Ma et al. Cardiovascular Diabetology (2022) 21:74 https://doi.org/10.1186/s12933-022-01516-6 Cardiovascular Diabetology REVIEW Open Access Cardiovascular disease in type 2 diabetes mellitus: progress toward personalized management Cheng‑Xu Ma1,2, Xiao‑Ni Ma1,2, Cong‑Hui Guan1,2, Ying‑Dong Li3, Dídac Mauricio4* and Song‑Bo Fu1,2* Abstract Cardiovascular diseases (CVDs) are the main cause of death among patients with type 2 diabetes mellitus (T2DM), particularly in low- and middle-income countries. To effectively prevent the development of CVDs in T2DM, consider‑ able effort has been made to explore novel preventive approaches, individualized glycemic control and cardiovas‑ cular risk management (strict blood pressure and lipid control), together with recently developed glucose-lowering agents and lipid-lowering drugs. This review mainly addresses the important issues affecting the choice of antidia‑ betic agents and lipid, blood pressure and antiplatelet treatments considering the cardiovascular status of the patient. Finally, we also discuss the changes in therapy principles underlying CVDs in T2DM. Keywords: Type 2 diabetes mellitus, Cardiovascular diseases, Hyperlipidemia, Hypertension, Therapy principle, Antidiabetic therapy Introduction note, T2DM accounts for approximately 90% of all diabe- Type 2 diabetes mellitus (T2DM) is a persistent state of tes cases, and cardiovascular (CV) events in people with hyperglycemia and glucose intolerance that occurs when T2DM are a major cause of the increased risk of early the body cannot respond fully to insulin, followed by an death and have become a rising threat to human health increase in insulin production and a subsequent insu- worldwide. lin deficiency. Once mainly limited to older adults in The major CV diseases (CVDs) associated with T2DM the twentieth century, T2DM is now the largest global include ischemic heart disease, heart failure (HF), stroke, health crisis of the twenty-first century, and although its coronary artery disease (CAD), and peripheral artery dis- prevalence and incidence have shown the fastest increase ease, and these complications can result in death for at in adults, T2DM is increasingly occurring in children least 50% of patients with T2DM [4]. Therefore, CVDs and adolescents [1]. Premature mortality from diabe- are of great concern in the disease progression and prog- tes increased by 5% during the period 2000–2016 [2]. nosis of T2DM. T2DM is characterized by insulin resist- Between 2000 and 2019, trends in deaths due to diabetes ance and hyperglycemia, which is usually, but not always, exhibited a 3% increase in age-standardized rates [3]. Of accompanied by abnormal lipid metabolism. Insulin resistance generally occurs early in the progression of T2DM and CVD [5]. Importantly, insulin resistance is *Correspondence: DMauricio@santpau.cat; fusb@lzu.edu.cn associated with a higher relative risk of CV events [6]. 1 Department of Endocrinology, The First Hospital of Lanzhou University, No. 1 Elevated blood glucose is strongly associated with the West Donggang Road, Lanzhou, Gansu 730000, People’s Republic of China 4 Department of Endocrinology & Nutrition, CIBER of Diabetes risk of both macrovascular and microvascular compli- and Associated Metabolic Diseases (CIBERDEM), Hospital de la Santa Creu cations in patients with T2DM [7]. Furthermore, excess i Sant Pau, Autonomous University of Barcelona, 08041 Barcelona, Spain accumulation of lipids may result in cardiac insulin Full list of author information is available at the end of the article © The Author(s) 2022. 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The Creative Commons Public Domain Dedication waiver (http://​creat​iveco​ mmons.​org/​publi​cdoma​in/​zero/1.​0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Ma et al. Cardiovascular Diabetology (2022) 21:74 Page 2 of 15 resistance, fibrosis and diastolic dysfunction [8]. Moreo- among patients with T2DM in Spain was ranged from 7 ver, hypoglycemia, which has generally been recognized to 41%, and in-hospital mortality rates due to CVD were as an adverse effect of glucose reduction, has also been between 6 and 11%[13]. reported as a risk factor for CVD among patients with The reduction in the incidence of CVD in T2DM is T2DM [9]. Overall, CVD associated with diabetes is a consistent with new findings from Ethiopia [14], Sweden major cause of death and disability among patients with [15], and South Korea [16]. However, in the study from T2DM. South Korea the risk of HF increased over the years 2006 To date, limited progress has been made in the pre- to 2015 [16], and this finding was also observed among vention of T2DM, and no country or health care sys- patients with a T2DM duration over 10 years and among tem is immune to the threat of T2DM. Although the those with a history of hypertension [17]. The occurrence incidence and mortality rate of CVD have decreased in of HF has been found to be related to diabetes duration, high-income countries, these countries account for only with a 17% increase in HF risk strongly associated with approximately 10% of the world population, and CVD each 5-year increase in diabetes duration [18]. incidence and mortality trends in T2DM patients in mid- The decreasing incidence of CVD among T2DM dle- and low-income countries remains unclear [10]. In patients has been reported in high-income countries, addition, considering the clinical burden of CVD com- such as Sweden, the USA, Canada, and the United King- plications in T2DM patients, attention to the joint man- dom, with a 3–5% yearly decline in the rates of CVD agement of T2DM and CVD has been increasing. In this since the early 1990s [19]. However, a large gap remains review, we focus more thoroughly on the current state of in the incidence of CV morbidity and mortality between the epidemiology of CVD in T2DM and on preventive people with T2DM and those without the disease. Unfor- measures and then explore measures to reduce the threat tunately, there is a paucity of data on CVD incidence from CVD in T2DM patients. among people with T2DM from middle- and low-income countries and in global investigations. Current trends in the epidemiology Consistent with the declining trend of CVD inci- of cardiovascular disease in T2DM dence, the incidence of death from CVD in T2DM stead- While globally the incidence of CVD among patients with ily dropped in 2019 [3]. There was approximately a 20% T2DM is 2–3 times higher than among those without reduction in the mortality rates in Sweden from 1998 T2DM, data suggest a decreasing trend worldwide in the through 2014 [15]. Additionally, a general trend toward overall prevalence of CVD attributed to T2DM. The cur- a reduction in T2DM mortality was reported in countries rently available data are shown in Table 1. Before 2016, from the European Union between 1990 and 2019 [20]. the prevalence of all CVDs in T2DM ranged from 14.3 Likewise, reductions in the death rate and the proportion to 46.9%[11], while a meta-analysis for the years 2007– of deaths from vascular causes decreased from 1988–94 2017 indicated a prevalence of 32%[4]. The weighted to 2010–15 in the USA [21]. A similar trend was also CVD prevalence in 2019 was reported to be 34.8% across observed in Hong Kong [22] and South Korea [16]. How- 13 countries, although there was a wide range between ever, in contrast to the findings of observational studies, a countries from 18.0% in Saudi Arabia to 56.5% in Israel. systematic review of diabetes CV outcome clinical trials [12]. There was a general trend of reduced incidence of reported no improvement in CV mortality in T2DM; the coronary artery disease, myocardial infarction, stroke possible cause underlying the difference between rand- and HF, and peripheral artery disease [12]. The study by omized controlled trials (RCTs) and real world data may Artime et.al demonstrated that the prevalence of CVD be the lack of standardized definitions of CVD outcomes (including HF) [23]. The overall estimated CVD mortality rates among patients with diabetes are higher in low- and middle-income countries than in high-income countries Table 1 Prevalence of cardiovascular disease in T2DM [24]. Thus, the global CVD-related mortality among peo- Outcome Before 2016 [11] 2007–2017 [4] 2019 [12] ple with diabetes in low-income countries may decrease All CVDs 14.3–46.9% 32% 34.8% in time, in-line with high-income countries. Coronary artery disease 1.8–25.6% 21% 10.9% Despite the trend in the reduction in the overall CVD Heart attack 3.3–17.8% 10% 4.6% mortality, the incidence and mortality rate of T2DM Stroke 1.7–17.7% 7.6% 5% continue to increase annually, and along with popula- Heart failure 14.9% 2.4% tion growth and aging, the total number of CVD- and Peripheral artery 2.6% T2DM-related deaths have increased worldwide [3]. The disease highest number of deaths due to diabetes in adults in CVD cardiovascular disease 2019 occurred in the Western Pacific region, followed by Ma et al. Cardiovascular Diabetology (2022) 21:74 Page 3 of 15 Southeast Asia, and the highest proportion of deaths due medical history, lifestyle behaviors, and CV and meta- to diabetes among patients under the age of 60 in 2019 bolic risk factors were included as considerations. Pre- was in Africa [24]. CVD and diabetes were among the top cision medical therapeutic approaches for patients with ten causes of death globally in 2019 and are a consider- T2DM with CVD will be gradually achieved [32]. able threat to human health. CVD risk assessment aims to provide appropriate A transition in the major cause of death in T2DM from regimens for the prevention and treatment of CVD in CVD to non-CVD was observed in the ALTITUDE trial T2DM. The American College of Cardiology (ACC) and [25]. Non-vascular, non-cancer causes of death among AHA have developed a risk stratification tool for primary American adults diagnosed with diabetes accounted for prevention in patients with T2DM; the Risk Estimator approximately 46.5% of all deaths during 2010–2015, and Plus tool can be used to calculate ten-year atherosclerosis the proportion of cancer-related deaths did not change CVD risk and provide individualized advice for patients from 1988 to 2015 [21]. A change in the leading cause aged 40–79 years. Risk stratification for secondary pre- of death from vascular causes to cancer among people vention is under clinical testing [33]. Alternatively, the with diabetes was observed in England from 2001 to 2018 European Society of Cardiology (ESC) recommends that [26]. In addition, a decrease in mortality due to cancer CVD risk stratification be divided into moderate-, high-, and CVD in older people with T2DM in Australia was and very high-risk levels for patients with either pre-DM observed, masking the rising excess risk among patients or established DM based on comorbidities and the dura- of younger ages [27]. There is a suggestion that younger- tion of the disease, rather than into primary or secondary onset T2DM may be associated with an increase in CVD- prevention groups. These three levels of risk stratifica- related mortality but a slight decrease in cancer-related tion support individualized diagnostic and therapeutic mortality [28]. In summary, notwithstanding some approaches to patient care in diabetes [34]. reductions in CVD mortality in T2DM, there is a paucity The ACC/AHA and ESC methods differ somewhat in of data about the leading cause of death among T2DM the criteria they use for risk stratification. The Risk Esti- patients, especially at younger ages. mator Plus does not account for the comorbidities and duration of diabetes, especially for adolescents due to Prevention of cardiovascular disease in T2DM the increase in obesity incidence, but it does consider A focus on efforts to prevent CVD events in high-risk age ≥ 40 years, sex, blood pressure, blood lipids, history populations might reduce mortality and decrease the of diabetes, smoking and drug use. Risk stratification for economic burden of heart attack and stroke. CVD can be secondary prevention accounts for age ≥ 75 years, DM, prevented or delayed by controlling blood glucose, blood hypertension, peripheral artery disease, previous stroke, pressure and cholesterol and with lifestyle changes such previous coronary artery bypass graft, history of HF, as stopping smoking, eating healthily, and increasing active smoking, and renal dysfunction. The ESC method physical activity. based on three levels of risk stratification recognizes the Primary prevention involves preventing or delaying complexity of developing CVD by considering comorbid- new-onset CVD in patients with T2DM. Early detec- ities and the duration of diabetes, and also accounts for tion of CVD-related risk factors in community-based obesity, renal impairment, left ventricular hypertrophy, high-risk populations and early diagnosis of T2DM in and retinopathy rather than a history of CV-related dis- subjects without CVD are needed. Secondary prevention ease. A comparison of the benefits of the risk estimator involves treatment of risk factors in diabetic patients with and that of risk stratification would be useful to obtain a established CVD. Comprehensive medical intervention consensus to facilitate the choice of individualized care in for secondary prevention among diabetic patients with patients with T2DM and CVD. clinical CVD was approved by the American Heart Asso- ciation (AHA) in 1999 [29]; a position statement by the Individualized glycemic management in patients American Diabetes Association (ADA) and the European with T2DM and CVD Association for the Study of Diabetes (EASD) in 2012 A meta-analysis of 102 prospective studies showed outlined the need for individualized glycemic targets and that fasting blood glucose concentrations ≥ 7 mmol/L glucose-lowering therapies in combination with compre- conferred an elevated risk of coronary heart disease hensive CV risk reduction, indicating that patient-cen- [35]. Additionally, impaired glucose tolerance and tered care must be a consideration in decision-making elevated HbA1c (> 5.7%) levels have been associated for secondary prevention among T2DM patients with with an increased risk of CVD [36]. An increased established CVD [30]. Beginning in 2018, the glucocen- blood glucose concentration in the general popula- tric strategy for the management of CVD in T2DM tran- tion or in patients with atherosclerotic CVD con- sitioned to patient-centered care [31], and individual fers an increased risk of all-cause mortality and CVD Ma et al. Cardiovascular Diabetology (2022) 21:74 Page 4 of 15 [37]. Individualized glycemic management may lead Antidiabetic treatment choice to improved prevention of CVD in T2DM. In this sec- The novel glucose-lowering agents, sodium-glucose tion, we focus on current aspects of individualized cotransporter 2 inhibitors and glucagon-like peptide-1 management of T2DM. receptor agonists, have been shown to lower athero- sclerotic CVD and HF risks independently of baseline Glycemic targets HbA1c[44]; this has led to newer treatment approach. A With respect to glycated hemoglobin (HbA1c) targets, reasonable regimen of glycemic control is associated with the AHA, ADA, ESC and ESC/EASD guidelines propose both glycemic targets and strategies of glucose-lowering a target of < 7%, and gives further recommendations for therapy, and the medical provider must prioritize the less stringent targets in older or more frail adults. A tar- patient’s CV state based on preference and the prescrip- get of ≤ 6.5% for those with an early diagnosis, who are tion history. not frail, and who do not have established atheroscle- rotic CVD. This is consistent with current ESC, ADA and Metformin AHA guidelines on DM and CVD [38–41](Table 2). The UK Prospective Diabetes Study (UKPDS 34) found Achieving a glycemic target of an HbA1c level < 7% that metformin therapy reduced all-cause mortality by for patients with T2DM reduces the incidence of the 36% and heart attack incidence by 39% among over- development of microvascular complications and CVD. weight patients with newly diagnosed T2DM [45]. More- A more stringent HbA1c goal (< 6.5%) is defined for over, a continued benefit of reductions in microvascular selected children and adolescents, those with a short risk, myocardial infarction and death over 10 years after duration of DM, lesser degrees of β-cell dysfunction and metformin therapy in that trial were reported [46]. Met- no evidence of CVD. An HbA1c target of < 6% may be formin administration may be the primary preventive optimal during pregnancy without significant hypogly- measure against the risk of CVD among patients with cemia. Furthermore, a less stringent HbA1c goal (< 8.0% newly diagnosed T2DM without established CVD. How- or even slightly higher) may be appropriate for patients ever, there is insufficient evidence for the use of met- with limited life expectancy, a history of advanced micro- formin for secondary prevention in patients with T2DM vascular or macrovascular complications, extensive and established CVD [47]. Only one RCT that included comorbid conditions, or long-standing T2DM [38]. The 68 patients with CAD showed a cardioprotective role of association of HF mortality with HbA1c goals in T2DM metformin [48], and in another trial, 36 patients with HF has a “U” shape, where a modest HbA1c level of 7.1–8.0% with reduced ejection fraction (HFrEF) showed increased is associated with the lowest mortality among patients myocardial efficiency after metformin treatment [49]. with HF and T2DM [42], whereas an HbA1c level < 6.0% Nonetheless, the additional benefits of metformin may or > 8%, and even > 10%, may increase the risk of incident include prevention of the occurrence of new T2DM and HF or HF-related hospitalization [43]. cancer [50, 51], weight gain and hypoglycemia, and pro- longed gestation in preterm preeclampsia [52]. Thus, Table 2 Targets for the control of glycemia Parameter Target Population Guideline References Glycemia HbA1c Consistent with current ADA guideline AHA [39] < 6% Pregnancy patients without significant hypoglycemia ADA [38] < 6.5% Children and adolescents patients with a short duration of DM, lesser degrees of β-cell dysfunction and no evidence of CVD < 7% Nonpregnant patients without significant hypoglycemia < 8% Patients with limited life expectancy or where the harms of treatment are greater than the benefits < 7% Patients with developing microvascular complications ESC/EASD [40] 6.0–6.5% Younger patients with a short duration of DM and no evidence of CVD < 8% or ≤ 9% Elderly patients with longstanding DM and limited life expectancy, and frailty with multiple comorbidities < 7% Older/frail adults ESC [41] ≤ 6.5% In early diagnosis, not frail and without established ASCVD DM diabetes Mellitus, CVD cardiovascular disease, T2DM type 2 diabetes mellitus, ASCVD atherosclerotic cardiovascular disease, AHA American Heart Association, ADA American Diabetes Association, ESC European Society of Cardiology, EASD European Association for the Study of Diabetes Ma et al. Cardiovascular Diabetology (2022) 21:74 Page 5 of 15 metformin administration is suitable for the treatment of in patients with T2DM resulted in a sustained to moder- patients with T2DM without established CVD as well as ate reduction of the composite CV death or hospitaliza- those with CVD. tion for HF, robust reduction of HF, moderate reduction of CV mortality, total mortality and major adverse car- Sodium‑glucose cotransporter 2 inhibitors diac events (MACE) [66]. Furthermore, a comprehensive A meta-analysis of three studies showed that sodium-glu- systematic review and network meta-analysis of RCTs cose cotransporter 2 (SGLT2) inhibitors reduced major provided direct evidence for the absolute benefits and adverse CV events by 11% in patients with T2DM and harms of SGLT-2 inhibitors in reducing CV outcomes in atherosclerotic CVD and reduced the risk of CV death patients with type 2 diabetes [67]. Importantly, this com- or hospitalization for HF by 23% and the risk of renal prehensive systematic review found that SGLT-2 inhibi- disease progression by 45% among patients with T2DM tors reduced all cause and CV mortality, myocardial [53]. SGLT2 inhibitors also reduced the risk of cardiac infarction, admission for heart failure and kidney failure, arrhythmias and atrial fibrillation/atrial flutter progres- without a reduction in non-fatal stroke. sion [54, 55]. In addition to the role of individual SGLT2 inhibitors, Currently, the approved SGLT2 inhibitors are empa- inhibitors of both SGLT1 and SGLT2 (dual SGLT1/2 gliflozin [56], canagliflozin [57], dapagliflozin [58], inhibitors) have the ability to reduce intestinal glucose ertugliflozin [59], tofogliflozin [60], luseogliflozin [61] absorption after meals since SGLT1 in the small intes- and ipragliflozin [61] (Table 3). The available studies tine [68]. Sotagliflozin, the first dual SGLT1/2 inhibitor, focused on CVD are mainly limited to the United States approved for T1DM and T2DM in the EU and T2DM and Europe; however, more recent real-world data have in the US, has exhibited CV benefits in patients with also shown a reduced risk of CV events across a wide T2DM and chronic kidney disease [69]; a similar result range of patient characteristics from 6 countries in the was shown in patients with T2DM and HFrEF or HFpEF Asia Pacific region, the Middle East, and North Ameri- [70]. The adverse events of sotagliflozin include diar- can regions [61]. In HF, empagliflozin administration rhea, genital mycotic infections, volume depletion, and was associated with improved clinical outcomes for the diabetic ketoacidosis. Dual inhibition of SGLT1/2 with HFrEF phenotype [62], and the overall risk of HF events licogliflozin treatment showed CV benefits in patients between HFrEF and HFpEF was reduced by canagliflozin with T2DM and HF, and licogliflozin has a greater effect [63], dapagliflozin [64], and ertugliflozin [65]. than empagliflozin on glucose lowering, weight loss, and Overall, data suggest that SGLT2 inhibitors have mod- systolic blood pressure reduction [71]. The CV benefits of erate benefits in CVD and robust benefits in HF and sotagliflozin seem to be equal to those of SGLT2 inhibi- renal disease and should be considered for primary and tors. Sotagliflozin and licogliflozin may be recommended secondary prevention of CVD and renal outcomes in as first-line therapies among patients with T2DM, patients with T2DM, regardless of existing atheroscle- regardless of the presence of atherosclerotic CVD or a rotic CVD or a history of HF [53]. A recent meta-analysis history of HF. by Giugliano et al. provided an update of all large CV Other trials of SGLT1/2 inhibitors, including LX4211 outcome trials (CVOTs) with SGLT-2 inhibitors, with [72], LX-2761, and YG-1699, for treating CVD in patients findings indicating that treatment with SGLT-2 inhibitors with T2DM are underway. Glucagon‑like peptide‑1 receptor agonists Five CVOTs, namely, LEADER3, SUSTAIN-6, REWIND, Table 3 Cardiovascular benefits of SGLT2 inhibitors HARMONY, and AMPLITUDE-O [73] have consist- ently shown the safety and efficacy of GLP-1 agonists Agents MACEs (HR) CV death (HR) HF (HR) Renal outcome in patients with T2DM and have provided evidence of a (HR) secondary preventive effect of GLP-1 agonists in T2DM patients with CVD and kidney disease. Nevertheless, the Empagliflozin [56] 0.86 0.62 0.65 0.5 ELIXA and EXSCEL trials did not show any benefit on Canagliflozin [57] 0.86 0.87 0.67 0.6 CVD or kidney outcomes (Table 4). Currently, a nota- Dapagliflozin [58] 0.93 0.98 0.73 0.76 ble decrease in CVD outcomes has been observed with Ertugliflozin [59] 0.97 0.92 0.7 0.81 several GLP-1 agonists; furthermore, GLP-1 agonists Tofogliflozin [60] – – – – promote a reduction in CV risk factors, and dulaglutide Luseogliflozin [61] – – – – showed strong evidence of primary prevention. Ipragliflozin [61] – – – – A systematic review and meta-analysis of RCTs – limited data, MACE major adverse cardiac event, HR hazard ratio, CV revealed that GLP-1 receptor agonists reduced MACE cardiovascular, HF heart failure Ma et al. Cardiovascular Diabetology (2022) 21:74 Page 6 of 15 Table 4 Cardiovascular benefits of GLP-1 agonists Trial Agents MACEs (HR/p) CV death (HR/p) HF (HR/p) Renal outcome (HR/P) ELIXA Lixisenatide 1.02/0.78 0.98/0.85 0.96/0.75 0.84/0.083 LEADER3 Liraglutide 0.87/0.01 0.98/0.85 0.87/0.14 0.78/0.003 SUSTAIN-6 Semaglutide 0.74/0.016 0.98/0.92 1.11/0.57 0.64/0.005 EXSCEL Exenatide 0.91/0.061 0.88/0.096 0.94/0.49 0.88/0.065 REWIND Dulaglutide 0.88/0.026 0.91/0.21 0.93/0.46 0.85/0.0004 HARMONY Albiglutide 0.78/0.0006 0.93/0.58 0.71/0.019 # AMPLITUDE-O Efpeglenatide 0.73/0.0069 0.72/0.07 0.61/0.04 0.68/ < 0.0001 p p values, # missing data, MACE major adverse cardiac events, HR hazard ratio, CV cardiovascular, HF heart failure by 14% and also reduced all-cause mortality by 12%, hos- to insulin glargine [79]. Available data show an impor- pital admission for HF by 11%, and the composite kid- tant effect of tirzepatide in terms of HbA1c reduction, ney outcome by 21%, with no increase in risk of severe weight loss, blood pressure and lipid profiles, with this hypoglycemia, retinopathy, or pancreatic adverse effects effect persisting for up to 2 years without increased CVD [73]. Another meta-analysis showed that GLP-1 receptor risk [80]. Tirzepatide displays primary preventive effects agonists are efficacious for treating obesity and T2DM in T2DM with or without CVD risk and may be a well- in children [74]. GLP-1 receptor agonists also safely positioned glucose-lowering agent in future therapeutic reduce total MACEs by 12%, hospital admission for HF regimens. by 9%, and composite kidney outcomes (reduction in uri- Clinical trials of dual GIP/GLP-1 agonists, such as nary albumin excretion) by 17% in adult T2DM patients combined GIP and GLP-1 infusion [81] and NNC0090- [75]. Unexpectedly, a beneficial effect on HF has been 2746 [82], are ongoing. observed with GLP-1 agonists. Furthermore, the largest and most current systematic review showed that GLP-1 Other antidiabetic agents agonists reduced all cause and CV mortality, myocardial Dipeptidylpeptidase-4 (DPP4) inhibitors have been infarction, non-fatal stroke, kidney failure and admis- reported to be neutral with regard to CV outcomes [83]. sion for HF in subjects with T2DM [67]. Overall, these However, the use of saxagliptin is associated with an important data provide novel insights into the benefits of increase in hospitalization for HF [84], which should be GLP-1 receptor agonists in CVD patients; however, the carefully considered. benefits they may confer to primary prevention patients Regarding sulfonylureas, these older agents are inex- are unclear. pensive and widely available and are used as glucose-low- In summary, GLP-1 agonists show a beneficial effect ering agents for T2DM patients with CVD. The UKPDS on CVD, HF, and kidney outcomes and a reduction in 33 has confirmed the reduced microvascular risk of sulfo- weight gain, blood pressure, and levels of HbA1c and nylureas [85]. In addition, the TOSCA.IT trial confirmed LDL-C. Therefore, GLP-1 agonists are recommended the CV safety of sulfonylureas [86]. Insulin is a widely in the context of secondary prevention in patients with extended therapeutic option. A meta-analysis showed T2DM and CVD. that insulin treatment does not increase the risk of CV Finally, because the dual GIP/GLP-1 agonists will soon mortality and myocardial infarction [87]. A RCT showed be introduced into clinical practice, it is worth address- that insulin glargine had a neutral effect on CV outcomes ing their potential. A phase 3 trial of tirzepatide showed [88], and insulin is widely used to treat T2DM with CVD. that the mean HbA1c level decreased from baseline by Finally, pioglitazone reduced key secondary macrovas- 1.87–2.07%, more participants met their HbA1c targets, cular outcomes in people with T2DM without CV events and weight loss ranged from 7.0 to 9.5 kg [76]. The effi- whose glucose levels were controlled with metformin cacy of tirzepatide treatment in patients with T2DM was monotherapy [86]. Although the PROactive trial failed to shown to be superior to that of treatment with 1.5 mg show an effect of pioglitazone on the primary compos- dulaglutide [77] and semaglutide [78]. Unfortunately, ite outcome, this drug resulted in a decrease in the sec- there are still no data on CVOTs with tirzepatide. How- ondary outcome (i.e., the classical 3 component MACE) ever, tirzepatide treatment showed a good safety profile [89]. Pioglitazone was also associated with a reduced risk in T2DM patients with a high risk of or established CVD, of diabetes, ischemic stroke, and myocardial infarction an improved effect on HbA1c in comparison with insu- in patients without diabetes [90]. An adverse effect of lin glargine, and no increases in MACE events compared pioglitazone is an increased risk of developing HF, thus Ma et al. Cardiovascular Diabetology (2022) 21:74 Page 7 of 15 pioglitazone should not be used to treat subjects with HF. The use of glucose-lowering agents should depend on Therefore, pioglitazone may be used as an add-on treat- CV status and T2DM complications. SGLT2 inhibitors ment to metformin for people with T2DM, as these drugs (empagliflozin, canagliflozin, and dapagliflozin) are asso- are widely available and affordable. ciated with a lower risk of HF hospitalization in patients with DM, and are recommended [94]. More importantly, the largest available systematic review found that SGLT2 Current recommendations on the use inhibitors and GLP-1 receptor agonists lowered all-cause of antidiabetic drugs with regard to CVD mortality, CV mortality, non-fatal myocardial infarction, Different scientific societies recommend the use of anti- and kidney failure. However, SGLT-2 inhibitors reduced diabetic therapies in CVD, including the AHA [39], the admission to hospital for HF more than GLP-1 receptor ADA [91], the ESC [41] and the ESC/EASD [40]; Chi- agonists, and GLP-1 receptor agonists reduced non-fatal nese scientific bodies, however, do not [92]. The overall stroke more than SGLT-2 inhibitors (which appeared to medication regimen is roughly similar, with a key focus have no effect) [67]. on metformin, GLP-1 agonists and SGLT2 inhibitors in One RCT has shown the efficacy of metformin in guidelines for treating CVD in T2DM patients (Table 5). patients with T2DM and HF [48]. Accordingly, met- The ADA and the EASD issued an update of their joint formin should be considered for treating patients with 2018 recommendations on management of hyperglyce- T2DM and HF (eGFR > 30 mL/min) [94]. Pioglitazone mia [93]. The major updates included: 1) SGLT2 inhibi- and saxagliptin are contraindicated in patients with tors are recommended in patients with T2DM and HF, HF or at risk of HF. Although initial data from RCTs of particularly those with HFrEF, to reduce hHF, MACE, GLP-1 agonists supported a neutral effect on the risk of and CV death and to prevent the progression of CKD, HF, a recent meta-analysis showed benefits of GLP-1 ago- HF, MACE, and CV death in patients with T2DM with nists in HF and diabetes [67]. However, current guide- CKD; 2) to reduce risk of MACE, GLP-1 receptor ago- lines recommend SGLT2 inhibitors as the most suitable nists can also be considered in patients with type 2 diabe- treatment in patients with HF. tes without established CVD with indicators of high risk, specifically, patients aged 55 years or older with coronary, carotid, or lower extremity artery stenosis > 50%, and left Hypertension ventricular hypertrophy. 3) for patients with type 2 dia- The presence of hypertension in patients with T2DM betes and established atherosclerotic CV disease (such as significantly increases the risk of CVD development, those with prior myocardial infarction, ischemic stroke, and a study revealed that evaluated blood pressure down unstable angina with ECG changes, myocardial ischemia to < 120 mm Hg and < 70 mm Hg could decrease mortal- on imaging or stress test, or revascularization of coro- ity, macrovascular, and microvascular events regardless nary, carotid, or peripheral arteries) where MACE is the of baseline systolic blood pressure [39]. Thus, lowering gravest threat, the level of evidence for MACE benefit is blood pressure reduces CVD events and microvascular greatest for GLP-1 receptor agonists. Table 5 Recommendations on the use of antidiabetic drugs Antidiabetic drugs choice Population Guideline References SGLT-2 inhibitor and /or GLP-1 RA Patients with T2DM with established atherosclerotic CVD, or multiple risk ADA [91] factors for CVD or established kidney disease irrespective of additional glucose lowering and metformin use SGLT-2 inhibitor Patients with T2DM and established HFrEF Initiated with metformin Patients with T2DM and/or stable HF Initiated with an SGLT-2 inhibitor or GLP-1 RA Patients with newly diagnosed T2DM and established atherosclerotic CVD, ESC/EASD [40] or very high risk factors for CVD before metformin use Initiated with metformin Overweight patients with T2DM without CVD and at moderate CV risk Metformin In persons with T2DM with atherosclerotic CVD ESC [41] Initiated with an SGLT-2 inhibitor or GLP-1 RA In patients with T2DM without atherosclerotic CVD, HF, or chronic kidney disease SGLT-2 inhibitor, GLP-1 agonists and metformin Consistent with current ADA guideline AHA [39] DM diabetes mellitus, CVD cardiovascular disease, T2DM type 2 diabetes mellitus, ASCVD atherosclerotic cardiovascular disease, ADA American Diabetes Association, ESC European Society of Cardiology, EASD European Association for the Study of Diabetes, HF heart failure, SGLT-2 sodium-glucose cotransporter -2, GLP-1 RA glucagon-like peptide-1 receptor agonist, ACC​American College of Cardiology Ma et al. Cardiovascular Diabetology (2022) 21:74 Page 8 of 15 complications and has a favorable effect on CVD out- is unclear. Overall, individualized blood pressure targets comes in patients with and without T2DM. are recommended based on CVD status and individual condition (Table 6). Blood pressure treatment target A target of 140/90 mmHg may be reasonable among Treatment choice patients with T2DM and stable CAD or patients with The ADA and ESC guidelines consistently recom- higher blood pressure targets; lower blood pressure mend that initial treatment should involve the drug targets of < 130/80 mmHg can be recommended for classes demonstrated to reduce CVD events in patients patients with a higher risk of stroke and microvascu- with T2DM and hypertension, and dual therapy, ACE lar complications, according to the AHA [95]. A target inhibitors or ARBs in conjunction with dihydropyri- of < 130/80 mmHg may be appropriate for patients with dine calcium channel blockers or thiazide diuret- diabetes and hypertension at higher CV risk (exist- ics are recommended as the first-line treatment[41, ing atherosclerotic cardiovascular disease (ASCVD) or 94]. For patients with a urine albumin-to-creatinine 10-year ASCVD risk ≥ 15%), whereas a blood pressure ratio ≥ 30 mg/g, initial treatment should include an ACE target of < 140/90 mmHg is recommended for individu- inhibitor or ARB. For patients with pre-DM, ACE inhib- als with diabetes and hypertension at lower risk for CVD itors or ARBs rather than diuretics or β-blockers are (10-year ASCVD risk < 15%). The ADA advises that a recommended due to the increased risk of new-onset reading higher than 120/80 mmHg in patients with T2DM from diuretics and β-blockers [96]. Nebivolol T2DM indicates the need for lifestyle intervention. In does not reduce insulin sensitivity and may be used as pregnant patients with diabetes and preexisting hyper- an antihypertensive treatment for T2DM patients [97]. tension, a blood pressure target of 110–135/85 mmHg In addition, a double-blind clinical trial has shown is suggested in the interest of reducing the risk for that the non-steroidal potent MRA blocker finer- accelerated maternal hypertension [91]. ESC guide- enone is efficacious and safe to reduce HF cardiac lines recommend that the initial target of < 140/90 mm biomarkers, HF, and albuminuria in T2DM. Differ- Hg with goal of 120–130/ < 80 mm Hg is suitable for ent trials also demonstrated a significant reduction in patients aged 18–69; the target of 130–139/ < 80 mm the primary outcome (CV death, non-fatal myocardial Hg, with < 130/ < 80 mm Hg being acceptable if toler- infarction, non-fatal stroke, or hospitalization for HF) ated is suitable for adults ≥ 70 years of age [41], although in those subjects with T2DM and chronic kidney dis- the blood pressure target for T2DM patients with CVD ease receiving finerenone [98–100]. Indeed, finerenone Table 6 Targets for the control of blood pressure Parameter Target Population Guideline References Blood pressure < 140/90 mmHg Patients with T2DM and stable coronary artery AHA [95] disease or with higher blood pressure target < 130/80 mmHg Patients with a higher risk of stroke and microvascu‑ lar complications < 140/90 mmHg Patients with DM and hypertension at lower risk for ADA [91] CVD (10 year atherosclerotic CVD risk < 15%) < 130/80 mmHg Patients with DM and hypertension at higher CV risk (existing atherosclerotic CVD or 10-year atheroscle‑ rotic CVD risk ≥ 15%) 110–135/85 mmHg Pregnant women with DM and preexisting hyper‑ tension < 120/80 mmHg Patients who need lifestyle intervention 130—139 / < 80 but not < 70 mmHg Older people (aged > 65 years) ESC/EASD [94] 130/ < 80 but not < 70 mmHg and < 130/ < 80 but Patients with hypertension and DM not < 70 mmHg if tolerated < 140/90 mmHg All treated patients ESC [41] 120–130 / < 80 mmHg Younger patients (18–69 years) 130–139/ < 80 mmHg and < 130 / < 80 mmHg if Patients aged ≥ 70 years tolerated DM diabetes mellitus, CVD cardiovascular disease, T2DM type 2 diabetes mellitus, ASCVD atherosclerotic cardiovascular disease, ADA American Diabetes Association, ESC European Society of Cardiology, EASD European Association for the Study of Diabetes, AHA American Heart Association Ma et al. Cardiovascular Diabetology (2022) 21:74 Page 9 of 15 significantly improved cardiorenal outcomes in patients Treatment choice with T2DM and kidney disease irrespective of HbA1c Meta-analysis has shown that statins are the most levels or insulin use [101]. Therefore, finerenone should effective therapy for reducing CV mortality, followed be considered for treatment of patients with T2DM, by PCSK9 inhibitors and statins in combination with and this agent is likely to be included as an impor- ezetimibe. PCSK9 inhibitors effectively reduce MACEs tant treatment option in future updates of current [105], and statin therapy and add-on treatment with guidelines. PCSK9 inhibitors or ezetimibe exhibit significant ben- efit in CVD outcomes [106]. Fibrate therapy reduces Lipid management major CVD events [107], and icosapent ethyl exerts a The presence of diabetic dyslipidemia in patients with risk reduction in CVD outcomes beyond lipid-lowering T2DM is, at least in part, a cause of CVD. Moreover, effects [108]. Overall, these lipid-lowering drugs have CV diabetic dyslipidemia, including elevated triglycer- benefits for secondary prevention. ides, low-density lipoprotein cholesterol (LDL-C) and Depending on the baseline LDL-C levels, the ini- low high-density lipoprotein cholesterol (HDL-C), tiation of statin therapy remains the first-line treat- is associated with increased CV events, especially in ment in patients (aged < 50 years) with a T2DM high-risk populations [102]. Accounting for metabolic duration < 10 years and without CVD risk factors or with dyslipidemia in CVD risk stratification is necessary for an LDL-C of > 100 mg/dL. In patients at very high CVD patients with T2DM [103]. risk, if the LDL-C target is not reached, despite treatment with the maximum tolerated statin dose, combination Lipid targets therapy with ezetimibe or a PCSK9 inhibitor is recom- The concept of “lower is better” regarding LDL levels has mended [41, 94]. In high- and very high-risk patients been supported for reducing the risk of CVD in patients with triglycerides of 200–500 mg/dL, statins combined with T2DM and CVD [104]. The ADA guidelines recom- with a fibrate or icosapent ethyl may be considered for mend that lifestyle interventions be initiated for indi- both macro- and microvascular benefits in patients with viduals with abnormal triglyceride levels (> 150 mg/dL) T2DM [109]. Statin therapy is contraindicated in patients and/or HDL-C levels (< 40 mg/dL for men, 50 mg/dL with pregnancy. for women), and an LDL-C target reduction of ≥ 50% or more from baseline is reasonable for patients with dia- Antiplatelet therapy betes and 10-year ASCVD risk of 20% or higher [91]. T2DM is associated with increased blood thrombo- The ESC/EASD guidelines recommend an LDL-C target genicity among patients with non-ST elevation acute of < 55 mg/dL for those with T2DM and at very high CV coronary syndrome [110]. Platelet ­P2Y12 expression is risk [94]. The AHA guidelines recommend an LDL-C tar- increased fourfold in patients with T2DM, and plate- get reduction of ≥ 50% from baseline for those with dia- let activation and hypercoagulation in T2DM induce a betes and clinical CVD [39]. The ESC established goals prothrombotic state and result in an increased risk for for LDL-C based on level of ASCVD risk [41]. With CVD events [111]. respect to lipid targets, the AHA/ADA and the ESC/ EASD guideline are shown in Table 7. Table 7 Targets for lipid control Parameter Target Population Guideline References Lipid LDL-C Reduction of ≥ 50% or more from baseline Adults with diabetes and 10 year atherosclerotic ADA [91] CVD risk of 20% or higher LDL-C Reduction of ≥ 50% from baseline Patients with DM and atherosclerotic CVD AHA [39] LDL-C Reduction of ≥ 50% from baseline and < 70 mg/dL Patients with T2DM > 40 years of age at high CVD risk ESC [41] LDL-C Reduction of ≥ 50% from baseline and < 55 mg/ Patients with T2DM at very high CVD risk dL LDL-C < 100 mg/dL Patients with T2DM at moderate CV risk ESC/EASD [94] < 70 mg/dL Patients with T2DM at high CV risk < 55 mg/dL Patients with T2DM at very high CV risk CV cardiovascular, ASCVD atherosclerotic cardiovascular disease, ADA American Diabetes Association, ESC European Society of Cardiology, EASD European Association for the Study of Diabetes, AHA American Heart Association, LDL-C low-density lipoprotein cholesterol, HDL-C high-density lipoprotein cholesterol, DM diabetes mellitus Ma et al. Cardiovascular Diabetology (2022) 21:74 Page 10 of 15 Aspirin infarction and MACEs with a lower risk of bleeding The use of aspirin decreases the risk of T2DM among among patients with atrial fibrillation and diabetes [127]. healthy men but not among women [112]. Low-dose aspirin (81 or 100 mg) is neutral for CVD outcomes and Treatment choice increases the risk for gastrointestinal bleeding when Depending on risk stratification and the risk of bleeding, used for primary prevention among patients with T2DM ESC guidelines recommend that aspirin be considered for [113]. Contemporary meta-analyses show that the use of primary prevention among patients with a risk of CVD or aspirin for the primary prevention of CV events needs to a diagnosis of CVD and low risk of bleeding [41, 94]. be reconsidered [114, 115] due to inconsistent CVD ben- Intensive secondary prevention is indicated for patients efits and an increased bleeding risk. with T2DM and CVD. Aspirin therapy (75–162 mg/day) In secondary prevention trials, meta-analyses showed is recommended as a secondary preventive strategy for that medium-dose aspirin (75–325 mg/day) reduces patients with T2DM and atherosclerotic CVD. For dia- vascular events over 2 years [116], an aspirin dose of betic patients with an aspirin allergy, clopidogrel (75 mg/ 75–150 mg daily is a protective regimen for patients with day) should be used [128]. Long-term dual antiplatelet occlusive vascular events [117], and aspirin therapy for therapy is approved for patients with additional high-risk the secondary prevention of CVD has long been estab- markers. lished [118]. Nonetheless, the longest duration of the The addition of clopidogrel to aspirin for people with included trials was just 4 years, and the aspirin effect CVD risk or established CVD is associated with a reduc- for longer term use this requires caution, particularly tion in myocardial infarction and ischemic stroke, how- in the post-acute setting [119]. Meta-analyses showed ever it also leads to an increase in bleeding [129]. This that early aspirin discontinuation in patients with acute regimen may increase CVD death among patients with coronary syndrome or percutaneous coronary inter- DM and microalbuminuria (≥ 30 μg/mL) [130]. The CV vention (PCI) prevented bleeding events with a neutral benefit of clopidogrel plus aspirin is reduced in T2DM effect on CVD outcomes [120], and the duration of aspi- due to high platelet reactivity, and increasing the dose of rin use (3 months) in patients undergoing complex PCI clopidogrel and aspirin may enhance antiplatelet effects reduced the risk of bleeding without increasing the risk [131, 132]. The benefit of an intensive antiplatelet regi- of ischemic events [121]. In acute settings, reducing the men in these patients is still unclear. The National Insti- duration of aspirin use (< 3 months) for secondary pre- tute for Health and Care Excellence (NICE) recommends vention of CVD may be proposed. prasugrel plus aspirin for people with ST elevation myo- cardial infarction after PCI. Prasugrel or ticagrelor plus P2Y12 inhibitors aspirin is recommended for people with non-ST eleva- Compared with aspirin, P ­ 2Y12 inhibitors reduce the risk tion myocardial infarction after PCI. Clopidogrel and oral of myocardial infarction and stroke in secondary pre- anticoagulants other than prasugrel or ticagrelor for up vention [122]; thus, P ­ 2Y12 inhibitors may be a useful to one year are recommended for people with acute coro- option for secondary prevention. ­P2Y12 inhibitors include nary syndrome and atrial fibrillation after PCI [133]. The prasugrel, ticagrelor and clopidogrel. Long-term admin- recommended duration of these regimens is > 30 months istration of clopidogrel reduces the risk of myocardial [134], while meta-analyses have indicated inconsistent infarction or vascular death, and the overall efficacy is results on the duration of dual antiplatelet therapy after superior to that of aspirin [123]. The benefits of prasug- PCI with drug-eluting stents [135, 136], and discontinua- rel and ticagrelor over clopidogrel are even greater, and tion of aspirin within 1 to 3 months with continued ­P2Y12 a reduction in CVD mortality was observed only with inhibitor monotherapy is recommended [137]. ticagrelor [124]. Ticagrelor exerts similar or greater inhi- For patients with DM and atrial fibrillation or periph- bition of platelet reactivity than prasugrel in diabetic eral artery disease, ESC guidelines recommend rivar- patients with CAD [125]. For patients after PCI, discon- oxaban therapy [94]. Rivaroxaban plus aspirin is the tinuation of aspirin within 1 to 3 months with contin- preferred long-term antithrombotic regimen for patients ued ­P2Y12 inhibitor monotherapy has a neutral effect on with chronic coronary syndrome and high-risk factors MACE outcomes with a reduction in bleeding [121]. [126]. Rivaroxaban Conclusion Rivaroxaban has been shown to reduce the incidence of The current main targets for the control of glycemia, CVD and an increased risk of bleeding among patients lipids and blood pressure levels in patients according to with chronic coronary syndrome [126]. Compared the most commonly used guidelines should be included to warfarin, rivaroxaban reduces stroke, myocardial as an individualized strategy to prevent CVD in T2DM Ma et al. Cardiovascular Diabetology (2022) 21:74 Page 11 of 15 (Tables 2, 6 and 7). Although the incidence and mortal- Author details 1 Department of Endocrinology, The First Hospital of Lanzhou University, No. ity rate of T2DM-related CVD have decreased, the preva- 1 West Donggang Road, Lanzhou, Gansu 730000, People’s Republic of China. lence and mortality rate of CVDs in patients with T2DM 2 The First Clinical Medical College of Lanzhou University, Lanzhou 730000, continues to rise, and most T2DM-related CVDs may be Gansu, China. 3 College of Integrated Traditional Chinese and Western Medi‑ cine, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu, China. prevented by lifestyle modification and the use of adjunc- 4 Department of Endocrinology & Nutrition, CIBER of Diabetes and Associated tive drugs. The notion of T2DM-related CVD care has Metabolic Diseases (CIBERDEM), Hospital de la Santa Creu i Sant Pau, Autono‑ transitioned from comprehensive medical intervention mous University of Barcelona, 08041 Barcelona, Spain. to precision diabetes therapy. For T2DM patients with Received: 15 March 2022 Accepted: 28 April 2022 established CVD, the GLP-1 agonists, SGLT2 inhibitors, and blood-pressure and lipid-lowering drugs provide an improved precision treatment approach. References 1. Diabetes. World Health Organization 2021, https://​www.​who.​int/​news-​ Abbreviations room/​fact-​sheets/​detail/​diabe​tes. Accessed 10 Nov 2021. T2DM: Type 2 diabetes mellitus; CVD: Cardiovascular disease; HF: Heart failure; 2. World health statistics 2020: monitoring health for the SDGs, sustain‑ CAD: Coronary artery disease; HFpEF: Heart failure with preserved ejection able development goals. Geneva: World Health Organization 2020. fraction; HFrEF: Heart failure with reduced ejection fraction; HbA1c: Hemo‑ Licence: CC BY-NC-SA 3.0 IGO. globin A1c; SGLT2: Sodium-glucose cotransporter 2; GLP-1: Glucagon-like 3. 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