Coronary revascularization in patients with stable coronary disease and diabetes mellitus

Abstract

Purpose of Study:

Diabetes mellitus accelerates the development of atherosclerosis. Patients with diabetes mellitus have higher incidence and mortality rates from cardiovascular disease and undergo a disproportionately higher number of coronary interventions compared to the general population. Proper selection of treatment modalities is thus paramount. Treatment strategies include medical management and interventional approaches including coronary artery bypass graft (CABG) surgery and percutaneous coronary interventions (PCI). The purpose of this review is to assimilate emerging evidence comparing CABG to PCI in patients with diabetes and present an outlook on the latest advances in percutaneous interventions, in addition to the optimal medical therapies in patients with diabetes.

Key Methods:

A systematic search of PubMed, Web of Science and EMBASE was performed to identify prospective, randomized trials comparing outcomes of CABG and PCI, and also PCI with different generations of stents used in patients with diabetes. Additional review of bibliography of selected studies was also performed.

Main Conclusions:

Most of the trials discussed above demonstrate a survival advantage of CABG over PCI in patients with diabetes. However, recent advances in PCI technology are starting to challenge this narrative. Superior stent designs, use of specific drug-eluting stents, image-guided stent deployment, and the use of contemporary antiplatelet and lipid-lowering therapies are continuing to improve the PCI outcomes. Prospective data for such emerging interventional technologies in diabetes is however lacking currently and is the need of the hour.

Keywords

Coronary artery disease CABG diabetes mellitus PCI coronary interventions atherosclerosis

Introduction

Diabetes mellitus and prediabetes affected 10% and 34% of the United States population in 2015 respectively and is the seventh leading cause of death in the US.¹ Diabetes is strongly associated with greater atherosclerotic burden, quicker coronary disease progression, and worse coronary outcomes with or without treatment.²

Management of stable CAD in diabetes involves medical management of risk factors and in certain cases, utilization of interventional strategies. Interventional approaches include percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG), with CABG historically having superior outcomes. Current evidence and guidelines lag behind rapid evolution in PCI technology and evaluating these new systems is bound to change future treatment paradigms. The aim of this review is to (a) enlist important clinical trials comparing CABG to PCI and comparing different stent types in diabetes, (b) discuss the strengths and weaknesses of the different coronary interventions, and (c) outline the latest technological advances paving the way for improved interventional outcomes.

Section I. Accelerated coronary artery disease in diabetes mellitus

The pathophysiologic milieu in diabetes accords a high risk of atherosclerosis³ and leads to complex coronary lesions with multi-segment, multivessel involvement.⁴ Atherosclerotic plaques in diabetes have a greater predilection for ulceration.⁵ Left anterior descending (LAD) artery is more severely affected and collateral vessel network is poorly developed⁶- anatomical variants at greater risk of poorer outcomes.

Hyperglycemia leads to the formation of advanced glycosylation end products (AGEs),⁷ which modify cell surface proteins and lipids, causing signaling abnormalities, excessive oxidative stress, and reduce vessel wall compliance. Diabetes promotes protein kinase C (PKC) activation and di-acyl glycerol (DAG) production. PKC/DAG accelerates atherosclerosis by promoting inflammation and smooth muscle cell recruitment.⁸ PKC activation also decreases endothelial nitric oxide (NO) production by inhibition of endothelial NO synthase (eNOS) and increases endothelin production, thus inhibiting vasodilation and increasing oxidative stresses.⁹

Diabetes mellitus promotes vascular inflammation by enhancing the expression of pro-inflammatory genes like nuclear factor-kB (NF-kB), which drives leukocyte and smooth muscle recruitment and increases macrophage lipid uptake. Diabetes accelerates vascular remodeling by activating matrix metalloproteinases (MMP-1 and 2), leading to vulnerable plaque physiology and heightens the risk of thrombosis and rupture.

Diabetes coexists with obesity and hypertension as part of the metabolic syndrome, both of which increase the risk of CAD. Lipid metabolism is altered in diabetes.¹⁰ Hypertriglyceridemia is the most common dyslipidemia associated with diabetes and exerts atherogenic effects indirectly through the metabolism of triglyceride-rich lipoprotein (TGRL). Smaller low-density lipoprotein cholesterol (LDL-C) particles in diabetes are more readily oxidized, which amplifies their atherosclerotic potential by permitting easier vessel wall uptake.¹¹ Protective lipid components like high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A1 have diminished levels in diabetes.¹²

Diabetes mellitus enhances platelet activity^13,14 (Figure 1 for the conceptual framework). Hyperglycemia promotes the expression of thromboxane (TxA2), p-Glycoprotein, and von-Willebrand Factor (vWF) - activators of platelet adhesion and activity.^15,16 Diabetes impairs platelet responsiveness to NO and prostaglandin I₂ (PGI₂)¹⁷-agents suppressing platelet activation. Diabetes modifies platelet receptor profile, decreasing anti-platelet drug effectiveness.

Figure 1.

Risk factors for coronary artery disease in diabetes. Progression of coronary artery disease is hastened in diabetes due to rapid atherosclerosis, impaired vessel wall reactivity, elevated circulating lipid levels, and thrombogenic platelet profile.

Intravascular imaging and histopathology have demonstrated decreased thickness of fibrous cap, higher lipid, calcium, and inflammatory burden in atherosclerotic plaques in patients with diabetes,¹⁸ histological variants that portend a higher risk of adverse event occurrence in these plaques.¹⁹

Section II: Treatment approaches in stable coronary artery disease in diabetes mellitus

Optimal medical therapy (OMT) is the cornerstone of stable CAD management. Guideline based medical therapeutics have demonstrated similar outcomes compared to interventional strategies in many large scale trials including COURAGE,²⁰ and ISCHEMIA²¹ trials. OMT is also the initial therapy for CAD in diabetes. BARI-2D²² and sub-analysis of the COURAGE trial showed no significant benefit of adding interventions over OMT (except for decrease in cardiovascular events in the CABG + OMT cohort in BARI-2D). Current anti-diabetic armamentarium includes sodium-glucose transporter-2 (SGLT-2) inhibitors and glucagon-like peptide (GLP)-1 agonists, which provide significant improvement in combined cardiovascular outcomes in patients with diabetes.^23–25

Anti-platelet therapy is another core component of CAD management and efficacy of antiplatelet agents in diabetes differ compared to patients without diabetes, necessitating careful selection of drugs. Optimal management of hyperlipidemia and hypertension is essential in decreasing the risk of cardiovascular events in diabetes mellitus, especially post PCI.²⁶

Procedural interventions for the treatment of CAD in diabetes is only recommended in particular situations (Table 1). A comprehensive assessment of coronary disease in diabetes using non-invasive testing is required to define risk and support interventional decision making. This can occur in the form of either dynamic (radionuclide, electrocardiography, echocardiography-based stress testing) or anatomic assessment (coronary computed tomography angiography [CCTA]).²⁷ Appropriate selection of patients and procedures is dependent on testing results and targeted outcomes. Our review will be focused on discussing aspects of interventional management in diabetes mellitus that can be utilized after proper clinical assessment.

Table 1.

Indications of utilization of PCI or CABG in the treatment of stable coronary artery disease in diabetes.^28–30

Indications of coronary intervention treatment in diabetes mellitus
• Acute coronary syndromes
• Anginal symptoms refractory to medical anginal therapy
• Large area of ischemia on cardiac functional testing
• Severe multi-vessel disease-causing cardiac dysfunction or severe anginal symptoms
• Severe left main or left anterior descending coronary artery disease

Optimal medical therapy is the initial line of management of stable CAD in diabetes and includes anti-diabetic drugs like SGLT-2 inhibitors/GLP-1 analogs, statins, anti-hypertensives, and antiplatelet agents.

CABG: coronary artery bypass graft; CAD: coronary artery disease; GLP: glucagon-like peptide; PCI: percutaneous coronary interventions; SGLT: sodium-glucose co-transporter.

Conventional approaches of revascularization

Patients with diabetes mellitus comprise one-third of all performed percutaneous interventions.³¹ Rates of incomplete revascularizations and complications from these procedures are much higher in patients with diabetes compared to the general population.^32,33 There are two main interventional approaches for the treatment of CAD and their outcomes have varied over the years, largely depending on varying clinical factors and technological advances (Figure 2).

Figure 2.

Major determinants of clinical outcomes after coronary artery interventions in diabetics. CABG is superior to PCI in diabetics, as per current evidence. However, rapid advances in PCI technology and drugs have improved outcomes of coronary stenting. The current best practices in decision making involve a “Heart Team,” comprising of cardiologists and cardiothoracic surgeons.

Coronary artery bypass grafting (CABG) involves the surgical transposition of autologous arteries/veins to bypass coronary artery blockages, providing coronary flow to the downstream myocardium.

Percutaneous coronary intervention (PCI) is the minimally invasive approach, which uses ballooning/stenting to open occluded coronary lesions. Early percutaneous interventions consisted of balloon dilation angioplasty. PCI currently involves stenting of the culprit lesions, which prevents vessel recoil and promises long term patency.

Comparative evidence of PCI and CABG diabetes

Early comparisons assessed CABG and PCI with balloon angioplasty. The diabetic cohort in CABRI trial (1994) (n = 125) had a statistically non-significant higher all-cause mortality rate in patients undergoing angioplasty.³⁴ The diabetic sub-group in BARI trial (1996) demonstrated significantly better 5-year survival rates in CABG (80.3%) group compared to the balloon angioplasty group (60.5%) (p = 0.003) and continued benefit of CABG even after 7 years.³⁵

Tables 2 to 4 summarize important trials comparing outcomes of CABG and PCI with BMS/1st/2nd generation drug-eluting stents (DES) and outcomes of BMS/1st generation compared to second generation DES, in patients with diabetes. Many of these studies are a subgroup analysis of the diabetic cohort of the main study population- thus decreasing their power.

Table 2.

Major trials comparing PCI using BMS and 1st generation DES to CABG.

Trial	Follow up	Design	Comparison	Primary outcome	Results of primary outcome	Drawbacks
SYNTAX³⁶ (2009)	5 years	Prospective randomized, diabetic subgroup data	CABG (n = 231) versus PCI (PES) (n = 221) in severe CAD	MACCE (death, MI, stroke or repeat revascularization)	PCI 46.55 versus CABG 29%, p < 0.01	Incomplete randomization (29.4% patients were pre-entered into nested registries). The PCI arm had significantly better medication compliance and intensity post procedure.
CARDIa³⁷ (2010)	1 year	Prospective randomized, noninferiority	CABG (n = 254) versus PCI (SES 69%, BMS 31%) (n = 256)	Death, MI, or stroke	PCI 13% versus CABG 10.5% (HR: 1.25, 95% CI = 0.75–2.09). PCI did not meet the criteria for non-inferiority	Underpowered for the primary outcome with a short follow-up period of 1 year. Type of stents used during the trial period. Clopidogrel use was disproportionate in the follow-up period − 54.4% in PCI versus 10.3% in CABG at one year.
ARTS I and II^38,39 (2011)	5 years	ARTS I – prospective randomized (BMS vs CABG). ARTS II – single arm SES use	CABG (n = 96), BMS (n = 112) versus SES (n =159)	MACCE	BMS 53.8%, SES 40.5%, CABG 23.4% (p < 0.001)	ARTS II was single arm only and was not randomized. No anti-platelet usage data was noted.
FREEDOM⁴⁰ (2012)	5 years	Prospective randomized	CABG (n = 947) versus PCI (SES 51%, PES 43%) (n = 953)	Death, MI or stroke	PCI 26.6% versus CABG 18.7%, p = 0.005	The trial was not conducted in a blinded fashion. Subjects had an average EUROscore of ±2.5, which is in the range of low to moderate risk and 83% of the study population had triple vessel disease and patients with lower disease burden and higher surgical risk had less representation.
VA CARDS⁴¹ (2013)	2 years	Prospective randomized	CABG (n = 103) versus PCI (n = 104) (both first and second generation DES)	Composite of all-cause mortality and non-fatal MI	CABG 18.4% versus PCI 25.3%, HR: 0.89; CI 0.47–1.71	The trial was underpowered due to inadequate sample size and follow-up period. Silent MIs were aggressively tracked through nuclear studies at regular intervals, leading to higher diagnosis exclusively noted in the surgical arm.

In many of the trials, data was obtained from sub-group analysis and thus lacked power.

CABG: coronary artery bypass graft; CI: confidence interval; DES: drug-eluting stent; HR: hazard ratio, MACCE: major adverse cardiovascular and cerebrovascular events; MI: myocardial infarction; PCI: percutaneous coronary intervention; PES: paclitaxel-eluting stent; SES: sirolimus-eluting stents.

Table 3.

Efficacy of PCI with second generation DES compared to first generation DES in diabetics.

Trial	Follow up	Design	Comparison	Primary outcome	Results of primary outcome	Drawbacks
ENDEAVOR IV⁴² (2009)	1 year	Prospective, randomized	Sub-analysis ZES (n = 241) versus PES (n = 236)	Target Vessel Failure (TVF) (a composite of cardiac death, MI, or clinically driven target vessel revascularization (TVR))	ZES 8.6% versus PES 10.8%, p = 0.53	Diabetic outcomes were a sub-analysis and lacked power. Follow-up period was small. Patients will severe coronary lesions and LMCAD were excluded.
NAPLES-DIABETES⁴³ (2009)	3 years	A prospective, open-label, randomized	ZES (n = 75) versus PES (n = 75) versus SES (n = 76)	MACE (death, MI, or clinically driven TVR)	No significant difference between PES and SES groups (p = 1.0) but a higher MACE rate in the ZES group versus both SES (p = 0.012) and PES group (p = 0.075).	The study was open-label and had a small sample size with inadequate power.
ESSENCE DIABETES⁴⁴ (2011)	8 months	Prospective randomized, noninferiority	EES (n = 149) versus SES (n = 151)	Angiographic in-segment late loss	EES non-inferior to SES	The endpoint was angiography based and did not have a clinical correlate. The power of the study was less than initially targeted
SORT-OUT IV⁴⁵ (2012)	9 and 18 months	Prospective randomized, single-blind, all comers, non-inferiority	Sub-analysis EES = 194 versus SES = 196	Combination of cardiac death, myocardial infarction, definite stent thrombosis, and clinically indicated target vessel revascularization at 18 months	EES was non-inferior to SES (10.3% vs 15.8%, RR = 0.63; CI = 0.36–1.11)	Diabetic outcomes were a sub-analysis and lacked power, was single-blind.
ESSENCE DIABETES II⁴⁶ (2013)	9 months	Prospective randomized, non-inferiority	R-ZES (n = 127) versus SES (n = 129)	Angiographic in-segment late loss	R-ZES non-inferior to SES	The trial was terminated early and lacked power for endpoint assessment.
SPIRIT V⁴⁷ (2012)	9 months	Single blinded, non-inferiority	EES (n = 218) versus PES (n = 106)	In-stent late loss	EES 0.19 mm superior to PES 0.39 mm, p = 0.001	Endpoint was angiography based and did not have a clinical correlate. Short follow-up duration
TUXEDO–India^48,49 (2016/17)	1 year/2 years	Prospective randomized, non-inferiority	PES (n = 889) versus EES (n = 899)	TVF (a composite of cardiac death, MI or clinically driven target vessel revascularization [TVR])	PES versus EES 1 year − 5.6% versus 2.9% (CI 0.8–4.5, p = 0.38), PES did not meet criteria for noninferiority. 2 years − 6.6% versus 4.3% p = 0.03.	Follow-up duration was inadequate for long term analysis. Syntax sub-analysis was not done.

Most of the trials have results generated from a subgroup analysis, thus being only hypothesis-generating.

EES: everolimus-eluting stent; PCI: percutaneous coronary intervention; MACE: major adverse cardiovascular event; PES: paclitaxel eluting stent; RR: relative risk; SES: sirolimus-eluting stent; TVF: target vessel failure; TVR: target vessel revascularization; ZES: zotarolimus-eluting stent.

Table 4.

Efficacy of second generation DES in diabetics compared to CABG.

Bangalore et al.¹⁷ (2015)	2.9 years	Observational, specified diabetic subgroup analysis	EES (n = 1487) versus CABG (n = 1487)	All-cause mortality	EES 3.89% versus CABG 3.73% (HR = 1.06, p = 0.65)	Observational study, no prospective analysis
BEST¹⁸ (2017)	2 years	Prospective randomized, diabetic subgroup analysis	EES (n = 177) versus CABG (n = 186)	Composite of death, MI, or target vessel revascularization	EES (19.2%) versus CABG (9.1%) (p = 0.007)	Diabetes outcomes were from a subgroup analysis. The study sample size was small and the follow-up duration was inadequate for long term analysis.
EXCEL^19,20 (2019)	3 years	A prospective open-label randomized, only LMCAD with low-moderate SYNTAX scores (<33, diabetic subcohort)	EES (n = 286) versus CABG (n = 286)	MACCE	EES PCI 20.7% versus CABG19.3%, p = 0.87	Diabetes outcomes were from the subgroup analysis. The trial was open-labeled and only recruited patients with LMCAD and low-moderate SYNTAX scores. Mortality outcomes benefited CABG
NOBLE²¹ (2019)	5 years	Prospective, open label, randomized, non-inferiority, diabetic sub-group analysis	PCI (first (10%) and second generation (90%- umirolimus) (n = 90) versus CABG (n = 94)	MACCE	CABG 28% versus PCI 40%, RR 1.56 CI: 0.93–2.59, p = 0.82	Diabetic outcomes were a sub-analysis and lacked power.

CABG: coronary artery bypass graft; EES: everolimus-eluting stent; LMCAD: left main coronary artery disease; PCI: percutaneous coronary intervention; MACCE: major adverse cardiovascular and cerebrovascular events; RR: relative risk.

Section III. CABG now and PCI for the future?

Superior cardiovascular outcomes of CABG over PCI in diabetes are primarily powered by higher rates of complete revascularization and preservation of natural endothelial responses in CABG, in comparison to maladaptive endothelial pathophysiology in a stented vessel.⁵⁰ This advantage is important in diabetes due to the severity of atherosclerosis noted in diabetes.

CABG introduces an “endogenous stent,” which bypasses multiple stenosed areas, leading to more complete revascularization and greater protection against future thrombosis, compared to stents, which revascularize single lesions. Autologous vessels are less immunogenic and thrombogenic than stents and provide a more physiologic milieu. Saphenous venous grafts (SVG) were initially used and are being increasingly replaced by arterial conduits due to higher rates of long-term venous graft failure from vessel remodeling.^51,52 Data from Coronary Artery Surgery Study (CASS) and other large-scale trials have demonstrated better long-term patency of arterial over venous grafts.^53–55 Internal mammary arterial (IMA) grafts, in particular, have preserved endothelial functions like vasodilation and have higher flow reserve (due to higher compliance).⁵⁶ Noncompliance with anti-platelet therapy is not lethal in CABG, as it can be in PCI.

Restenosis and thrombosis are the primary pathogenic mechanisms involved in poorer outcomes in PCI treated vessels and these are intensified in diabetes. Restenosis involves narrowing of the stented sites due to fibro-inflammatory deposition, starting as an initial thrombogenic reaction, followed by migration of inflammatory cells and finally intimal hyperplasia and remodeling.⁵⁷ Stents are foreign bodies and thus more thrombogenic, which translate into increased risk of early (<1-month) or late (1-month–1-year) in-stent thrombosis.⁵⁸ Delayed healing and impaired endothelialization of the stented area play a role in this process.⁵⁹ Multivessel disease, requiring multiple stents, amplifies these risks.

Intervention rates are, however, disproportionately skewed toward the use of PCI,^60,61 despite the evidence-based superiority of CABG. Minimal invasiveness and shorter post-procedural stay times make PCI a very attractive approach for patients. CABG entails a greater risk of early post-procedural stays and events including deep tissue infection due to open sternotomy and higher stroke risk due to use of cardiopulmonary bypass.⁶² The “test and treat” approach involving diagnostic catheterization getting converted into a PCI procedure might be another possible reason for increasing PCI utilization. Physician biases can affect disclosures, especially when the diagnostic and therapeutic options are intertwined.⁶³ The benefits of new PCI technologies are occasionally applied by conjecture, as rapidly changing advances result in the sparsity of prospective data.

Case-based therapeutic adjudication

Risk factor-based individualized assessment is essential to stratify patients for the best interventional approach. A “Heart Team” comprising primarily of cardiologists and cardiothoracic surgeons, helps achieve a multi-disciplinary consensus and is seen to improve outcomes.⁶⁴ Scoring systems such as EUROscore and SYNTAX also guide decision making. EuroSCORE I & II predict mortality post-cardiac surgery.^65–67 These scores are however not well validated in the diabetic population. SYNTAX score⁶⁸ estimates CAD severity and complexity. Higher SYNTAX scores are associated with a greater benefit of CABG over PCI. Post-hoc analysis of SYNTAX scores of treated diabetic patients in the FREEDOM trial noted the correlation of SYNTAX scores with PCI outcomes but showed no benefit of SYNTAX score calculation in changing recommendations from CABG to PCI.⁶⁹ Many of the trials discussed in Tables 2 to 4 exclude high-risk surgical patients, patients with complex lesions, recent MI, heart failure, and prior revascularization, thereby creating an inclusion bias.

Left ventricular systolic dysfunction (LVSD), a major complication of CAD, is considered to be a risk factor for a major surgery like CABG. However, evidence from the STICH trial showed that the addition of CABG to medical therapy helped in a significant reduction of cardiovascular hospitalizations and cardiovascular mortality over medical therapy alone in patients with LVSD.⁷⁰ A 12-year follow-up retrospective study demonstrated significant improvement in MACCE and overall mortality with CABG over PCI in diabetic patients with LVSD (ejection fraction <35%).⁷¹ Further prospective studies are needed to clear the air regarding the use of CABG in this population, who have a higher surgical risk, but might benefit more with the bypass option in the long run.

Left main coronary artery disease (LMCAD) in CAD portends a high risk of future complications and poorer outcomes and has typically been treated with CABG in the diabetes population. Comparative evidence in cases of isolated left main coronary artery disease (LMCAD) in diabetes has also been updated, with data from MAIN-COMPARE and EXCEL showing similar cardiovascular outcomes with PCI compared to CABG in diabetes.^72,73

Chronic total occlusions (CTO), defined as chronic (>3 months) complete coronary occlusion (TIMI 0 flow), are more common in diabetes.⁷⁴ CTOs are mostly treated by anginal medical therapy and CABG. CTO PCI is considered high risk and is performed in centers with high volume and expertise. Single vessel CTO and patients with previous CABG are probable candidates for CTO PCI.

Another clinical situation for preferential PCI utilization in diabetes is post CABG worsening of CAD. Repeat surgery in such cases confers a high mortality risk and PCI is a decent option.⁷⁵

Recent advances in PCI and CABG technology

The advances in interventional cardiology are progressing at a breakneck speed. Major progress has been made in developing new-generation DES, which have thinner construction, bio-similar designs, and better and longer drug effect and delivery. Bioresorbable DES^/scaffolds (BR-DES/BRS) are advanced generation stents with a bioresorbable design and a theoretically lower risk of thrombosis. However, early BRS stents demonstrated a higher incidence of very late thrombosis in BRS group,^76,77 which led to their withdrawal from the market. Outcomes of newer BRS/BD-DES look promising, with long term data awaited.^78,79

Imaging strategies including fractional flow reserve (FFR), optical coherence tomography (OCT), and instantaneous wave-free ratio (iFR) are used to re-stratify intermediate lesion severity in angiographic studies, which leads to a significant change in the treatment plan. However, the benefit in diabetes has not been proven.⁸⁰

Improved PCI outcomes with proper stent selection, placement location, and technique. Intravenous ultrasound (IVUS) and optical coherence tomography (OCT) guided stent placement techniques are being utilized in defining coronary lesion characteristics and severity. These intracoronary imaging techniques guide in appropriate stent selection, length, placement site, and technique to refine outcomes.^81,82 IVUS and OCT also help in defining post-stenting expansion and possible mal-apposition and dissection, thus helping in post stenting risk minimization.⁸³ Targeted interventions in plaques with high risk characteristics diagnosed with OCT/IVUS allows selective PCI utilization in the most severe areas and narrows the therapeutic difference between PCI and CABG in patients with diabetes.⁸⁴

Aspirin and clopidogrel have sub-optimal activity in diabetics, due to modified platelet membranes, altered eicosanoid, and anti-platelet metabolism.^85–87 Newer agents like prasugrel and ticagrelor have demonstrated better cardio and cerebrovascular event rates in PCI treated patients in diabetes compared to the old agents- a result of faster action, more effective platelet inhibition, additional endothelial benefit, and no first-pass requirement for these agents.^88,89

SGLT-2i/GLP-1a also improve cardiovascular endpoints (discussed above) and should be used as first-line agents in diabetes with a history of or high risk of CAD. Patients with diabetes have a high residual coronary risk even after maximal therapy with statins. Treatment with ezetimibe and Proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors reduce the added lipidomic risk by further reduction of LDL-C levels.^90–92 Omega 3 fatty acids are another tool in the CAD treatment armamentarium, eicosapentaenoic acid demonstrating a significant reduction in adverse cardiovascular outcomes in the large prospective REDUCE-IT trial.⁹³

In CABG, revascularization using bilateral IMA has shown mixed results in the general population with a mortality benefit in large observational studies and meta-analysis^94,95 countered by results of the large ART trial (2019), which demonstrated no significant 10-year mortality benefit.⁹⁶ Off-pump CABG and minimally invasive CABG have not had a significant impact on outcomes with CABG.

Hybrid coronary revascularization (HCR)^97,98 attempts to utilize left IMA for LAD bypass (providing maximal survival advantage) coupled with non-LAD small vessel PCI. This approach is particularly helpful when bypasses of particular vessels or an advanced thoracic approach is prohibitive or if second arterial conduits are not available. Current data points toward similar outcomes to traditional CABG.^97,99 This option is not common practice and the lack of large prospective analysis limits widespread use.

Section IV. Conclusion

Coronary artery disease and diabetes mellitus are both modern era epidemics and have a closely dependent relationship. Typical approaches and outcomes of CAD therapies in the general population cannot be extrapolated to diabetics due to a significantly increased risk of CAD in the latter. Current evidence points to a very strong benefit of CABG over PCI in this patient population, both in terms of repeat events and mortality. With current advances in technologies in the domain of PCI and the latest anti-diabetes and anti-platelet drugs, we do anticipate improved outcomes in the future with minimally invasive techniques. Risk stratification and an open discussion with the patient about the risks and benefits of each procedure is essential. The role of the primary physician is vital for secondary prevention and maintaining compliance, which is important for thrombosis prevention. There have been tremendous advances in PCI technology. Nonetheless, on the evidence-based front, the superiority of CABG stands as of now.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number UL1TR001412 to the University at Buffalo. Dr. Sharma also received support from the NHLBI K08HL131987.

ORCID iDs

Salman Bhat

Umesh C Sharma

References

Prevention CfDCa. National diabetes statistics report, 2020. Atlanta, GA: Centers for Disease Control and Prevention, U.S. Dept of Health and Human Services, 2020.

Cordero

López-Palop

Carrillo

, et al. Comparison of long-term mortality for cardiac diseases in patients with versus without diabetes mellitus. Am J Cardiol 2016; 117(7): 1088–1094.

Sarwar

Gao

Seshasai

, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet 2010; 375(9733): 2215–2222.

Wang

Angiographic characteristics of the coronary artery in patients with type 2 diabetes. Exp Clin Cardiol 2002; 7(4): 199–200.

Kovarnik

Chen

Mintz

, et al. Plaque volume and plaque risk profile in diabetic vs. non-diabetic patients undergoing lipid-lowering therapy: a study based on 3D intravascular ultrasound and virtual histology. Cardiovasc Diabetol 2017; 16(1): 156.

Shen

Ding

Dai

, et al. Reduced coronary collateralization in type 2 diabetic patients with chronic total occlusion. Cardiovascular Diabetology 2018; 17(1): 26.

Fishman

Sonmez

Basman

, et al. The role of advanced glycation end-products in the development of coronary artery disease in patients with and without diabetes mellitus: a review. Mol Med 2018; 24(1): 59.

Rask-Madsen

King

GL.

Proatherosclerotic mechanisms involving protein kinase C in diabetes and insulin resistance. Arterioscler Thromb Vasc Biol 2005; 25(3): 487–496.

Rask-Madsen

King

GL.

Mechanisms of disease: endothelial dysfunction in insulin resistance and diabetes. Nat Clin Pract Endocrinol Metab 2007; 3(1): 46–56.

10.

Mooradian

AD.

Dyslipidemia in type 2 diabetes mellitus. Nat Clin Pract Endocrinol Metab 2009; 5(3): 150–159.

11.

Gardner

Fortmann

Krauss

RM.

Association of small low-density lipoprotein particles with the incidence of coronary artery disease in men and women. JAMA 1996; 276(11): 875–881.

12.

Mazzone

Chait

Plutzky

Cardiovascular disease risk in type 2 diabetes mellitus: insights from mechanistic studies. Lancet 2008; 371(9626): 1800–1809.

13.

Schoos

Dangas

Mehran

, et al. Impact of hemoglobin A1c levels on residual platelet reactivity and outcomes after insertion of coronary drug-eluting stents (from the ADAPT-DES Study). Am J Cardiol 2016; 117(2): 192–200.

14.

Ferroni

Basili

Falco

, et al. Platelet activation in type 2 diabetes mellitus. J Thromb Haemost 2004; 2(8): 1282–1291.

15.

Halushka

Rogers

Loadholt

, et al. Increased platelet thromboxane synthesis in diabetes mellitus. The Journal of Laboratory and Clinical Medicine 1981; 97(1): 87–96.

16.

Brunner

Klinger

Weisbort

, et al. Thromboxane, prostacyclin, beta-thromboglobin, and diabetes mellitus. Clinical Therapeutics 1984; 6(5): 636–642.

17.

Akai

Naka

Okuda

, et al. Decreased sensitivity of platelets to prostacyclin in patients with diabetes mellitus. Horm Metab Res 1983; 15(11): 523–526.

18.

Sugiyama

Yamamoto

Bryniarski

, et al. Coronary plaque characteristics in patients with diabetes mellitus who presented with acute coronary syndromes. J Am Heart Assoc 2018; 7(14): e009245.

19.

Prati

Romagnoli

Gatto

, et al. Relationship between coronary plaque morphology of the left anterior descending artery and 12 months clinical outcome: the CLIMA study. European Heart Journal 2019; 41(3): 383–391.

20.

Boden

O‘Rourke

Teo

, et al. Optimal medical therapy with or without PCI for stable coronary disease. New Engl J Med 2007; 356(15): 1503–1516.

21.

Maron

Hochman

Reynolds

, et al. Initial invasive or conservative strategy for stable coronary disease. New England Journal of Medicine 2020; 382(15): 1395–1407.

22.

BARI 2D Study Group. A randomized trial of therapies for type 2 diabetes and coronary artery disease. New Engl J Med 2009; 360(24): 2503–2515.

23.

Marso

Bain

Consoli

, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. New Engl J Med 2016; 375(19): 1834–1844.

24.

Zelniker

Wiviott

Raz

, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet 2019; 393(10166): 31–39.

25.

American Diabetes Association. 10. Cardiovascular Disease and Risk Management: Standards of Medical Care in Diabetes—2020. Diabetes Care 2020; 43(Supplement 1): S111–S134.

26.

Gæde

Lund-Andersen

Parving

H-H

, et al. Effect of a multifactorial intervention on mortality in type 2 diabetes. New Engl J Med 2008; 358(6): 580–591.

27.

Arnold

Bhatt

Barsness

, et al. Clinical management of stable coronary artery disease in patients with type 2 diabetes mellitus: a scientific statement from the American Heart Association. Circulation 2020; 141(19): e779–e806.

28.

Neumann

F-J

Sousa-Uva

Ahlsson

, et al. 2018 ESC/EACTS guidelines on myocardial revascularization. European Heart Journal 2018; 40(2): 87–165.

29.

Henderson

O‘Flynn

. Management of stable angina: summary of NICE guidance. Heart 2012; 98(6): 500–507.

30.

(NICE) NIfHaCE. Stable angina: management [updated 2016. Guidelines], https://www.nice.org.uk/guidance/cg126/chapter/1-Guidance (2011).

31.

Cram

House

Messenger

, et al. Indications for percutaneous coronary interventions performed in US hospitals: a report from the NCDR^®. Am Heart J 2012; 163(2): 214–222.

32.

Elezi

Kastrati

Pache

, et al. Diabetes mellitus and the clinical and angiographic outcome after coronary stent placement. J Am Coll Cardiol 1998; 32(7): 1866–1873.

33.

Kogan

Ram

Levin

, et al. Impact of type 2 diabetes mellitus on short- and long-term mortality after coronary artery bypass surgery. Cardiovasc Diabetol 2018; 17(1): 151.

34.

Kurbaan

Bowker

Ilsley

, et al. Difference in the mortality of the CABRI diabetic and nondiabetic populations and its relation to coronary artery disease and the revascularization mode. Am J Cardiol 2001; 87(8): 947–950. A3.

35.

BARI Investigators. Seven-year outcome in the Bypass Angioplasty Revasculari-zation Investigation (BARI) by treatment and diabetic status. J Am Coll Cardiol 2000; 35(5): 1122–1129.

36.

Kappetein

Head

Morice

, et al. Treatment of complex coronary artery disease in patients with diabetes: 5-year results comparing outcomes of bypass surgery and percutaneous coronary intervention in the SYNTAX trial. Eur J Cardiothorac Surg 2013; 43(5): 1006–1013.

37.

Kapur

Hall

Malik

, et al. Randomized comparison of percutaneous coronary intervention with coronary artery bypass grafting in diabetic patients: 1-year results of the CARDia (Coronary Artery Revascularization in Diabetes) trial. J Am Coll Cardiol 2010; 55(5): 432–440.

38.

Serruys

Unger

Sousa

, et al. Comparison of coronary-artery bypass surgery and stenting for the treatment of multivessel disease. New Engl J Med 2001; 344(15): 1117–1124.

39.

Serruys

Ong

Morice

, et al. Arterial Revascularisation Therapies Study Part II: sirolimus-eluting stents for the treatment of patients with multivessel de novo coronary artery lesions. EuroIntervention 2005; 1(2): 147–156.

40.

Farkouh

Domanski

Sleeper

, et al. Strategies for multivessel revascularization in patients with diabetes. New Engl J Med 2012; 367(25): 2375–2384.

41.

Kamalesh

Sharp

Tang

, et al. Percutaneous coronary intervention versus coronary bypass surgery in United States veterans with diabetes. J Am Coll Cardiol 2013; 61(8): 808–816.

42.

Kirtane

Patel

O‘Shaughnessy

, et al. Clinical and angiographic outcomes in diabetics from the ENDEAVOR IV trial: randomized comparison of zotarolimus- and paclitaxel-eluting stents in patients with coronary artery disease. JACC Cardiovasc Interv 2009; 2(10): 967–976.

43.

Briguori

Airoldi

Visconti

, et al. Novel approaches for preventing or limiting events in diabetic patients (Naples-diabetes) trial: a randomized comparison of 3 drug-eluting stents in diabetic patients. Circ Cardiovasc Interv 2011; 4(2): 121–129.

44.

Kim

Lee

Park

, et al. Randomized comparison of everolimus-eluting stent versus sirolimus-eluting stent implantation for de novo coronary artery disease in patients with diabetes mellitus (ESSENCE-DIABETES): results from the ESSENCE-DIABETES trial. Circulation 2011; 124(8): 886–892.

45.

Okkels Jensen

Thayssen

Hansen

, et al. Randomized comparison of everolimus-eluting and sirolimus-eluting stents in patients treated with percutaneous coronary intervention: the Scandinavian Organization for Randomized Trials with Clinical Outcome IV (SORT OUT IV). Circulation 2012; 125(10): 1246–1255.

46.

Park

Lee

Park

, et al. Comparison of zotarolimus-eluting stent versus sirolimus-eluting stent for de novo coronary artery disease in patients with diabetes mellitus from the ESSENCE-DIABETES II trial. The American Journal of Cardiology 2013; 112(10): 1565–1570.

47.

Grube

Chevalier

Guagliumi

, et al. The SPIRIT V diabetic study: a randomized clinical evaluation of the XIENCE V everolimus-eluting stent vs the TAXUS Liberté paclitaxel-eluting stent in diabetic patients with de novo coronary artery lesions. Am Heart J 2012; 163(5): 867–875. e1.

48.

Kaul

Bangalore

Seth

, et al. Paclitaxel-eluting versus everolimus-eluting coronary stents in diabetes. New Engl J Med 2015; 373(18): 1709–1719.

49.

Kaul

Bhagwat

Pinto

, et al. Paclitaxel-eluting stents versus everolimus-eluting coronary stents in a diabetic population: two-year follow-up of the TUXEDO-India trial. EuroIntervention 2017; 13(10): 1194–1201.

50.

van Buuren

Dahm

Horskotte

. Stent restenosis and thrombosis: etiology, treatment, and outcomes. Minerva Med 2012; 103(6): 503–511.

51.

Raza

Blackstone

Houghtaling

, et al. Influence of diabetes on long-term coronary artery bypass graft patency. J Am Coll Cardiol 2017; 70(5): 515–524.

52.

Caliskan

de Souza

Böning

, et al. Saphenous vein grafts in contemporary coronary artery bypass graft surgery. Nat Rev Cardiol 2020; 17(3): 155–169.

53.

Myers

Blackstone

Davis

, et al. CASS Registry long term surgical survival. Coronary Artery Surgery Study. J Am Coll Cardiol 1999; 33(2): 488–498.

54.

Goldman

Zadina

Moritz

, et al. Long-term patency of saphenous vein and left internal mammary artery grafts after coronary artery bypass surgery: results from a Department of Veterans Affairs Cooperative Study. J Am Coll Cardiol 2004; 44(11): 2149–2156.

55.

Lytle

Loop

Cosgrove

, et al. Long-term (5 to 12 years) serial studies of internal mammary artery and saphenous vein coronary bypass grafts. J Thorac Cardiovasc Surg 1985; 89(2): 248–258.

56.

Otsuka

Yahagi

Sakakura

, et al. Why is the mammary artery so special and what protects it from atherosclerosis? Ann Cardiothorac Surg 2013; 2(4): 519–526.

57.

Weintraub

WS.

The pathophysiology and burden of restenosis. Am J Cardiol 2007; 100(5a): 3k–9k.

58.

Eppihimer

Sushkova

Grimsby

, et al. Impact of stent surface on thrombogenicity and vascular healing: a comparative analysis of metallic and polymeric surfaces. Circ Cardiovasc Interv 2013; 6(4): 370–377.

59.

Joner

Finn

Farb

, et al. Pathology of drug-eluting stents in humans: delayed healing and late thrombotic risk. J Am Coll Cardiol 2006; 48(1): 193–202.

60.

Mokadam

Melford Jr

Maynard

, et al. Prevalence and procedural outcomes of percutaneous coronary intervention and coronary artery bypass grafting in patients with diabetes and multivessel coronary artery disease. J Card Surg 2011; 26(1): 1–8.

61.

de la Hera

Delgado

Hernandez

, et al. Prevalence and outcome of newly detected diabetes in patients who undergo percutaneous coronary intervention. Eur Heart J 2009; 30(21): 2614–2621.

62.

Stamou

Hill

Dangas

, et al. Stroke after coronary artery bypass: incidence, predictors, and clinical outcome. Stroke 2001; 32(7): 1508–1513.

63.

Pandey

McGuire

de Lemos

, et al. Revascularization trends in patients with diabetes mellitus and multivessel coronary artery disease presenting with non-ST elevation myocardial infarction: insights from the national cardiovascular data registry acute coronary treatment and intervention outcomes network registry-get with the guidelines (NCDR ACTION Registry-GWTG). Circ Cardiovasc Qual Outcomes 2016; 9(3): 197–205.

64.

Yamasaki

Abe

Horikoshi

, et al. Enhanced outcomes for coronary artery disease obtained by a multidisciplinary heart team approach. Gen Thorac Cardiovasc Surg 2019; 67(10): 841–848.

65.

Nashef

SAM

Roques

Sharples

, et al. EuroSCORE II. Eur J Cardio-Thorac Surg 2012; 41(4): 734–745.

66.

Nashef

Roques

Michel

, et al. European system for cardiac operative risk evaluation (EuroSCORE). Eur J Cardiothorac Surg 1999; 16(1): 9–13.

67.

Holmes

Patel

, et al. Comparison of EuroSCORE II, original EuroSCORE, and the society of thoracic surgeons risk score in cardiac surgery patients. Ann Thorac Surg 2016; 102(2): 573–579.

68.

Cavalcante

Sotomi

Mancone

, et al. Impact of the SYNTAX scores I and II in patients with diabetes and multivessel coronary disease: a pooled analysis of patient level data from the SYNTAX, PRECOMBAT, and BEST trials. Eur Heart J 2017; 38(25): 1969–1977.

69.

Esper

Farkouh

Ribeiro

, et al. SYNTAX score in patients with diabetes undergoing coronary revascularization in the FREEDOM Trial. J Am Coll Cardiol 2018; 72(23, Part A): 2826–2837.

70.

Velazquez

Lee

Jones

, et al. Coronary-artery bypass surgery in patients with ischemic cardiomyopathy. New Engl J Med 2016; 374(16): 1511–1520.

71.

Nagendran

Bozso

Norris

, et al. Coronary artery bypass surgery improves outcomes in patients with diabetes and left ventricular dysfunction. J Am Coll Cardiol 2018; 71(8): 819–827.

72.

Lee

Ahn

Yoon

, et al. Long-term (10-year) outcomes of stenting or bypass surgery for left main coronary artery disease in patients with and without diabetes mellitus. J Am Heart Assoc 2020; 9(8): e015372.

73.

Milojevic

Serruys

Sabik

, et al. Bypass surgery or stenting for left main coronary artery disease in patients with diabetes. J Am Coll Cardiol 2019; 73(13): 1616–1628.

74.

Iglesias

Degrauwe

Rigamonti

, et al. Percutaneous coronary intervention of chronic total occlusions in patients with diabetes mellitus: a treatment-risk paradox. Curr Cardiol Rep 2019; 21(2): 9.

75.

Morrison

Sethi

Sacks

, et al. Percutaneous coronary intervention versus coronary artery bypass graft surgery for patients with medically refractory myocardial ischemia and risk factors for adverse outcomes with bypass: a multicenter, randomized trial. Investigators of the Department of Veterans Affairs Cooperative Study #385, the Angina With Extremely Serious Operative Mortality Evaluation (AWESOME). J Am Coll Cardiol 2001; 38(1): 143–149.

76.

Lipinski

Escarcega

Baker

, et al. Scaffold thrombosis after percutaneous coronary intervention with ABSORB bioresorbable vascular scaffold: a systematic review and meta-analysis. JACC Cardiovasc Interv 2016; 9(1): 12–24.

77.

Wykrzykowska

Kraak

Hofma

, et al. Bioresorbable scaffolds versus metallic stents in routine PCI. New Engl J Med 2017; 376(24): 2319–2328.

78.

Haude

Ince

Kische

, et al. TCT-188 safety and clinical performance of the drug-eluting absorbable metal scaffold in the treatment of subjects with de novo lesions in native coronary arteries at 36-month follow-up: BIOSOLVE-II and BIOSOLVE-III. J Am Coll Cardiol 2019; 74(13, Supplement): B187.

79.

Buiten

Ploumen

Zocca

, et al. Thin composite-wire-strut zotarolimus-eluting stents versus ultrathin-strut sirolimus-eluting stents in BIONYX at 2 years. JACC Cardiovasc Interv 2020; 13(9): 1100–1109.

80.

Van Belle

Cosenza

Baptista

, et al. Usefulness of routine fractional flow reserve for clinical management of coronary artery disease in patients with diabetes. JAMA Cardiol 2020; 5(3): 272–281.

81.

Song

Kang

Mintz

GS.

Value of intravascular ultrasound in guiding coronary interventions. Echocardiography 2018; 35(4): 520–533.

82.

Nguyen

Seto

Contemporary practices using intravascular imaging guidance with IVUS or OCT to optimize percutaneous coronary intervention. Expert Rev Cardiovasc Ther 2020; 18(2): 103–115.

83.

Räber

Mintz

Koskinas

, et al. Clinical use of intracoronary imaging. Part 1: guidance and optimization of coronary interventions. An expert consensus document of the European Association of Percutaneous Cardiovascular Interventions. Eur Heart J 2018; 39(35): 3281–3300.

84.

Dettori

Milzi

Burgmaier

, et al. Prognostic irrelevance of plaque vulnerability following plaque sealing in high-risk patients with type 2 diabetes: an optical coherence tomography study. Cardiovasc Diabetol 2020; 19(1): 192.

85.

Angiolillo

Bernardo

Sabaté

, et al. Impact of platelet reactivity on cardiovascular outcomes in patients with type 2 diabetes mellitus and coronary artery disease. J Am Coll Cardiol 2007; 50(16): 1541–1547.

86.

Christensen

Grove

Würtz

, et al. Reduced antiplatelet effect of aspirin during 24 hours in patients with coronary artery disease and type 2 diabetes. Platelets 2015; 26(3): 230–235.

87.

Geisler

Anders

Paterok

, et al. Platelet response to clopidogrel is attenuated in diabetic patients undergoing coronary stent implantation. Diabetes Care 2007; 30(2): 372–374.

88.

Angiolillo

Badimon

Saucedo

, et al. A pharmacodynamic comparison of prasugrel vs. high-dose clopidogrel in patients with type 2 diabetes mellitus and coronary artery disease: results of the Optimizing anti-Platelet Therapy In diabetes MellitUS (OPTIMUS)-3 trial. Eur Heart J 2011; 32(7): 838–846.

89.

Steg

Bhatt

Simon

, et al. Ticagrelor in patients with stable coronary disease and diabetes. New Engl J Med 2019; 381(14): 1309–1320.

90.

Sabatine

Leiter

Wiviott

, et al. Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial. Lancet Diabetes Endocrinol 2017; 5(12): 941–950.

91.

Ray

Colhoun

Szarek

, et al. Effects of alirocumab on cardiovascular and metabolic outcomes after acute coronary syndrome in patients with or without diabetes: a prespecified analysis of the ODYSSEY OUTCOMES randomised controlled trial. Lancet Diabetes Endocrinol 2019; 7(8): 618–628.

92.

Giugliano

Cannon

Blazing

, et al. Benefit of adding ezetimibe to statin therapy on cardiovascular outcomes and safety in patients with versus without diabetes mellitus: results From IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). Circulation 2018; 137(15): 1571–1582.

93.

Bhatt

Steg

Miller

, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. New Engl J Med 2019; 380(1): 11–22.

94.

Buttar

Yan

Taggart

, et al. Long-term and short-term outcomes of using bilateral internal mammary artery grafting versus left internal mammary artery grafting: a meta-analysis. Heart 2017; 103(18): 1419–1426.

95.

Itagaki

Cavallaro

Adams

, et al. Bilateral internal mammary artery grafts, mortality and morbidity: an analysis of 1 526 360 coronary bypass operations. Heart 2013; 99(12): 849–853.

96.

Taggart

Benedetto

Gerry

, et al. Bilateral versus single internal-thoracic-artery grafts at 10 years. New Engl J Med 2019; 380(5): 437–446.

97.

Puskas

Halkos

DeRose

, et al. Hybrid coronary revascularization for the treatment of multivessel coronary artery disease: a multicenter observational study. J Am Coll Cardiol 2016; 68(4): 356–365.

98.

Saha

Naqvi

Goldberg

Hybrid revascularization: a review. Cardiology 2018; 140(1): 35–44.

99.

Tajstra

Hrapkowicz

Hawranek

, et al. Hybrid coronary revascularization in selected patients with multivessel disease: 5-year clinical outcomes of the prospective randomized pilot study. JACC Cardiovasc Interv 2018; 11(9): 847–852.