Diabetes is one of the most important chronic non-communicable diseases threatening global human health, and several national multicenter epidemiological studies have confirmed that the prevalence of diabetes in adults in China is more than 9%, and diabetes may be developing faster than we expected, and has become a major public health problem in China.
Numerous epidemiological studies have shown that diabetes is an independent risk factor for cardiovascular disease and that diabetics are a high-risk group for cardiovascular disease. In the 20 years after the diagnosis of diabetes, diabetic vascular complications will occur one after another, and the cost of treatment will account for 80% of all direct medical costs, which will become a huge economic burden for our society.
It is now accepted that patients with diabetes without heart disease have the same risk of cardiovascular death as patients with myocardial infarction without diabetes, and that patients with type 2 diabetes have 2-4 times the risk of cardiovascular disease than non-diabetic patients, and that their cardiovascular disease is more severe and widespread than the latter, with a worse prognosis and an earlier age of onset, and a series of meta-analyses have confirmed that about 70% of patients with type 2 diabetes die from cardiovascular complications A series of meta-analyses have confirmed that approximately 70% of patients with type 2 diabetes die from cardiovascular complications. Although type 1 diabetics have a lower incidence of cardiovascular events than type 2 diabetics, their relative risk of death from ischemic heart disease is seven to tens of times higher than that of the non-diabetic population.
This has drawn significant attention to cardiovascular events in diabetes, both nationally and internationally. In recent years, the results of several multicenter, large-sample, long-term, randomized controlled clinical trials for the treatment of diabetes have been published, confirming that diabetic patients have many risk factors for atherosclerosis, such as dyslipidemia, hypertension, hypercoagulable state and thrombotic tendency, and their great danger is to lead to various serious complications, among which cardiovascular events are the most serious complications of diabetes and also affect patients’ quality of life Among them, cardiovascular events are the most serious complications of diabetes mellitus and the main cause of quality of life and threat to patients.
In 2001, Sherwin proposed at the annual meeting of the American Diabetes Association (ADA) that the treatment of type 2 diabetes should “go beyond the traditional concept of glucose-centeredness” to comprehensively prevent and treat multiple risk factors of cardiovascular disease. Recent studies at home and abroad have shown that comprehensive control of multiple risk factors in diabetic patients can prevent or delay the occurrence and development of cardiovascular disease, and that improving lifestyle, controlling blood glucose and blood pressure, lowering lipids, reducing body weight, and antithrombotic therapy should be the basis for the treatment of cardiovascular events in diabetes.
The ADA published the 2015 ADA Standards for the Medical Management of Diabetes (hereinafter referred to as the 2015 ADA Standards), which make further recommendations for the prevention and treatment of cardiovascular disease in diabetes based on the latest evidence-based evidence and expert opinion. In this paper, we analyze and compare the above contents with the relevant contents of the Chinese guidelines for the prevention and treatment of type 2 diabetes (2013 edition) (hereinafter referred to as the 2013 Chinese guidelines) to further deepen the understanding of diabetic cardiovascular disease, to better guide the management and improve the prognosis of patients with type 2 diabetes, and to provide some insight into the research and clinical practice related to diabetic cardiovascular disease.
1. Screening
Both the 2015 ADA criteria and the 2013 Chinese guidelines recommend that risk factors for cardiovascular disease should be assessed at least annually at the time of diabetes diagnosis and thereafter, including current and past history of cardiovascular disease, age, presence of cardiovascular risk factors (smoking, dyslipidemia, hypertension and family history, obesity), and renal impairment (albuminuria).
Specifically, blood pressure should be measured at each follow-up visit in diabetic patients; patients with elevated blood pressure should be confirmed by repeat measurements on another day (level B); lipids should be screened at first diagnosis, initial medical evaluation, or in diabetic patients aged ≥ 40 years, with regular follow-up (every 1-2 years) at a later date (level E); those receiving lipid-regulating drugs may be tested more frequently as needed to assess efficacy; routine screening for coronary artery disease is not recommended for patients without associated symptoms. Routine screening for coronary heart disease does not improve prognosis as long as cardiovascular disease risk factors are treated (Class A).
2. Control of risk factors for cardiovascular disease
2.1 Blood glucose control The macroangiopathy caused by long-term hyperglycemia is the main cause of disability and death, although many international studies are still inconsistent in their conclusions on the cardiovascular protective effect of intensive glucose lowering on diabetic patients, there is no doubt that “strengthening blood glucose management is an indispensable and important part of the prevention and treatment of cardiovascular events in diabetes”. How to reduce the incidence of cardiovascular events in diabetic patients through optimal glycemic management is an issue that every clinician should focus on.
In terms of early screening and primary prevention in patients with diabetes, both the 2015 ADA standards and the 2013 Chinese guidelines recommend that patients with prediabetes reduce the risk of diabetes through dietary control and exercise, with regular follow-up and psychosocial support to ensure long-term adherence to a good lifestyle. Regular blood glucose checks and close attention to screening for cardiovascular disease risk factors (e.g., smoking, hypertension, dyslipidemia, etc.) are recommended, and appropriate interventions are given.
Intensive glycemic control in patients in the early stages of diabetes is associated with a reduced risk of microangiopathy, myocardial infarction, and death, according to the long-term follow-up results of the DCCT and UKPDS studies. Therefore, both the 2013 Chinese guidelines and the 2015 ADA criteria recommend that in patients with newly diagnosed and early-stage type 2 diabetes, a strategy of tight glycemic control should be used to reduce the risk of diabetic complications, whereas in people with longer duration of diabetes, older age and multiple cardiovascular risk factors or those who have had cardiovascular disease, intensive glycemic control measures do not reduce the risk of cardiovascular disease and death.
On the contrary, the ACCORD study also showed that intensive glycemic control was associated with an increased risk of all-cause mortality in these populations. Therefore, both the 2013 Chinese guidelines and the 2015 ADA standards recommend that patients who are older, have a longer duration of diabetes and have had cardiovascular disease should fully balance the pros and cons of intensive glycemic control, adopt an individualized strategy in the selection of glycemic control goals, and develop a patient-centered diabetes management model.
In terms of blood glucose level monitoring and efficacy assessment, both the 2013 Chinese guidelines and the 2015 ADA standards provide requirements for glycosylated hemoglobin (HbAlc), which is the main indicator of long-term glycemic control. 2015 ADA standards state that HbAlc should be tested at least twice a year (level E) for patients who are on treatment (and have stable glycemic control). For patients who change their treatment regimen or whose glycemic control is suboptimal, HbAlc (level E) should be tested 4 times per year. A reasonable HbAlc control goal for most non-pregnant adults is <7% (Level B).
A more stringent HbAlc target (e.g., <6.5%) is recommended for patients with type 2 diabetes of shorter duration, treated with lifestyle interventions or metformin only, and for patients with longer life expectancy or without significant cardiovascular disease, in the absence of significant hypoglycemic response during treatment (Class C). For patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, more co-morbidities, and longer duration of diabetes who have difficulty achieving glycemic targets despite diabetes self-management education (DSME), appropriate glucose testing, or multiple effective doses of glucose-lowering medications including insulin, an appropriately lenient HbAlc target (e.g., <8%) should be given (Level B). Level B).
Relevant epidemiological studies have confirmed that postprandial glucose is also a better predictor of cardiovascular disease risk, and its pathogenic mechanism is related to the toxic effects of oxidative stress on the vascular endothelium and its contribution to overall blood glucose. 2015 ADA criteria recommend routine monitoring of postprandial glucose in diabetic patients with fasting glucose at the target but HbAlc still above the target, and controlling postprandial glucose levels to bring HbAlc at the target, thus reducing The occurrence of cardiovascular events in diabetic patients. In recent years, more studies have proposed to reduce blood glucose fluctuations while focusing on achieving blood glucose targets, emphasizing individualized glucose reduction and simultaneous treatment of multiple risk factors for cardiovascular disease.
2.2 Blood pressure control Hypertension is one of the common complications or concomitant diseases of diabetes mellitus, and its prevalence is related to the type of diabetes mellitus, age, obesity and ethnicity, etc. The incidence of hypertension is reported to be 30%-80% at home and abroad. Hypertension in patients with type 2 diabetes mellitus is usually a manifestation of the coexistence of multiple cardiometabolic risk factors and can precede the onset of diabetes mellitus.
The coexistence of diabetes and hypertension significantly increases the risk of developing and progressing cardiovascular disease, stroke, nephropathy, and retinopathy, and increases the rate of disability and death in patients with diabetes. Conversely, controlling hypertension significantly reduces the risk of development and progression of diabetic complications. The awareness rate, treatment rate and control rate of hypertension among diabetic patients in China are low, and improving the above “three rates” is the main task to prevent and treat hypertension in combination with diabetes.
The 2013 Chinese guidelines and the 2015 ADA standards both state that the diagnostic criteria for hypertension in patients with diabetes are the same as those for other populations, but there are slight differences in blood pressure control goals. 2013 Chinese guidelines recommend that patients with diabetes combined with hypertension should have a systolic blood pressure control goal of < 140 mmHg and a diastolic blood pressure of < 80 mmHg. The 2015 ADA criteria recommend a systolic BP control goal of < 140 mmHg and a diastolic BP of < 90 mmHg (Class A) in patients with diabetes mellitus combined with hypertension.
This lower diastolic BP target is based on the HOT study, although the HOT study concluded that diastolic BP ≤ 80 mmHg was associated with significant cardiovascular benefit in patients with diabetes mellitus and hypertension, and that actual diastolic BP levels and mean BP values did not meet the BP target recommended by the 2014 ADA criteria.
Taking into account the latest evidence-based medical evidence and meta-analysis, the 2015 ADA criteria have been revised to indicate that lower blood pressure control levels may be more appropriate for younger patients or those with chronic kidney disease who have increased urinary albumin excretion rates. The new blood pressure control criteria are also consistent with the newly published 2014 U.S. Guidelines for the Management of Hypertension in Adults (JNC 8) for blood pressure control in adults 18 years of age and older with diabetes mellitus combined with hypertension.
Regarding specific blood pressure lowering protocols, both the 2015 ADA criteria and the 2013 Chinese guidelines suggest that initial interventions for elevated blood pressure in patients with diabetes should depend on blood pressure levels, i.e., patients with diabetes with blood pressure levels > 120/80 mmHg should begin lifestyle interventions to prevent the development of hypertension. Lifestyle interventions are an important means to control hypertension and should be an important part of self-management for diabetic patients, mainly including health education, reasonable diet (low salt and fat, low saturated fat and trans fatty acids, diet rich in dietary fiber), regular exercise, smoking cessation and salt restriction, weight control, and psychological balance.
The 2013 Chinese guidelines state that those with blood pressure ≥ 140/80 mmHg may be considered for initiation of pharmacological antihypertensive therapy. Diabetic patients with systolic blood pressure ≥ 160 mmHg must initiate antihypertensive therapy. The 2015 ADA guidelines state that in addition to lifestyle interventions, patients with blood pressure ≥ 140/80 mmHg should receive immediate pharmacological treatment and promptly adjust the type and dose of medication to achieve the blood pressure standard (Class A). This suggests that pharmacological interventions for patients with diabetes mellitus combined with hypertension in China may be somewhat later than those in Europe and the United States.
In terms of specific drug selection, both the 2013 Chinese guidelines and the 2015 ADA criteria recommend that angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor antagonists (ARB) should be the mainstay (Class B), which may often require a combination of antihypertensive drugs with calcium antagonists, diuretics, and β-blockers. The selection of drugs should take into account the efficacy, cardioprotective effect, safety and compliance factors, such as the application of ACEI, ARB drugs and diuretics should pay attention to the monitoring of blood creatinine and potassium levels.
In addition, the 2015 ADA criteria state that there is increasing evidence that elevated blood pressure during sleep is associated with the incidence of cardiovascular events, so it is recommended that one or more antihypertensive medications be taken at bedtime (Class A), and in this regard Hermida et al. confirmed by the MAPEC study that the use of antihypertensive medications at bedtime in patients with diabetes reduced the risk of cardiovascular events by more than 50%. When monitored blood pressure levels at bedtime were categorized into 5 classes, the risk of cardiovascular events was found to decrease progressively with lower blood pressure.
However, this simple and inexpensive chronotherapy has limitations, possibly because patients with severe cardiovascular disease are more prone to nocturnal hypotension and inadequate perfusion of vital organs, and further studies are needed to clarify the safety of bedtime regimens in these high-risk populations. The 2013 Chinese guidelines are silent on this issue.
For women with diabetes mellitus combined with chronic hypertension during pregnancy, and either preexisting hypertension or hypertension complicated by pregnancy may aggravate their existing diabetes mellitus complications, the 2015 ADA standard recommends the same target values for lowering blood pressure as the 2013 Chinese guidelines. In terms of drug selection, ACEI and ARB are also contraindicated during pregnancy (E), and diuretics may reduce uteroplacental perfusion due to their effect on blood volume.
The first two are associated with a high risk of cardiovascular disease in patients with type 2 diabetes mellitus. A meta-analysis including large studies such as FIELD, CARDS, HPS, and a subgroup analysis of the ACCORD study showed that lipid-modifying therapy can reduce the incidence of cardiovascular disease in patients with diabetes.
The current rate of statin use among diabetic patients in China is not satisfactory. In a study to investigate the impact of risk factor control on clinical outcome in Chinese patients with type 2 diabetes (Study 3B), 72% of patients had combined hypertension and/or dyslipidemia, while the proportion of diabetic patients with combined dyslipidemia treated with statins was only 40.2%, indicating that approximately 50% of diabetic patients were not treated with lipid-lowering therapy as recommended by the guidelines. Therefore, it is important to optimize the clinical decision-making pathway for lipid-lowering therapy to benefit more patients with diabetes.
The 2013 Chinese guidelines recommend that LDL-C levels should be the primary goal of lipid-modifying drug therapy, and that specific LDL-C targets should be set for different populations: for patients with combined cardiovascular disease, LDL-C targets should be <1.8 mmol/L. For patients with diabetes without cardiovascular disease who have one or more risk factors for cardiovascular disease, LDL-C targets should be <1.8 mmol/L. The 2015 ADA standard removes the specific requirement for a lipid-lowering target, stating that statin use should be based on an assessment of risk factors rather than LDL-C results.
This revision to the 2015 ADA criteria is generally consistent with the 2013 cholesterol guidelines published by the American College of Cardiology (ACC) and the American Heart Association (AHA), a guideline with important implications for lipid management, which rejected the LDL-C target values used in the National Cholesterol Education Program (NCEP) Adult Treatment Panel Report 3 (ATP III) based on evidence from evidence-based medicine and clinical trials, and explained the reasons for eliminating target values for lipid-lowering therapy: 1) The panel was unable to find support for (ii) it was not clear how much lower LDL-C would further reduce the risk of atherosclerotic cardiovascular disease; and (iii) the need for multiple drugs to achieve a specific LDL-C target could cause adverse effects.
Professor Henry Ginsberg disagrees with the guideline’s elimination of LDL-C targets, arguing that clinicians should be provided with clear LDL-C targets because “the lower the LDL-C, the greater the benefit” has been clearly established. Although there is some disagreement about whether to set LDL-C targets, it is undisputed that reducing the risk of atherosclerotic cardiovascular disease is an important goal of lipid management in diabetes and that statin therapy is an important tool for reducing the risk of atherosclerotic cardiovascular disease in diabetes, and the 2013 Chinese guidelines are highly consistent with the 2015 ADA criteria in this regard.
The 2013 Chinese guidelines state that regardless of baseline lipid levels, statins should be used in patients with diabetes mellitus whose lipid levels do not meet the standard on the basis of lifestyle interventions, and if the maximum tolerated dose of statins does not meet the above treatment goals or if LDL-C levels are slightly higher than 2.6 mmol/L and patients have an indication for statins, a 30%-40% reduction in LDL-C from baseline with statins may also provide significant cardiovascular protection.
Unlike the 2013 Chinese guideline that recommends LDL-C level-based dosing, the 2015 ADA standard recommends statins for almost all patients with diabetes, introduces the concept of statin intensity therapy for different risk strata, and classifies patients with diabetes into 3 categories according to age: ① those aged <40 years without cardiovascular risk factors other than diabetes do not need to use statins, and those with additional cardiovascular risk factors (e.g. If additional cardiovascular risk factors are present (e.g. baseline LDL-C level ≥ 2.6 mmol/L, hypertension, smoking, overweight/obesity), moderate or high intensity statin therapy should be used, and high intensity statin therapy should be used if definite cardiovascular disease (previous cardiovascular events or acute coronary syndrome) is present (Class A);
(2) Those aged 40-75 years should be treated with moderate-intensity statin (Class A) if no additional cardiovascular risk factors are present, and with high-intensity statin (Class A) if cardiovascular risk factors (Class B) or definite cardiovascular disease (Class A) are present; (3) Those aged ≥75 years should be treated with moderate-intensity statin if no additional cardiovascular risk factors are present, and with moderate-intensity or high-intensity statin if cardiovascular risk factors are present, and with definite cardiovascular disease (Class A). (3) Those aged ≥ 75 years should be treated with moderate-intensity statin if they have no additional cardiovascular risk factors. The specific starting dose of statin therapy is generally consistent with the 2013 ACC/AHA guidelines for cholesterol therapy (Table 1).
In addition, both the 2013 Chinese guidelines and the 2015 ADA criteria suggest that other types of lipid-regulating drugs (Class C) may be considered in patients with type 2 diabetes who are intolerant to statins or to achieve HDL-C and triglyceride targets (triglycerides <1.7 hdl-c="">1.0 mmol/L and HDL-C >1.3 mmol/L in women). However, in patients with type 2 diabetes mellitus who are at high risk of cardiovascular disease, combination of other lipid-regulating drugs with statin therapy does not further reduce the risk of cardiovascular disease and death in patients with diabetes mellitus; therefore, neither the 2013 Chinese guidelines nor the 2015 ADA criteria recommend combination therapy (Class A). Statin therapy is contraindicated in women during pregnancy (Class B).
In recent years, the focus of attention on statin therapy has been on the increased incidence of new-onset diabetes caused by statins, which may limit their wider use to some extent. 2015 ADA standards clearly state that the cardiovascular protective effect of statin use will be much higher than the risk of diabetes, which is consistent with the Expert Consensus on Safety Evaluation of Statins published in 2014 in China.
2.4 Anti-platelet agents NCEP ATP III states that diabetes is an equivocal risk for coronary heart disease, and since 75% of diabetic patients ultimately die from thrombotic disease, platelet activation plays a key role in this. Therefore, antiplatelet therapy is particularly important for diabetic patients.
The 2015 ADA criteria and the 2013 Chinese guidelines share the following recommendations for antiplatelet therapy in patients with diabetes: for patients with type 1 and type 2 diabetes at high risk for cardiovascular disease, consider aspirin for primary prevention (Class C); for patients with diabetes with a history of prior cardiovascular disease, consider aspirin for secondary prevention (Class C). Aspirin is not recommended for the prevention of cardiovascular disease in adults with diabetes mellitus at low risk for cardiovascular disease (e.g., men < 50 years of age or women < 60 years of age without major other risk factors) because the potential benefits may be outweighed by the potential adverse effects of bleeding (Class C);
Patients of these ages with multiple other risk factors require clinical judgment (Level E); clopidogrel (75 mg/d) may be considered as an alternative therapy for patients who are allergic or intolerant to aspirin and must receive antiplatelet therapy (Level B); dual antiplatelet therapy is recommended up to 1 year after an episode of acute coronary syndrome (Level B); aspirin in people under 21 years of age is associated with the development of Reye’s syndrome and therefore Aspirin is not recommended in this population.
With regard to the dose of aspirin, both the 2013 Chinese guidelines and the 2015 ADA standards recommend low-dose aspirin to minimize adverse effects. 2015 ADA standards recommend a dose of 75-162 mg/d, with the most common low dose being 81 mg; the 2013 Chinese guidelines recommend a dose of 75-150 mg/d, with the most common low dose being 100 mg.
Accordingly, clinicians can follow the 2015 ADA standards and use low-dose aspirin to reduce the risk of cardiovascular complications in diabetes. In the future, the role of aspirin in diabetes and the exact mechanism of aspirin resistance can be further studied to explore and improve the treatment strategy of aspirin in diabetes, so that more diabetic patients can use aspirin more rationally to prevent cardiovascular complications and improve their quality of life.
2.5 Coronary artery disease The 2015 ADA criteria state that in patients with diabetes mellitus diagnosed with coronary vascular disease, aspirin and statin therapy are recommended if not contraindicated (Class A), and ACEI should be considered to reduce the risk of cardiovascular events (Class C); in patients with previous myocardial infarction, β-blockers should be continued for at least 2 years after myocardial infarction (Class B); in patients with symptoms of heart failure, thiazolidinediones should be avoided (Class B); and in patients with symptoms of heart failure, thiazolidinediones should be avoided (Class C). Metformin can be applied to patients with stable congestive heart failure if their renal function is normal; Metformin should be avoided in diabetic patients with unstable condition or hospitalized for congestive heart failure (Class B).
3, 2015 ADA standards for China’s inspiration
As the most authoritative academic institution related to diabetes prevention and treatment in China, the Chinese Medical Association’s Diabetes Division (CDS) has been formulating the Chinese Guidelines for the Prevention and Treatment of Type 2 Diabetes since 2003, and revised them in 2007, 2010 and 2013 respectively. However, due to the late start of clinical research in China and the low level of accumulated evidence, much of the evidence on which the previous guidelines were based originated from clinical studies conducted in foreign populations, and due to the limited awareness of and compliance with the guidelines by clinicians at all levels, the 2013 Chinese guidelines still have the problem of insufficient emphasis on the interaction and low sensitivity in the diagnosis and treatment of cardiovascular events in type 2 diabetes mellitus. The prevention and control of cardiovascular events in diabetic patients is not as strong as in Europe and the United States.
The 2015 ADA standards combine the epidemiological trends and ethnic characteristics of diabetes and cardiovascular disease, fully evaluate and utilize the evidence of recent international clinical studies in diabetes and related fields, and refer to relevant guidelines or consensus opinions, and gradually improve the understanding of the close relationship between glucose metabolism and cardiovascular disease, and change the comprehensive intervention strategies for cardiovascular events in diabetic patients. This article analyzes and compares this section with the 2013 Chinese guidelines to better grasp the international frontier, deepen the understanding of cardiovascular disease in diabetes mellitus, and provide some insight into the research related to cardiovascular events in diabetes mellitus in China.
Although there are still specific issues that need to be analyzed in the context of national data and national conditions, we have reason to believe that the evolving Chinese Guidelines for the Prevention and Control of Type 2 Diabetes and its various practical activities can effectively prevent and control diabetes and various complications, improve the quality of survival of patients, reduce the burden of disease, deliver benefits to the health of diabetic patients and the public, and contribute to the cause of diabetes prevention and control in the world from China.