of the brachial artery. It is used to assess the degree of arterial obstruction and luminal stenosis and is a common tool for the early diagnosis of obstructive lower extremity disease[56,57]. Studies have shown that the frequency of coronary events increases with decreasing ABI and its predictive accuracy is higher than that of the Framingham risk score[58]. The sensitivity and specificity of ABI for predicting coronary events are 16.5% and 92.7%, respectively, and 41.0% and 87.9%, respectively, for predicting cardiovascular death[59]. Normal reference values for ABI ranges from 1.00 to 1.30, with 0.91–0.99 indicating a borderline state, ABI ≤ 0.9 indicating lower extremity arterial pathology, and ABI > 1.30 indicating vascular calcification and impaired arterial elasticity[60].
  2. baPWV: Measured by recording pulse wave propagation time and distance in the brachial and ankle arteries. baPWV represents the speed of pulse wave propagation to the peripheral vasculature during the ejection of blood from the heart. It serves as an index for evaluating atherosclerotic or coronary atherosclerotic diseases and can be used independently to predict the risk of cardiovascular and cerebrovascular events[61,62]. baPWV has a normal reference value of < 1,400 cm/s, and values above this threshold indicate decreased elasticity of the large- and middle-sized arteries and increased arterial stiffness[63]. However, it should be noted that baPWV results are susceptible to several factors, including blood pressure.
  3. Carotid ultrasound: The carotid artery is a site prone to atherosclerosis, and sclerotic lesions in the carotid artery often develop before they do in the coronary arteries and cerebral vessels. Carotid ultrasound is used to evaluate the presence of carotid artery lesions by measuring intima-media thickness (IMT), atherosclerotic plaques, internal artery diameter, stenosis, and hemodynamic parameters. A meta-analysis showed that each 0.1 mm increase in carotid IMT was associated with a 15% increase in the risk of coronary heart disease and a 17% increase in the risk of stroke[64]. Compared to the healthy population, patients with T2DM already have an early and pre-diabetic concomitant damage of the carotid artery intima. Carotid stenosis and atherosclerosis further increase the risk of cardiovascular and cerebrovascular events and all-cause mortality in patients with T2DM[65,66]. Therefore, early evaluation of carotid stenosis and plaques to predict the risk of CVD is recommended for patients with T2DM, especially those with other concomitant risk factors for cardiovascular and cerebrovascular disease (such as smoking, hyperlipidemia, hypertension, and history of stroke or transient ischemic attack)[67]. Carotid IMT ≥0.9 mm or the presence of carotid atheromatous plaque suggests carotid artery disease[68]. If carotid lesions are diagnosed, further CT or magnetic resonance imaging (MRI) angiography should be performed to evaluate the condition of the lumen and plaque.
  4. CCTA: This is used to evaluate coronary artery calcification for risk stratification of coronary artery disease and the structure of the coronary artery lumen and wall, and to identify high-risk plaques and prognostic evaluation. Coronary artery calcification scores can be used for risk stratification of coronary artery disease by observing the degree of coronary artery wall calcification[69,70]. Currently, the most common scoring system used in the clinic is the Agatston score. An Agatston score of 0 predicts a low 10-year risk of cardiovascular events in patients with T2DM, a score <100 indicates a low risk of cardiovascular events (2.1-fold increased risk of coronary events), a score ranging from 100 to 400 indicates an intermediate risk of cardiovascular events (4.2-fold increased risk of coronary events), and a score >400 indicates a high risk of cardiovascular events (7.2-fold increased risk of coronary events)[71]. CCTA allows for visualization of the lumen and wall structure for qualitative analysis of coronary plaque characteristics and density. High-risk plaques indicated by CCTA, such as positive remodeling, low-density and high-volume plaques, spotty plaque calcification, and “napkin ring” sign, are closely associated with clinical outcomes. Patients with ≥2 of these high-risk factors have a 9.17-fold increase in the incidence of major adverse cardiovascular events (MACEs) compared to patients without these factors[72]. Thus, CCTA can be used for a quantifiable follow-up of lesion progression and evolution of coronary heart disease or atherosclerotic plaques. In addition, CCTA can be used for monitoring pericoronary fat, assessing coronary inflammation, tracking changes in vascular inflammation after plaque rupture events, and predicting all-cause mortality and cardiac mortality[73]. The results of the FACTOR-64 trial showed that CCTA screening of diabetic patients without cardiovascular disease symptoms and with a disease duration of at least 3–5 years did not reduce the risk of cardiovascular events (all-cause mortality, non-fatal myocardial infarction, or the composite endpoint of unstable angina requiring hospitalization) at a mean follow-up period of 4 years compared to standard care[74]. Therefore, screening for CCTA is recommended for T2DM patients with a long duration of disease (eg, over 10 years) or other tests, such as electrocardiography (ECG) suggesting possible asymptomatic myocardial ischemia or comorbidities of large- or medium-sized vessels, such as stroke and peripheral vascular disease. However, the clinical use of CCTA requires the exclusion of contraindications, such as a known history of severe iodine contrast allergy, renal insufficiency [GFR < 60 mL min−1 (1.73 cg)−1], or pregnancy or suspected pregnancy.

Recommendation 4: Patients with T2DM should undergo ABI, baPWV, and carotid ultrasound evaluation at diagnosis and at least once annually and subsequently at follow-up to evaluate vascular lesions and predict the risk of cardiovascular events.

Recommendation 5: T2DM patients with a long duration of disease (eg, over 10 years) or who may have asymptomatic myocardial ischemia or comorbidities of large- or medium-sized vessels should undergo CCTA to evaluate coronary artery calcification, luminal stenosis, and plaque burden.

Target organ damage

The risk assessment of target organ damage is an important component of the risk assessment of panvascular disease in patients with T2DM. An early detection of subclinical target organ damage and timely intervention can reverse subclinical target organ damage. Therefore, assessment of target organ damage should be proactively performed as early as possible in patients with T2DM.

Heart

CVD is often asymptomatic at early stages in patients with T2DM. Therefore, clinicians should proactively assess heart structure and function in patients with T2DM, and patients with symptoms should undergo relevant examinations and treatment promptly.

  1. N-terminal pro-B-type natriuretic peptide/B-type natriuretic peptide (NT-proBNP/BNP): The development and progression of cardiovascular events in patients with T2DM is significantly associated with increased NT-proBNP concentrations[75–77]. Every 100 pg/mL increase in NT-proBNP is associated with a 12% increase in a 5-year cardiovascular event-related hospitalization rate in patients with T2DM[78]. NT-proBNP >125 pg/mL predicts a higher risk of future cardiovascular events in patients with T2DM[79–81]. The results of the PONTIAC trial showed that T2DM patients with NT-proBNP > 125 pg/mL who underwent intensified cardioprotective therapy had a 65% reduced risk of hospitalization or death from cardiovascular disease after 2 years[82]. T2DM patients are recommended to be tested for NT-proBNP/BNP at least once annually. If NT-proBNP >125 pg/mL or BNP >50 pg/mL is discovered or if elevated test values are detected by serial monitoring, which is suggestive of possible alterations of heart structure or function, further transthoracic echocardiography evaluation and immediate initiation of cardioprotective therapy are required[83] while increasing the frequency of follow-up, with testing recommended at least once every 6 months.
  2. High-sensitivity cardiac troponin (hs-cTn): hs-cTn is a specific and highly sensitive marker of myocardial injury[84] and can reflect chronic subclinical myocardial injury in patients with T2DM[85,86]. The results of the ARIC trial showed that patients with T2DM had a significantly higher risk of elevated hs-cTnT (≥14 ng/L) compared to the non-diabetic population and a significantly increased relative risk of coronary heart disease, heart failure, and all-cause mortality within the next 5 years[87]. Therefore, T2DM patients are recommended to be tested for hs-cTn at least once annually. If the test value exceeds the upper limit of the reference value or if elevated values are detected by serial monitoring, which is suggestive of cardiomyocyte damage, cardioprotective therapy should be initiated immediately[83] while increasing the frequency of follow-up, with testing recommended at least once every 6 months.
  3. T2DM patients should undergo routine ECG annually. Those with myocardial ischemic manifestations on ECG or symptoms of chest tightness and precordial catch syndrome should undergo cardiac stress testing or CCTA.
  4. Transthoracic echocardiography: Patients with T2DM are prone to structural and functional changes in the left ventricle and often present with subclinical left ventricular diastolic insufficiency[88–90]. Transthoracic echocardiography can be used for the early diagnosis of changes in left ventricular diastolic function by measuring atrial and ventricular volumes, measuring early diastole flow velocity (E) and late diastole flow velocity (A), calculating the E/A ratio, and other indexes to observe the cardiac anatomy[91,92]. Transthoracic echocardiography is recommended for T2DM patients with elevated myocardial markers or comorbid hypertension, abnormal ECG, or abnormal cardiac auscultation findings.
  5. Other indexes: High-sensitivity C-reactive protein (hs-CRP) is associated with an increased risk of CVD, with hs-CRP ≥ 0.2 mg/L significantly increasing the risk of cardiovascular events[93]. In addition, novel inflammatory response markers such as growth differentiation factor 15, which reflects cellular injury and inflammatory response, and soluble suppression of tumorigenicity 2, which reflects the degree of cardiomyocyte dysfunction and tissue fibrosis, have also been significantly associated with the development of CVD[94–97]. These inflammatory markers warrant further attention and investigation before they can be clinically relevant. It should also be noted that the specificity of these markers may be significantly affected by any concomitant infectious or autoimmune diseases.

Recommendation 6: Patients with T2DM should be tested for NT-proBNP/BNP and hs-cTn at the time of diagnosis and at least once annually and subsequently at follow-up. If NT-proBNP >125 pg/mL, BNP >50 pg/mL, hs-cTn exceeding the upper limit of the reference range is discovered, or elevated NT-proBNP/BNP and hs-cTn test values are detected by serial monitoring, cardioprotective therapy should be initiated immediately, and the frequency of follow-up should be increased.

Recommendation 7: Patients with T2DM should undergo ECG at the time of diagnosis and at least once annually and subsequently at follow-up. In addition, transthoracic echocardiography should be performed in T2DM patients with elevated myocardial markers or comorbid hypertension, abnormal ECG, or abnormal cardiac auscultation findings.

Brain

The assessment of cerebrovascular disease in patients with T2DM includes extracranial vascular assessment, intracranial vascular assessment, assessment of cognitive function, and assessment of the small vessel and microvascular damage.

  1. Extracranial vascular assessment: T2DM patients with risk factors such as a history of smoking, dyslipidemia, hypertension, or cerebrovascular diseases such as stroke and transient ischemic attack should undergo an assessment of extracranial vessels (extracranial segment of carotid artery, extracranial segment of vertebral artery, and subclavian artery). The assessment includes IMT and the presence, size, stability, and degree of luminal stenosis of atherosclerotic plaques, and blood flow velocity. Carotid ultrasound is a common test for extracranial vessel assessment and has the advantages of being non-invasive, simple, reproducible, and inexpensive. Other tests that can be performed include ultrasound of the aortic arch, CT angiography of the aortic arch branches, and contrast-enhanced MR angiography.
  2. Intracranial vascular assessment: T2DM is an independent risk factor for intracranial arterial stenosis and atherosclerosis. T2DM patients with concomitant risk factors for stroke, including a history of smoking, hypertension, and carotid plaques, should undergo intracranial vascular assessment (including the bilateral intracranial segment of the internal carotid arteries, bilateral middle cerebral arteries, bilateral anterior cerebral arteries, bilateral intracranial segment of the vertebral arteries, basilar artery, and bilateral posterior cerebral arteries). The assessment should include intracranial vascular blood flow velocity, degree of stenosis or occlusion, plaque formation, and development of collateral circulation. Transcranial Doppler ultrasound (TCD) is a common clinical examination. Other non-invasive tests include CT or MR angiography of the head.
  3. Cognitive function assessment: Patients with T2DM often present with cognitive impairment such as memory loss, comprehension loss, and executive dysfunction[98]. Therefore, T2DM patients aged ≥ 65 years or who present with difficulty with self-care activities (such as errors in insulin dose calculation and difficulties with carbohydrate calculation) resulting in a significant decline in clinical condition are recommended to undergo cognitive function assessment (commonly used neuropsychological assessment tools include the Mini-Mental State Examination and Montreal Cognitive Assessment) every 1–2 years, as appropriate.
  4. Assessment of small-vessel and microvessel damage: In T2DM patients, small-vessel and microvessel damage in brain tissue manifest primarily as multiple luminal infarcts, microhemorrhages, cerebral white matter lesions, and brain atrophy. Patients with T2DM are recommended to undergo at least one head CT or MRI (including T1WI, T2WI, and fluid attenuation inversion recovery sequences, diffusion-weighted imaging, and susceptibility weighting imaging) and other structural imaging of brain tissue after diagnosis. These examinations should be completed to assess possible alterations and determine the need for referral to neurology, especially in patients with a high risk of cognitive dysfunction[99].

Recommendation 8: T2DM patients with risk factors such as a history of smoking, dyslipidemia, hypertension, or cerebrovascular diseases such as stroke and transient ischemic attack should undergo an assessment of extracranial vessels.

Recommendation 9: T2DM patients with concomitant risk factors for stroke, including a history of smoking, hypertension, and carotid plaques should undergo intracranial vascular assessment.

Recommendation 10: T2DM patients aged ≥ 65 years or having difficulty with self-care activities resulting in a significant decline in clinical condition are recommended to undergo a cognitive function assessment every 1–2 years, as appropriate. In addition, patients with a higher likelihood of cognitive dysfunction should undergo structural imaging of the brain tissue, such as CT or MRI of the head.

Peripheral blood vessels

Peripheral vascular disease in patients with T2DM is usually referred to as lower extremity atherosclerotic disease (LEAD), which often involves small- and medium-sized arteries such as the deep femoral and anterior tibial arteries more often in patients with T2DM than in the non-diabetic population[100,101]. Clinically, LEAD is often comorbid with coronary artery disease and cerebrovascular disease and is suggestive of coronary artery disease and cerebrovascular disease[102]. LEAD can also increase the risk of cardiovascular events and mortality in patients with T2DM[103,104].

T2DM patients over 50 years of age are recommended to undergo routine LEAD assessment. Moreover, T2DM patients with risk factors associated with the development of LEAD, such as comorbid cardiovascular disease, dyslipidemia, hypertension, history of smoking, or diabetes mellitus, for over 5 years should be evaluated at least once annually. In addition, a comprehensive examination and evaluation of arterial lesions should be performed for T2DM patients with foot ulcers and gangrene regardless of age[60]. This evaluation should include a comprehensive assessment of clinical symptoms and signs and a physical examination of the arteries. If abnormalities are found, ABI and color Doppler ultrasound of the lower extremity arteries should be performed.

  1. Assessment of clinical symptoms and signs: Intermittent claudication is a common symptom of LEAD that manifests as weakness of the lower limbs and pain in the thigh or calf muscles when walking. Patients with severe cases of LEAD may present with ischemic rest pain, ischemic ulcers, or gangrene.
  2. Arterial physical examination: Skin temperature measurement, pulse palpation of the dorsalis pedis artery and posterior tibial artery, and auscultation for femoral artery bruits can provide valuable information for assessing asymptomatic LEAD. If abnormalities are found in these examinations, ABI and color Doppler ultrasound of the lower extremity arteries should be performed.
  3. ABI: T2DM patients with resting ABI ≤0.90 should be diagnosed with LEAD regardless of whether symptoms of lower extremity discomfort are present. Patients with lower extremity discomfort (ABI ≥ 0.90) with decreased ABI during exercise and resting, such as a 15%–20% decrease in ABI after exercise bike stress testing, should also be diagnosed with LEAD. Patients with resting ABI < 0.40, ankle artery pressure < 50 mmHg (1 mmHg = 0.133 kPa), or toe pressure < 30 mmHg should be diagnosed with severe limb ischemia.
  4. Other examinations: Color ultrasound Doppler of the lower extremity arteries is also often used in the screening and diagnosis of LEAD because it is non-invasive, highly accessible, and can be used to assess the status of the arterial wall, including IMT, atherosclerotic plaques, and calcification. Moreover, this technique can be used for diagnosis of LEAD if luminal stenosis or occlusion is present[101]. Diagnosis of LEAD can be further confirmed by CT or MR angiography and digital subtraction angiography when necessary to further elucidate the patient’s condition and rationalize a treatment plan.

Recommendation 11: T2DM patients over the age of 50 years or with risk factors associated with the development of LEAD, such as comorbid cardiovascular disease, dyslipidemia, hypertension, history of smoking, or diabetes mellitus, for over 5 years should be evaluated for LEAD at least once annually.

Recommendation 12: The assessment of peripheral vascular disease in T2DM patients should include the assessment of clinical symptoms and signs such as intermittent claudication, skin temperature measurement, pulse palpation of the dorsalis pedis artery and posterior tibial artery, and auscultation for femoral artery bruits. If any of these abnormalities are present, ABI, color Doppler ultrasound of the lower extremity arteries, and other examinations should be performed.

Kidney

DKD may be asymptomatic at early stages, and regular assessment can facilitate early its detection and diagnosis. Therefore, T2DM patients should undergo urine albumin and serum creatinine testing for the early detection of DKD at the time of diagnosis and at least once annually subsequently[105].

  1. Urine albumin: Excretion of albumin in the urine is measured by the urine albumin creatinine ratio (UACR), with UACR ≥ 30 mg/g considered positive. The detection of urinary albumin is should be performed with first-morning urine. Outpatients can be tested with random urine; however, urinary creatinine must be tested simultaneously for accuracy[106]. Because multiple factors such as fever, significant hyperglycemia, uncontrolled hypertension, infection, congestive heart failure, and pregnancy can lead to a transient increase in urinary albumin excretion[107], T2DM patients with abnormal UACR are recommended to undergo UACR re-examination within 3–6 months. Albuminuria should only be diagnosed if at least two of three results are at or outside the threshold value and other influencing factors are excluded.
  2. Serum creatinine: Serum creatinine is used to calculate the estimated GFR (eGFR) using either the CKD Epidemiology Collaboration (CKD-EPI) formula (see http://www.nkdep.nih.gov) or the Modification of Diet in Renal Disease (MDRD) formula. eGFR < 60 mL min−1 · (1.73 m2) −1 is diagnosed as decreased GFR[108]. This formula is only applicable to patients with stable blood creatinine levels and not in cases of pregnancy, acute renal failure, amputation, paraplegia, and reduced muscle mass or muscle wasting diseases such as severe obesity or malnutrition, or in patients with special diets (such as the vegan diet).
  3. Other indexes: Biomarkers of glomerular filtration barrier injury (such as urinary transferrin and urinary IgG), glomerular endothelial cell and podocyte injury (such as α-actin 4, mucopolysaccharide, nephrin, podocalyxin, and antibodies to synaptopodin), and renal tubular injury (such as cystatin C, β2-microglobulin, α1-microglobulin, retinol-binding proteins, neutrophil gelatinase-associated lipocalin transport protein, and kidney injury molecule-1)[109–112], can also facilitate the early detection of renal injury in diabetic patients; however, further research is needed to validate this.
  4. Clinically, DKD is often diagnosed based on persistently elevated UACR and/or decreased eGFR excluding other CKDs[105]. After a diagnosing of DKD, the grade of CKD should be determined based on eGFR and urinary albumin levels to assess the risk of DKD progression and evaluate its frequency (Table 2). Patients in stages G4A3 and G5 have complex disease states, rapid progression, and more complications (including electrolyte disorders, severe edema, and polyserous effusions). They are recommended to undergo re-examination at an increased frequency of four or more times per year, depending on the clinical condition of the patient.
Table 2 - Risk of CKD progression and assessment frequency based on eGFR and UACR grade [108]
eGFR [mL·min¹·(1.73 m²)¹] UACR grade
A1 (UACR < 30 mg/g) A2 (UACR: 30–299 mg/g) A3 (UACR ≥ 300 mg/g)
Grade 1 (G1): ≥90 1 (if CKD present) 1 2
Grade 2 (G2): 60–89 1 (if CKD present) 1 2
Grade 3a (G3a): 45–59 1 2 3
Grade 3b (G3b): 30–44 2 3 3
Grade 4 (G4): 15–29 3 3 ≥4
Grade 5 (G5): <15 ≥4 ≥4 ≥4
Values in the table: recommended number of re-examinations per year. Background colors represent a risk of CKD progression. Green: low risk; Yellow: moderate risk; Orange: high risk; Red: extremely high risk.
CKD: chronic kidney disease; eGFR: estimated glomerular filtration rate; UACR: urine albumin/creatinine ratio

Recommendation 13: Patients with T2DM should undergo UACR and serum creatinine testing at the time of diagnosis and at least once annually subsequently.

Recommendation 14: After diagnosing of DKD, the grade of CKD should be determined based on eGFR and urinary albumin levels to assess the risk of DKD progression and evaluate its frequency.

Retina

DR is a chronic complication highly specific to T2DM patients. In addition to impairing visual acuity, DR significantly increases the risk of cardiovascular disease and all-cause mortality in patients with T2DM[113,114]. T2DM patients are also at a high risk for early-onset eye diseases such as cataracts, glaucoma, keratopathy, and ischemic optic neuropathy. Therefore, T2DM patients should undergo a comprehensive eye examination promptly after diagnosis to assess visual acuity, intraocular pressure, iridocorneal angle, and the iris, lens, and fundus (to observe capillary hemangioma, intraretinal hemorrhage, hard exudates, cotton wool spots, intraretinal microvascular abnormalities, venous beading, neovascularization, vitreous hemorrhage, preretinal hemorrhage, and fibrous hyperplasia).

  1. Assessment methods: Non-dilated fundus examination, which has better sensitivity and specificity, is recommended for DR screening. High-quality fundoscopy images can screen out the most clinically significant cases of DR[115,116]. However, it should be noted that a non-dilated fundus examination is ineffective in screening for diabetic macular edema (DME). If severe DME or signs of moderate DR beyond the non-proliferative stage are present, it is recommended to refer the patient to an ophthalmologist for optical coherence tomography and fluorescein angiography, as well as fundus ultrasonography if necessary[117]. In addition, in some diabetic patients with miosis and/or cataract, the image quality of non-dilated fundus examination is often substandard, and referral to an ophthalmologist is required for further examination. In recent years, artificial intelligence has demonstrated great potential for DR screening, staging, and diagnosis[118,119]. Thus, hospitals or medical institutions can apply relevant artificial intelligence software or systems approved by the State Food and Drug Administration for fundus screening.
  2. Assessment frequency: T2DM patients without DR should be evaluated once every 1–2 years. If DR has developed, the follow-up interval should be shortened. Patients with NPDR should be evaluated annually, patients with moderate NPDR should be evaluated every 3–6 months, and patients with severe NPDR and PDR should be evaluated every 3 months. Pregnant T2DM patients should undergo ophthalmologic examination before or at the first obstetric examination, every 3 months during pregnancy, and within 1 year after delivery[116,120]. DR that progresses or threatens vision should be followed up and managed by an ophthalmologist.

DR is often associated with DKD, and DR with comorbid microalbuminuria can also be used as an adjunctive diagnostic indicator for diabetic nephropathy[121]. Therefore, T2DM patients presenting with microalbuminuria or decreased GFR should be screened for DR.

Recommendation 15: Patients with T2DM should undergo a comprehensive eye examination at the time of diagnosis and at least once every 1–2 years subsequently to assess visual acuity, intraocular pressure, iridocorneal angle, the iris, and the lens. The frequency of assessment should be increased in patients with DR.

Recommendation 16: T2DM patients with microalbuminuria or decreased GFR require immediate DR screening.

MANAGEMENT STRATEGIES FOR PANVASCULAR DISEASE IN T2DM PATIENTS

Management strategies for panvascular disease in patients with T2DM are comprehensive. Emphasis is placed on glycemic, blood pressure, lipid, and weight control based on lifestyle interventions and anti-platelet therapy when indicated, depending on the vasculopathy or target organ damage in panvascular disease.

Lifestyle interventions

Lifestyle interventions are the foundation for the management of panvascular disease in T2DM patients. Long-term compliance is recommended for all T2DM patients with comorbid panvascular disease. Principal interventions include dietary management, exercise, weight management, smoking cessation, and alcohol restriction[68,120].

  1. Dietary management: This includes rational diet and balanced nutrition. The “Chinese Guidelines for the Prevention and Treatment of Type 2 Diabetes Mellitus (2020 edition)” recommends a daily energy intake of 25–30 kcal/kg for diabetes patients, which can be adjusted as needed based on weight, activity level, age, sex, and stress level. Patients with T2DM should reduce sodium intake by limiting daily sodium intake to 5 g, with further restriction in patients with comorbid hypertension. Potassium intake can be increased appropriately. Patients are encouraged to consume more potassium-rich foods, such as fresh vegetables, fruits, and legumes. In patients with good renal function, low-sodium potassium-enriched salt can be used as a substitute for table salt[122]. Patients with DKD should pay attention to protein and potassium intake. The recommended protein intake for DKD patients not on dialysis is 0.8–1.0 g/kg/day; because dialysis patients are often malnourished, protein intake in these patients can be increased to 1.0–1.2 g/kg/day[123]. Protein sources should primarily include high-quality animal protein, and supplementation with compound α-keto acid preparations can be considered if necessary. For patients with diabetic nephropathy with comorbid hyperkalemia, foods containing potassium should be restricted, and appropriate therapeutic measures should be taken. Similarly, changes in blood electrolytes should be monitored regularly to facilitate timely treatment plan adjustment as needed.
  2. Exercise management: Reasonable levels of exercise can improve insulin sensitivity, skeletal muscle function, and metabolic disorders, which improves quality of life. Patients with T2DM should engage in at least 150 minutes of moderate-intensity aerobic exercise plus resistance training every week. However, attention should be paid to individualized exercise programs based on the patient’s disease duration, disease severity, and complications before exercise, and monitoring blood glucose before and after exercise to prevent hypoglycemia. For patients with concomitant peripheral vascular disease, such as ischemic foot with intact skin, the most effective exercise is the treadmill exercise or walking at an intensity sufficient to trigger intermittent claudication, followed by a 30–45 minutes of rest, at least three times a week for at least 3–6 months[124–127].
  3. Weight management: Patients who are overweight or obese should consider weight loss and long-term adherence to maintain a body mass index of 20.0–24.0 kg/m2. Overweight or obese T2DM patients should avoid the use of hypoglycemic drugs that increase body weight and should prioritize the use of a glucagon-like peptide-1 receptor agonist (GLP-1RA) and sodium-glucose cotransporter-2 inhibitor (SGLT2i), which have weight-improving effects[128].
  4. Smoking cessation: Smoking increases the risk of CVD in patients with T2DM[129]. Smoking cessation is associated with a reduced risk of CVD, reduced all-cause mortality[130], and delayed development of diabetic nephropathy[131]. Patients with T2DM are advised against smoking. Moreover, passive smoking should be avoided, and patients who smoke should quit promptly.
  5. Alcohol restriction: Patients with T2DM are advised against alcohol consumption. If alcohol is consumed, the total energy contained in the alcohol should be calculated. The amount of alcohol consumed in a day should not exceed 15 g for women and 25 g for men (15 g of alcohol is equivalent to 350 mL of beer, 150 mL of wine, or 45 mL of hard liquor). Alcohol should not be consumed more than twice per week.

Recommendation 17: Patients with T2DM should maintain good adherence to long-term lifestyle interventions, including dietary management, exercise, weight management, smoking cessation, and alcohol restriction.

Blood glucose management

Glucose reduction strategies include lifestyle management, glucose monitoring, diabetes education, and the use of hypoglycemic agents. T2DM patients with panvascular disease should receive systematic diabetes self-management education and be able to perform effective glucose monitoring (capillary glucose monitoring, continuous glucose monitoring, and measurement of time-in-range HbA1c and glucose), as well as continuing education of disease management concepts for diabetes-related panvascular disease.

  1. Glycemic control targets: HbA1c is the most critical index reflecting glycemic control. The HbA1c control target should be stratified and adjusted immediately as needed based on the patients age, disease duration, condition, and adverse drug reactions[132]. For younger T2DM patients or those with shorter disease duration, longer life expectancy, no complications, and uncomplicated CVD without hypoglycemia or other adverse reactions, stricter HbA1c control targets (for example, <6.5% or even as close to normal as possible) should be established. Conversely, for older T2DM patients or those with longer disease duration, a history of severe hypoglycemia, shorter life expectancy, microvascular or macrovascular complications, or severe comorbidities, relatively lenient HbA1c targets can be established.
  2. Selection and use of hypoglycemic drugs: Drug selection should be individualized based on the vascular lesions and target organ damage in T2DM patients with panvascular disease. Metformin remains the first choice and foundational drug for glycemic control in all T2DM patients[120].

T2DM panvascular disease with the heart, brain, or peripheral vasculature as target organs should be treated with GLP-1RA or SGLT2i in addition to metformin as long as it is not contraindicated. T2DM panvascular disease with the kidney as the target organ, such as in the presence of proteinuria, should be treated with SGLT2i in addition to metformin to delay the progression of DKD as long as it is not contraindicated and the patient has eGFR ≥45 mL min−1 (1.73 m2) −1. The use of GLP-1RA can be considered if SGLT2i cannot be used. If the retina is the target organ of T2DM panvascular disease and if there are concomitant high-risk factors for cardiac, cerebral, or peripheral vascular diseases, such as age ≥55 years and at least one of coronary, carotid, or lower limb artery stenosis ≥50%, or left ventricular hypertrophy, the patient should also be treated with GLP-1RA or SGLT2i in addition to metformin as long as it is not contraindicated.

If this treatment does not meet therapeutic requirements after 3 months, a different class of hypoglycemic agent should be added. If oral medication and 1–2 daily insulin injections (basal or premixed insulin) do not meet requirements, the treatment regimen can be adjusted to multiple insulin therapy (basal-bolus insulin or multiple daily premixed insulin) in T2DM patients with good self-management ability. Thiazolidinediones (such as rosiglitazone and pioglitazone) should be avoided in patients with DME, as evidence suggests that they may increase the risk of DME[133]. In patients with DKD, if the GFR is decreased, hypoglycemic agents with less excretion from the kidneys may be preferred. Patients with eGFR <45 mL min−1 · (1.73 m2) −1 should be treated with oral medications adjusted according to the drug instructions or with insulin[105]. Adverse effects associated with hypovolemia, such as orthostatic hypotension and dehydration, should be avoided during initial dosing of SGLT2. Renal function should be monitored at least once annually before and during initial dosing for any development of acute kidney injury. SGLT2i should be discontinued in patients with eGFR <30 mL min−1 · (1.73 m2) −1.

In T2DM patients aged ≥60 years, before initiating hypoglycemic agent therapy, the effects on organ function that influence the choice of hypoglycemic agent, the need for the combination of drugs, and factors affecting medication adherence (economic factors and self-management ability) should be evaluated holistically. In addition, the possible adverse effects of the hypoglycemic agent used must be fully considered, to prevent the development of severe hypoglycemia.

Figure 1 shows an illustration of blood glucose management for panvascular disease in T2DM patients.

F1
Figure 1.:
Flowchart for glycemic management of panvascular disease in T2DM patients. DR: diabetic retinopathy; DKD: diabetic kidney disease; GLP-1RA: glucagon-like peptide-1 receptor agonist; HbA1c: glycated hemoglobin; SGLT2i: sodium-glucose cotransporter-2 inhibitors; T2DM: type 2 diabetes mellitus.

Recommendation 18: Glucose reduction strategies for T2DM patients with panvascular disease include lifestyle management, glucose monitoring, diabetes education, and the use of hypoglycemic agents. Metformin alone or in combination with GLP-1RA or SGLT2i should be selected as the first-line hypoglycemic agent as long as it is not contraindicated.

Blood pressure management

Blood pressure should be routinely measured in patients with T2DM after diagnosis and at follow-up. If necessary, home and 24-hours ambulatory blood pressure monitoring are recommended for effective blood pressure management. Lifestyle intervention, including health education, reducing sodium intake, increasing potassium intake, proper diet, weight control, smoking and alcohol cessation, increasing exercise, reducing mental stress, and maintaining psychological balance, remain important measures for controlling hypertension[134].

  1. Blood pressure management targets: The targets include <130/80 mmHg for adults and <135/85 mmHg for pregnant women. Blood pressure reduction targets may be relaxed in older patients depending on the severity of comorbidities, assessment of treatment tolerance, and possible treatment adherence-related factors. The recommended blood pressure target is <140/90 mmHg for patients aged ≥65 years and <150/90 mmHg for patients aged ≥80 years[128].
  2. Intervention regimen for T2DM patients with elevated blood pressure: Systolic blood pressure 130–139 mmHg or diastolic blood pressure 80–89 mmHg can be managed non-pharmacologically for no more than 3 months. Pharmacological treatment should be introduced if the blood pressure target cannot be reached. Patients with blood pressure ≥140/90 mmHg should be started on medication in addition to non-pharmacological management. Patients with blood pressure ≥160/100 or 20/10 mmHg above the target should be immediately started on anti-hypertensive drug therapy, and a combination therapy regimen should be initiated.
  3. Selection and use of anti-hypertensive drugs: Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) are the first choice for anti-hypertensive drugs. In T2DM patients with concomitant stable coronary artery disease, ischemic stroke, or DKD, a combination with calcium channel blockers is preferred[135,136]. A combination with β-blockers is preferred in patients with a history of myocardial infarction or current exertional angina[137]. In patients with DKD, ACEIs/ARBs are safe when serum creatinine is ≤265 μmol/L (3.0 mg/dL); however, it is debatable whether ACEIs/ARBs should be used when serum creatinine is >265 μmol/L[138]. UACR, serum creatinine, and blood potassium levels should be followed up regularly during anti-hypertensive therapy in patients with DKD, and the treatment regimen should be adjusted immediately as needed. If serum creatinine is <30% higher than the baseline value after medication, anti-hypertensive therapy can be used with caution; however, if it exceeds 30%, a dose reduction or drug withdrawal should be considered.

Recent studies have found that angiotensin receptor-neprilysin inhibitors are a novel class of anti-hypertensive drugs with multiple protective effects on target organs such as the heart, kidney, and blood vessels and are recommended as anti-hypertensive options for panvascular disease in T2DM patients[139]. In addition, SGLT2i or GLP-1RA can mildly lower systolic blood pressure while lowering glucose levels, and the effect of SGLT2i or GLP-1RA on blood pressure should be considered when adjusting anti-hypertensive treatment regimens.

Recommendation 19: The blood pressure management target in T2DM patients with panvascular disease is <130/80 mmHg for adults, <140/90 mmHg for patients aged ≥65 years, and <150/90 mmHg for patients aged ≥80 years. The anti-hypertensive drugs of choice are ACEI, ARB, and, depending on the blood pressure target, a combination with diuretics, calcium channel blockers, mineralocorticoid receptor antagonists, and selective beta-blockers.

Blood lipid management

Lipid management should be based on the choice of intervention and control targets based on the target organ of panvascular disease in T2DM patients. Lipid-lowering strategies include lipid-lowering drug therapy (statins, ezetimibe, PCSK9 inhibitors) with lifestyle interventions as a foundation, which are important measures for maintaining appropriate lipid levels and controlling dyslipidemia and include reducing the intake of saturated fatty acids, trans fatty acids, and cholesterol, increasing the intake of ω-3 polyunsaturated fatty acids, reducing body weight, increasing exercise, smoking cessation, and alcohol restriction[140].

  1. T2DM patients with panvascular disease with target organs of the heart, brain, or peripheral blood vessels: (1) Lipid target: LDL-C <1.4 mmol/L or ≥50% reduction from baseline levels; (2) lipid-lowering strategy: initiation of statin therapy based on lifestyle interventions, and direct initiation of statin therapy in combination with ezetimibe for patients with high baseline LDL-C values; if LDL-C remains at ≥1.4 mmol/L with statins plus ezetimibe, the addition of PCSK9 inhibitors is recommended[141].
  2. The target organ of panvascular disease in T2DM patients is the kidney: If urinary proteinuria is present, the patient should first be evaluated for concomitant heart, brain, or peripheral blood vessel disease and risk factors for panvascular disease[105,141]. If there is no relevant history or risk factors, lipid target: LDL-C <2.6 mmol/L; if there is no history of heart, brain, or peripheral blood vessel disease but any of the following risk factors are present: age ≥45 years for males or ≥55 years for females, a history of smoking, low HDL-C (<1.0 mmol/L), body mass index ≥28 kg/m2, hypertension, or family history of early-onset ischemic heart disease, the lipid target should be LDL-C <1.8 mmol/L or ≥50% reduction from baseline levels. Lipid-lowering strategy: initiation of statin therapy based on lifestyle interventions. If LDL-C remains at ≥1.8 mmol/L after statin therapy, the addition of ezetimibe is recommended, and if the target is not reached, the addition of PCSK9 inhibitors can be considered[141]. Statins and fibrates, which do not damage renal function, are preferred to lipid-lowering drugs in patients with diabetic nephropathy. However, immediate adjustment of drug doses should be made based on changes in renal function.

Recommendation 20: Lipid management of panvascular disease in patients with T2DM should be based on selecting control targets based on the target organ of the lesion. For target organs such as the heart, brain, or peripheral vasculature, lipid target: LDL-C <1.4 mmol/L or ≥50% reduction from baseline levels. If the target organ is the kidney, and there is no history or risk factors for heart, brain, or peripheral vascular disease, the lipid target is LDL-C <2.6 mmol/L. If there is no history of heart, brain, or peripheral vascular disease but any of the following risk factors are present: age ≥45 years for males or ≥55 years for females, history of smoking, low HDL-C (<1.0 mmol/L), body mass index ≥28 kg/m2, hypertension, or family history of early-onset ischemic heart disease, the lipid target should be LDL-C <1.8 mmol/L or ≥50% reduction from baseline levels.

Anti-platelet therapy

The role of anti-platelet therapy in the secondary prevention of heart, brain, and peripheral vascular disease has been demonstrated in numerous clinical studies, and it is effective in reducing the risk of cardiovascular events by 19%–25%, with a reduction of risk of non-fatal myocardial infarction by one-third, non-fatal stroke by one-fourth, and fatal vascular events by one-sixth[142,143]. Therefore, patients with heart, brain, and peripheral vascular disease should be treated aggressively with anti-platelet therapy and aspirin (75–150 mg/day) as secondary prevention; the risk of bleeding should be adequately assessed. Patients with an allergy to aspirin should be treated with clopidogrel (75 mg/day) as secondary prevention.

Prospective large-scale clinical studies evaluating the efficacy and safety of aspirin in primary prevention are lacking, and the risk–benefit ratio to the patient must be carefully evaluated. The benefit of anti-platelet therapy for primary prevention of heart, brain, and peripheral vascular disease in patients with T2DM is primarily in high-risk groups, such as patients aged ≥50 years with at least one additional risk factor, such as a family history of early-onset cardiovascular disease, hypertension, dyslipidemia, history of smoking, or CKD/proteinuria, where aspirin (75–150 mg/day) is recommended for primary prevention except in cases of contraindications, adverse effects caused by aspirin, and aspirin intolerance[144]. However, aspirin is not recommended for primary prevention in T2DM patients aged ≥60 years[145,146]. When blood pressure is controlled to <150/90 mmHg, anti-platelet therapy is initiated to prevent stroke.

Recommendation 21: Patients with T2DM and concomitant heart, brain, and peripheral vascular disease should be treated aggressively with anti-platelet therapy and aspirin (75–150 mg/day) as secondary prevention; the risk of bleeding should be adequately assessed.

SUMMARY OF RISKS AND OUTLOOK

The number of T2DM cases is rapidly increasing worldwide, and the incidence of panvascular disease has become a major problem. Treatment should be based on multidisciplinary cooperation and interdisciplinary integrated management while remaining patient-centered, and disease management should be comprehensive throughout the entire cycle. Moreover, the strengths of academic institutions, research institutions, medical institutions, businesses, physicians, and patients should be fully mobilized to build a multidisciplinary crossover platform to investigate the pathogenesis and effective prevention and control strategies of panvascular disease in diabetic patients at multiple levels from basic to clinical sciences. The field of diabetes-associated panvascular disease is expected to continue to develop in the future in improve its prevention, diagnosis, and management.

FUNDING

National Key Research and Development Program of China (2021YFC2500500).

AUTHOR CONTRIBUTIONS

All the authors participated in the writing of the consensus.

CONFLICTS OF INTEREST STATEMENT

Junbo Ge is the Editor-in-Chief of Cardiology Plus. Yong Huo is an Editorial Board member of Cardiology Plus.

DATA SHARING STATEMENT

Data will be available to other researchers upon request to the corresponding authors.

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Keywords:

Type 2 diabetes mellitus; Panvascular diseases; Risk assessment; Consensus

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