Take-home messages
- Coronary artery disease is quite common among diabetics in all age groups.
- Atypical presentations like gastroesophageal reflux disease and silent myocardial infarction demand a high index of suspicion.
- Greater attention to guideline-directed therapies to attain the targets of glycaemia, blood pressure, and lipids is needed.
- More frequent use of ticagrelor and high-dose statins plus ezetimibe, thrombin-inhibitors, and icosapent ethyl are needed in high-risk subsets.
- Be mindful of higher risk of short-and long-term complications like major adverse cardiac events.
ACS acute coronary syndrome
CABG coronary artery bypass grafting
CAD coronary artery disease
COPD chronic obstructive pulmonary disease
CVD cardiovascular diseases
DM diabetes mellitus
GERD gastroesophageal reflux disease
HTN hypertension
LAD left anterior descending artery
MVD multiple vessel disease
SMI silent myocardial ischaemia
Introduction
Diabetes mellitus (DM) is a major risk factor for cardiovascular diseases (CVDs). With the projected rise in DM in most parts of the world, CVDs are also expected to mirror the rise [1]. DM affects CVDs in many ways; there is an increase in prevalence and the complications of coronary artery disease (CAD), atrial fibrillation (AF), cerebrovascular disease, peripheral vascular disease, and essential hypertension (HTN) than in non-diabetic subjects. CAD in DM is quite common (2-to-4-fold) and, despite many similarities, has many clinically relevant differences. The prevalence, clinical presentations, response to therapy including medical and surgical revascularisation, the rate of complications, and outcomes despite optimal management, are different and are more demanding.
This brief narrative review highlights some practical tips for practicing cardiovascular physicians and other care providers on the salient features of the impact of DM on CAD, particularly its atypical manifestations, the differences in management and outcomes, how to minimise risks, and to improve outcomes.
Pathogenesis of Atherosclerosis and Atherothrombosis in DM versus without DM
The process of atherosclerosis and atherothrombosis commences earlier in age, progresses faster, and is associated with more complications including premature morbidity and mortality among diabetics. Various mechanisms are implicated in the pathogenesis of CAD, including epigenetic changes, intracellular metabolic changes resulting in greater oxidative stress, and endothelial dysfunction. DM is a prothrombotic and a hypercoagulable state predisposing to thrombus formation, increased thrombin generation by platelets, impaired fibrinolysis resulting from increased levels of plasminogen activator inhibitor-1 (PAI-1), low-grade inflammation that raise the circulatory levels of interleukin-6, fibrinogen, and tissue factor expression in vascular cells [2].
Most diabetic patients have insulin resistance, hyperinsulinemia, and vascular calcification. These not only promote the occurrence of atherosclerosis but can also accelerate the progression of stable plaques to unstable plaques or rupture of the plaques, leading to thrombosis and precipitating acute coronary syndrome and even mortality, particularly if attention is delayed [3]. The platelets play a pivotal role in atherogenesis and its thrombotic complications [4].
Overall coronary atherosclerosis is more severe and diffuse having a striking appearance at coronary angiography.
The Atypical Manifestations of Acute Coronary Syndromes
A recent study showed that diabetic patients present more often with atypical chest pains, and thus are more likely to experience a delay in diagnosis and treatment [5]. The atypical presentations and the course of the illness are considerably influenced by accompanying comorbidities like HTN, dyslipidaemias, and complications of DM like autonomic neuropathy, an altered pain threshold, and the onset age of CAD symptoms [5].
A) Painful ACS
Chest pain may be quite different in location, severity, and accompanying symptoms. Any physician can easily misinterpret the early symptoms and signs, thus delaying well-timed management. At times, this may have serious consequences including death.
Usually, the severity of pain/discomfort is less than what is described by the patients without DM. The location of the pain may be atypical, for example, localized to only the right side of the chest, the nape of the neck, jaw, or shoulders, or the upper part of the back or in the epigastric region. Epigastric discomfort/pain commonly resembles acute gastroesophageal reflux disease (GERD), leading to an incorrect diagnosis which can be a serious error. If the epigastric discomfort/pain improves and the overall condition does not deteriorate, the diagnosis is missed altogether. It may only be discovered incidentally on a 12-lead ECG conducted prior to routine medical evaluations, such as for insurance purposes, or at follow-up for other cardiovascular and non-cardiovascular illnesses.
The pain/discomfort of ACS sometimes masquerades as acute shoulder arthritis, cervical spondylitis, jaw or dental pains, and muscular pains. Accompanying symptoms like palpitation, dyspnoea, and syncope, may or may not be present. However, sweating is usually less severe.
B) Symptomatic but Painless ACS
The pain/discomfort may be strikingly absent or so mild that it easily be overlooked or dominated by other symptoms like acute indigestion, acidity in the stomach, dyspnoea, dizziness, syncope, palpitation, and sweating [5]. In one study from the UK, about 20.2% of patients presented with such symptoms and experienced higher mortality than patients who presented with chest pain at one month and one-year follow-up [6]. Acute onset of wheezing due to acute pulmonary oedema could be easily confused with acute bronchial asthma.
Therefore, the first onset of acute bronchial asthma beyond 30-years of age should raise a strong suspicion for ACS. Besides syncope, elderly individuals may present such as an acute confusional state or an unexplained and acute deterioration in general physical and mental condition, including acute fatigue and exhaustion with or without other common accompanying symptoms [5,7]. The outcomes are adverse for these patients. A high index of suspicion is imperative to diagnose such patients in time .
C) Silent Myocardial Infarction or Silent ACS
When (Many times) symptoms are so atypical, vague, mild, or short-lasting, patients may either not seek medical attention or may relegate the symptoms to preexisting diseases such as GERD, cervical spondylosis, shoulder arthritis, fatigue due to exertion, or even breathlessness or wheeziness due to worsening of chronic obstructive pulmonary disease (COPD). Sometimes the patients consult their physicians who fail to entertain the possibility of ACS and instead attribute the symptoms to a worsening of co-existing disorders [8]. Often, ACS develops during sleep and is missed altogether; a few patients die during sleep because of this condition. Silent ACS is more common in patients with DM and HTN as well as in women and elderly individuals. A high index of suspicion is imperative to rule ACS in or out in these patients. Following the event, either the patient recovers or may experience sudden deterioration or they may even die [8]. In one study, silent myocardial infarction was encountered in 8.2% of patients during their first myocardial infarction and had more than 3-fold mortality and major adverse cardiovascular events (MACE) [9].
In another study, the prevalence of silent myocardial infarction was 28.5% in diabetics and 21.5% in non-diabetics, with a mean infarct size of 11.8% of the left ventricle [10]. In a multi-ethnic study from the US, in community-based samples (MESA study subjects) of cardiac magnetic resonance imaging (CMR), the prevalence of myocardial scarring suggestive of old myocardial infarction was 7.9%, at a mean age of 68 years. Interestingly, 78% were unrecognized at electrocardiogram (ECG) and clinical evaluation and had no history of ACS [11]. It is possible that many patients, particularly those with larger infarctions, may have died undiagnosed. Only those with minor and uncomplicated heart attacks could have survived to be identified later, particularly with characteristic ECG (mostly q-wave infarctions) changes suggestive of old myocardial infarctions.
It appears that silent ACS is commonly under-suspected and underdiagnosed, necessitating a very high index of suspicion in the susceptible high-risk subjects as mentioned above. It is important to diagnose them in time to avoid complications like MACE, including greater premature mortality in the long term.
Atypical Presentations in Chronic Stable Coronary Artery Disease
A) Silent myocardial ischaemia (SMI) is very common, and is more in severity, frequency, and duration among diabetics. SMI is commoner in men and patients with diabetic retinopathy [5,12]. As the pain is characteristically absent, the patient may continue to exert until they develop one or more complications of ischaemia such as ACS, acute pulmonary oedema, or features suggestive of lowered cardiac output like marked weakness, exhaustion, dizziness, cold sweats, and even syncope.
B) Symptomatic ischaemic patterns: in addition to chest pain or discomfort during effort, at times it develops following meals, and/or exposure to cold. The pain/discomfort may be localised to the epigastrium, and be misinterpreted as GERD following meals, effort, or exposure to the cold. Episodes of symptomatic and silent ischaemia commonly occur in the same patient, with the latter more frequent than the symptomatic ones.
Therapy For CAD in DM
Lifestyle measures
Lifestyle measures are imperative and have disease-modifying properties. Besides the diabetic diet, the overall principles are the same as for non-diabetics. However, bodyweight control and all risk-multiplying comorbidities - particularly hypertension, dyslipidaemia and tobacco abuse - deserve special attention to achieve their guideline-recommended goals. Adherence to regular physical activities and avoidance of all precipitating activities and events such as undue physical and mental exertion, and episodes of hypoglycaemia (silent or symptomatic), need greater emphasis and monitoring. The diabetic diet needs attention and counselling at each visit, preferably with a nutritionist, with attention to avoidance of hypoglycaemia as it may precipitate ACS and is associated with poor outcomes at long-term follow-up.
Regular isotonic exercises like moderate-intensity walking (minimum 30-minute daily/at least 5 days per week) and isometric muscle strengthening exercises (for about 20 minutes on alternate days), along with yoga and relaxation techniques are of greater importance in prevention and rehabilitation. The restriction of animal proteins in the diet has been shown to reduce insulin resistance and is encouraged [13]. Pneumococcal vaccination, yearly influenza vaccination, and coronavirus vaccination including booster doses are imperative to prevent adverse outcomes. The patients must be warned to avoid excessive or unusual mental and physical exertion.
All diabetics and their caring family members must be educated periodically, particularly about the importance of compliance with lifestyle measures and therapeutics. They should also be educated about various atypical presentations of ACS, including silent myocardial infarctions and other CVDs, and to raise the alarm and seek medical attention in time, whenever needed.
Medical therapies
The overall principles of management and therapeutics are like those in non-diabetics. The higher risk of short- and long-term MACE is common . Therefore, greater attention to guidelines-directed therapies to attain the recommended targets of glycaemia, blood-pressure, and lipids is needed.
The overall response to therapy may be less satisfactory but metabolically neutral beta-blockers like carvedilol and labetalol may have an edge due to the neutral effect on glucose and lipids. Due to the blunting of sympathetic stimulation, particularly with beta blockers, some episodes of hypoglycaemia could be easily missed (hypoglycaemia unawareness). Treating physicians and patients must be mindful of such episodes, particularly in patients on insulin and oral sulfonylureas. Recent data and guidelines recommend Sodium-glucose co-transporter 2 inhibitors (SGLT2i) and/or Glucagon-like peptide-1 receptor agonists (GLP-1RA) in additions to lifestyle measures, to control glycaemia as they afford additional cardiovascular protection, and do not produce hypoglycaemia. Metformin is also a suitable addition or alternative, however, the use of insulin and high-dose sulfonylurea should be deferred, minimised, or avoided unless deemed necessary.
Aspirin resistance is common in diabetics. Clopidogrel also has greater resistance in diabetics than in non-diabetics. Ticagrelor [14], and prasugrel (only in patients undergoing percutaneous coronary intervention [PCI]) could provide better efficacy at a reasonable risk of bleeding, with improved short- and long-term outcomes.
Statins may be relatively less effective, the targets for low-density lipoprotein cholesterol (LDL-C) <70mg% for secondary prevention in high-risk patients, <55mg% in very high-risk patients, and even <40mg% in extremely high-risk subjects are guideline-based though harder to achieve in clinical practice.
Non-statin-based therapies like ezetimibe are commonly added to statins. Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) like alirocumab and evolocumab and small interfering RNA (siRNA) like inclisiran, albeit more expensive, may be needed to achieve LDL-C targets to obviate the excessive risks in very high-risk patients. The REDUCE-IT trial recently showed that in addition to statins, icosapent ethyl (IPE) 2 gm twice daily reduces MACE by 25% in high-risk patients, including among diabetics with elevated fasting serum triglycerides (>135 mg% despite statins). A thrombin-inhibitor-based therapy like low-dose rivaroxaban (2.5 mg twice daily with aspirin after 1-year of ACS) has improved outcomes in diabetics and other high-risk groups [15]. Greater use of ticagrelor, high-dose statins plus ezetimibe, low-dose rivaroxaban, and IPE is often needed to avoid MACE.
Revascularisation therapies
Medical revascularisation by percutaneous coronary interventions (PCI) involves the relief of coronary artery obstructions with or without stenting. There is an increased risk of acute complications like acute coronary dissection. As atherosclerosis is diffuse, more, and longer stents are often needed. Following PCI, acute stent thrombosis is more common than in non-diabetics. DM is one of the risk factors for stent restenosis. The overall response to medical revascularisation is poorer and is shorter-lasting than in non-diabetics [16]. Therefore, surgical revascularisation is the preferred option, particularly in patients with multiple vessel disease (MVD) with involvement of proximal left anterior descending artery (prox LAD), if acceptable to the patient and their family.
Surgical revascularisation is a guideline-recommended therapy despite slightly higher immediate postoperative complications like a greater risk of infection, delayed healing of the wound, etc. Despite the challenges, coronary artery bypass grafting (CABG) is preferred particularly in patients with MVD with/without prox LAD as it has shown better long-term outcomes and freedom from repeat procedures [17].
Teleconsultations, remote monitoring, and the application of newer technologies like artificial intelligence, etc., are rapidly progressing to deliver timely attention and care in hours of need.
Prevention
The best treatment of CAD in DM is prevention at all levels.
- A multifactorial risk reduction strategy to prevent CAD in DM is imperative, with greater attention to achieving optimal guideline-directed targets of common concomitant risk-multiplying disorders like hypertension, dyslipidaemia, etc. The zero-tobacco policy is ideal, though harder to achieve without tobacco treatment clinics.
- Greater attention to therapeutic lifestyle changes (TLC) and therapeutics like SGLT2i, GLP-1RA, and statins, along with non-statin therapeutics, to achieve guideline-recommended targets are needed. Optimal control of glycaemia on a long-term basis is a must in order to avoid or delay micro-and macrovascular complications of DM.
- Avoidance of episodes of hypoglycaemia (symptomatic and silent) is a must, as such episodes lead to sympathetic over-stimulation, which may precipitate serious arrhythmia and ACS. At long-term follow-up, symptomatic and silent episodes of hypoglycaemia are associated with poorer MACE, including death.
- Measures to reduce insulin resistance through weight management plans, bariatric surgery (if body mass index is >35 kg/m2), increased physical activity, and reduction in the intake of animal proteins are relevant; as insulin resistance is very common and one of the major players in DM and its cardiovascular complications.
- Repeated reminders with a focus on TLC and on rehabilitation for secondary and tertiary prevention are equally rewarding.
Conclusions
Diabetes mellitus besides metabolic is a vascular disease, associated with extensive atherosclerosis and complications.
Atypical presentations of acute coronary disease mask other common pre-existing disorders such as gastroesophageal reflux disease, chronic obstructive pulmonary disease, shoulder arthritis, and generalised weakness due to nonspecific illness. In elderly diabetics, the presentation of acute coronary disease can often be vague, mild, or self-limiting, such that even the physician may fail to consider the possibility of acute coronary disease (silent acute coronary disease). Sometimes, acute deterioration of mental status could also be due to acute coronary disease. A high index of suspicion is therefore imperative to diagnose acute coronary disease in time to avoid major adverse cardiac events, including death.
Overall, the principles therapies of coronary artery disease in diabetes mellitus are similar to those for non-diabetics. However, more aggressive medical therapies, with guideline-directed control of all coexisting disorders like hypertension, dyslipidaemia, and tobacco avoidance are important to avoid major adverse cardiac events.
CABG is a better option than medical therapy alone in patients with multiple vessel disease with involvement of proximal left anterior descending artery if revascularisation is indicated. Proper and regular sessions of education about the disease process, therapeutic lifestyle changes, and how to receive medical attention in hours of need are mandatory. Upcoming technologies like teleconsultation and artificial intelligence-based approaches hold great promise.
The best treatment for coronary artery disease in diabetes mellitus is prevention. Prevention at any stage in the natural history of the disease (primordial, primary, secondary, tertiary, quaternary) is exceedingly important to contain the emerging epidemic of diabetes mellitus and coronary artery disease.
For further information, see the ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD [18].
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