Introduction
Recent ESC Guidelines (1) emphasize the prevention and treatment of atherosclerosis related cardiovascular diseases (ASCVD) through the type 2 diabetes mellitus (T2DM) lens: disease duration, presence of cardiovascular (CV) risk factors, asymptomatic as well as clinically overt ASCVD progressively increase the thrombotic risk in patients. Among ASCVD, coronary artery disease (CAD) is highly prevalent in T2DM (≈ 20%) and contributes to ≈30% of ASCVD-related deaths.(2) We highlight the most recent advances in the approach to the T2DM patient with CAD.
Revascularisation strategies
The anatomical pattern of CAD in T2DM patients influences the prognosis and response to revascularization. Patients with diabetes mellitus (DM) are more likely to have left main and multivessel CAD, and coronary pathology is more frequently diffuse involving small vessels.(3) The indications for myocardial revascularization are the same in patients with and without T2DM (4).
Elective coronary artery bypass surgery (CABG) or percutaneous coronary intervention (PCI)?
Single vessel disease is usually treated with PCI. The FREEDOM trial randomized 1,900 patients with multivessel CAD and DM, but no left main stenosis, to elective CABG or PCI with a first-generation drug eluting stent (DES).(5) The primary endpoint of all-cause death, non-fatal myocardial infarction (MI), or stroke at 5 years occurred in 26.6% of patients in the PCI and 18.7% in the CABG groups (P=0.005). Furthermore, in the DM subgroup (n=452) of the SYNTAX trial, the 5 year need for repeating revascularization was higher in the PCI group than in the CABG group (HR 2.75; P < 0.001).(6) Moreover, a recent meta-analysis of 11 trial, involving 11,518 patients allocated to PCI with stents or CABG, showed that among DM patients (38% of the cohort), mortality was 15.7 and 10.1% (HR 1.44, 95% CI 1.20–1.74; P=0.0001), respectively, while no difference was observed among patients without DM.(7) These findings support a benefit for DM patients from CABG compared with PCI. In the subgroup of 505 patients with DM in the EXCEL trial, studying left main disease, the primary endpoint of death, MI, or stroke at 3 years occurred in 21.2% of patients in the PCI and 19.4% in the CABG arms (HR 1.04, 95%CI:0.70–1.55),(8) suggesting that newer generation DES may reduce the gap between CABG and PCI in the future.
The appropriate revascularisation modality in patients with DM and multivessel disease should be discussed by the Heart Team, considering the individual cardiac and extracardiac characteristics, as well as preferences of a well-informed patient. Current evidence indicates that in stable patients with coronary anatomy suitable for both procedures and low predicted surgical mortality, CABG is superior to PCI in reducing the composite risk of death, MI, or stroke, and death only.(1) However, in DM patients with low complexity of coronary anatomy (SYNTAX score ≤22), PCI has achieved similar outcomes to CABG with respect to death as well as to death, MI, or stroke.(1) No large studies comparing CABG with PCI in patients with ACS and DM are available. However, it was recently shown that complete revascularisation with PCI reduced the combined primary endpoint of CV death and MI compared to treating the infarct-related artery only in patients with ST-elevation MI and multivessel disease. This was shown in the entire cohort of 4,041 patients, with no significant difference in the subgroup of 787 DM patients.(9) Collectively, these studies indicate that full revascularisation of all significant lesions may be of extra value in DM.
Antithrombotic treatment
Current evidence for antithrombotic treatment of T2DM patients with CAD derives from sub-group analyses of clinical trials largely including non-DM patients, with major intrinsic methodological limitations given the unique pro-thrombotic and metabolic profile of T2DM.
Dual antiplatelet therapy (DAPT) post-acute coronary syndrome (ACS)
DAPT including low-dose aspirin and a P2Y12 receptor blocker, either prasugrel or ticagrelor is the recommended treatment post-ACS for 1 year (1) based on the TRITON-TIMI-38 and PLATO trials, respectively. Registry data indicate that DAPT is prescribed for significantly longer time in DM vs. non-DM patients post-DES.(10) DAPT with prasugrel showed a trend toward higher proportional benefit in the DM vs. non-DM cohorts as compared to clopidogrel (HR 0.70 vs. 0.86, respectively, P-interaction 0.09) in the TRITON-TIMI trial.(11) In the PLATO trial, DAPT with ticagrelor showed a similar benefit in DM and non-DM cohorts.(12) A head-to-head comparison for DAPT with prasugrel or ticagrelor (DM patients n=892, ≈22%) has been recently completed,(13) showing significantly higher major adverse cardiovascular events rate (HR 1.36, 95%CI:1.09-1.70), no difference in bleeding and higher discontinuation rate for ticagrelor vs. prasugrel.(14)
The optimal antiplatelet treatment post-CABG in T2DM also relies on studies including DM and non-DM patients, and depends on whether CABG is performed in ACS or stable CAD.(4, 15) The 2019 ESC guidelines recommend DAPT after CABG post-ACS for 12 months.(15)
Regardless the type of trial and antithrombotic strategy, the residual absolute incidence of serious vascular events is consistently higher in DM vs. non-DM patients, in agreement with high in vivo platelet activation.(16) The highest event rate is consistently reported in insulin-treated DM patients.(11, 12) Given this high residual risk, implementing drug adherence is fundamental, since interrupting either the P2Y12 inhibitor or aspirin from DAPT, particularly in the first 6 months, seems associated with significantly worse outcomes.(17) Observational studies and trials consistently showed that ≈1 out of 10 patients prematurely interrupt ticagrelor due to dyspnea, a ticagrelor-specific adverse effect (HR 6.40, 95%CI: 5.39-7.41 vs. comparators).(18, 19), also in T2DM patients.(20) Thus, the possibility of low adherence to DAPT due to dyspnoea should be carefully considered and monitored on an individual basis in DM patients when prescribing ticagrelor.
De-escalation from a more effective P2Y12 inhibitor (prasugrel or ticagrelor) to clopidogrel based on platelet function testing has no proven benefit in T2DM and can, in fact, be potentially harmful by reducing antithrombotic protection.(21) Notably, clopidogrel has a wide variability and increased poor responsiveness rate in DM as compared to non-DM patients, due to low generation of clopidogrel active metabolite.(22) Therefore, clopidogrel may be particularly ineffective in T2DM.
Prolonged antithrombotic treatment post acute coronary syndrome (ACS)
Different strategies are possible beyond 12 months post-ACS, but these strategies were never selectively tested in T2DM patients. DAPT with prasugrel can be continued up to 30 months.(14) Patients between 1 to 3 years post-MI, can continue DAPT with a reduced ticagrelor (60 mg bid) dosing or up to 3 years.(23) The benefit/risk balance of this combination beyond 3 year and in patients with a history of MI over 3 years remains unknown. DM patients with chronic CAD on aspirin may benefit from adding rivaroxaban 2.5 mg twice daily.(24)
All combined, long-term antithrombotic treatments are consistently associated with a variable but significant increase in bleeding risk, therefore a careful and periodical check of the bleeding risk factors and preventing gastrointestinal bleeding with gastroprotective drugs(25) is important.
DM patients without previous MI but with stable angina and/or documented CAD are at a very high cardiovascular risk, which can also be considered as a ‘risk modifier’.(1) Based on the SAPAT trial,(26) low-dose aspirin is the reference chronic treatment. Intensified antiplatelet treatment adding ticagrelor has shown minimal cardiovascular protection (HR 0.90, 95%CI: 0.81-0.99), but a significant ≈2-fold increase both in TIMI major and in intracranial bleeding.(20) Therefore, DAPT with ticagrelor has no net benefit in these high-risk DM patients.
Conclusions
Metabolic control and anti-thrombotic treatment represent the pillars to prevent and treat micro- and macrovascular diseases and organ damage in T2DM. As depicted in the Figure below, ASCVD risk moves across a continuum, where metabolic control (glucose, lipid, blood pressure) has to be timely and progressively instituted, together with an appropriate anti-thrombotic prevention and treatment and coronary intervention in patients at highest risk, i.e patients with overt ASCVD (left panel) and/or cardiovascular risk factor burden or documented atherosclerotic disease (middle panel).
Metabolic control with optimal glucose levels is the cornerstone of diabetes treatment (right panel) to prevent microvascular organ damage. Antithrombotic treatment and revascularisation prevent and cure ASCVD regardless of the clinical severity (middle panel). The optimal combination of the two can effectively reduce target organ damage (cerebral, cardiac and renal) in T2DM patients.
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