All guidelines reviewed: a roadmap to screen, diagnose and treat diabetes

Background

Increased obesity, stress and unhealthy life style have caused the prevalence of diabetes mellitus (DM) to rise in Europeans aged 20–79 years to over fifty million. This figure is expected to reach 64 million by 2030 with would-be related healthcare costs hitting the 90 billion Euro mark (1).
Further than preventing its onset, physicians can help to prevent the delayed recognition of various forms of coronary artery disease (CAD) in these patients. Adults with diabetes have a two to four times increased risk for heart disease and stroke than those without. Diabetes worsens prognosis and causes increased health care spending (2).
Careful multifactorial clinical assessment in each patient can achieve the necessary prevention and treatment. Find here a closer look at how to handle each aspect of managing the disease according to the latest guidelines on the topic.

Screening

There are three screening groups of patients according to the recommendations from the World Health Organisation (WHO), and the American Diabetes Association also observed by the European guidelines:

• The general population
• Those with assumed abnormalities (e.g. obese, hypertensive, or with a family history of DM) and 
• Patients with CVD (3,4).  

The screening strategy is to start with a DM risk score and to investigate individuals with a high value with first-hand HbA1c and/or FPG using the FINnish Diabetes RIsk SCore (FINDRISC)(5). 

Diagnosis

In both diabetics and impaired glucose tolerance (IGT) patients cardiovascular risk assessment is the basis for multifactorial management. 

• Diagnosis is based on a combination of HbA1c and FPG or an OGTT if still in doubt. 
• Measuring the FPG (>7.0 mmol/L), 2hPG (>11.1 mmol/L) or HbA1c (>6.5%) is in order.

Risk levels

Risk assessment includes classical risk factors, glycaemic status, albuminuria, presence of macrovascular and microvascular disease as well as search for arrhythmias and atrial fibrillation especially. 
Cardiovascular disease prevention is important since over 65% of mortality in these patients is caused by CV disease. Progression of IGT to DM can be delayed by lifestyle intervention in about 50% of individuals. The latest joint European Society Guidelines on CVD prevention determine the risk for developing CVD:

• Very high risk:  patients with DM and at least one other CV risk factor or target organ damage are at very high risk for developing CVD.
• High risk: patients with DM and no CV risk factor are at high risk for developing CVD. 

Findings

Ankle-brachial index (ABI), carotid artery intima-media thickness and plaques imaging, arterial stiffness and cardiac autonomic neuropathy (CAN) may be considered useful cardiovascular markers, adding predictive value to the usual risk estimates (6,7,8).
CAC and myocardial perfusion scintigraphy findings are synergistic for the prediction of cardiovascular events.

Lifestyle changes

Those at high risk of T2DM and/or with established IGT are to be given appropriate lifestyle counseling

• Moderate to vigorous physical activity of ≥150 min/week is recommended for prevention of T2DM and CVD. 
• Daily consumption of vegetable and fruits, increased dietary fiber intake, moderate intake of simple carbohydrates, replacement of saturated fat by monounsaturated or polyunsaturated fat and weight reduction >5% if BMI >25 kg/m2 should be advised. 
• Smoking cessation in all subjects with DM and IGT. 

Glycaemic targets

Glucose lowering should be individualised taking duration of DM, co-morbidities and age into account. 

• An HbA1c target of <7.0% (<5,3 mmol/mol) for reduction of microvascular and macrovascular disease is recommended in both DM Type 1 and Type2 with acknowledgement of individual patient requirements (9).
• Tight diabetes control should be applied early in younger subjects without attendant co-morbidities. 
• More stringent targets (e.g. HbA1c 6.0–6.5% (42–48 mmol/mol]) might be considered in selected patients with short disease duration, long life expectancy, and no significant CVD, if obtained without producing hypoglycaemia.

Blood pressure

Blood pressure (BP) control in diabetic patients with hypertension lowers the risk of cardiovascular events. The latest ESC guidelines on hypertension treatment in diabetics recommends

• Starting drug treatment when systolic blood pressure is => 140mmHg, with target BP goal <140/85mmHg.
• Combination of blood pressure lowering agents is to achieve blood pressure control (10). A RAAS blocker (ACE-I or ARB) should be used in the treatment of hypertension particularly in the presence of proteinuria, with avoidance of simultaneous administration of two RAAS blockers (ONTARGET study).
• Evidence supports the use of an ACE-I, rather than a calcium channel blocker, as initial therapy to prevent or delay the occurrence of microalbuminuria. 
• Thiazides and beta-blockers are associated with an increased risk of developing T2DM, but it is not known whether they result in clinically important metabolic adverse events. 

Dyslipidaemia

A cluster of lipid abnormalities with moderate elevation of fasting and non-fasting TGs and low HDL-C accompanies T2DM. Statin therapy is recommended in patients with T1DM and T2DM at very high-risk with an LDL-C target of <1.8 mmol/L (<70 mg/dL) or at least a ≥50% LDL-C reduction if this target goal cannot be reached. Statin therapy is also recommended in patients with T2DM at high risk with an LDL-C target of <2.5 mmol/L (<100 mg/dL). It may be considered to have a secondary goal of non–HDL-C <2.6 mmol/L (<100 mg/dL) in patients with DM at very high risk and of <3.3 mmol/L (<130 mg/dL) in patients at high risk. The use of drugs that increase HDL-C to prevent CVD in T2DM is not recommended. 

Antiplatelet therapy

Low CVD risk : Antiplatelet therapy with aspirin in DM-patients at low CVD risk is not recommended.
High CVD risk: Antiplatelet therapy for primary prevention may be considered in high risk patients or on an individual basis. Aspirin at a dose of 75–160 mg/day is recommended as secondary prevention in DM. A P2Y12 receptor blocker is recommended in patients with DM and ACS for 1 year and in those subjected to PCI. In patients with PCI for ACS preferably prasugrel or ticagrelor should be given. Clopidogrel is recommended as an alternative antiplatelet therapy in case of aspirin intolerance.

Multifactorial approach

Hypertension, hyperlipidaemia and diabetes are parts of the deadly metabolic syndrome, causing graduate polyvascular changes and increased morbidity and mortality. Patients with glucose abnormalities need early assessment of

• Risk factors 
• Micro and macrovascular disease and autonomic dysfunction
• Co-morbidities (e.g. heart failure and arrhythmias);
• Inducible ischaemia by use of exercise testing
• Stress echocardiography, or myocardial scintigraphy and
• Myocardial viability and LV function by means of echo-Doppler and/or magnetic resonance imaging.

Treatment should be target-driven for all risk factors. Patient education and life style advice as a part of a personalised multifactorial management approach are the basis of successful patient treatment.

Coronary artery disease

Patients with CAD but without previously known diabetes, should have their glycaemic state evaluated. Elevated levels of HbA1c and FPG may establish the diagnosis of DM, but a normal value does not exclude glucose abnormalities. The appropriate screening method is an OGTT, which should not be performed earlier than 4–5 days after an ACS to minimise false positive results (11).
In patients with stable CAD and DM, optimal medical treatment should be considered the preferred treatment, unless there are large areas of ischemia or significant left main or proximal LAD lesions. b-Blockers are effective in improving prognosis in post-MI patients. Treatment with ACE-I or ARB should be started during hospitalisation for ACS and continued in patients with DM and LVEF, 40%, hypertension, or chronic kidney disease, and considered in all patients with ST-elevation myocardial infarction (STEMI). Patients with DM and stable CAD are also recommended to receive an ACE-I (12). Statin therapy is indicated in diabetic patients and CAD to reduce the risk for cardiovascular events (13). In secondary prevention, low-dose aspirin (75– 160 mg) or clopidogrel (separately or in combination) reduces risk of stroke, MI and vascular death. Insulin based glycaemic control should be considered in ACS patients with significant hypergelicaemia (>10mmol/l or >180 mg/dl) with the target adapted to possible comorbidities.

Coronary revascularisation

Early angiography with revascularisation should be proposed to diabetic patients with acute coronary syndromes. Revascularisation procedures performed in DM patients, results in higher long-term risk which is challenged by a more diffuse atherosclerosis, higher risk for restenosis after PCI and saphenous graft occlusion after coronary artery bypass graft surgery. In DM patients presenting with STEMI, primary PCI is recommended over fibrynolisis  if performed within recommended time limits. CABG is preferred if the myocardial area at risk is large (multi-vessel disease, complex coronary lesions, SYNTAX Score >22) to improve event free survival. In DM patients subjected to PCI, DES rather than BMS are recommended to reduce risk of target vessel revascularisation.  Antithrombotic treatment in DM patients undergoing coronary revascularization for stable angina or ACS is no different from those without DM (14)

Heart Failure

Diabetic patients with heart failure have a 12-fold higher mortality comparing to patients without heart failure. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers improve symptoms and reduce mortality and are indicated in T2DM and heart failure (15). In addition to an ACE-I (or, if not tolerated, an ARB) a b-blocker should be given to all patients with an LVEF ≤40% to reduce mortality and hospitalization. Low-dose mineralocorticoid receptor antagonists (MRA) are indicated in patients with persistent symptoms NYHA Class II–IV and an LVEF ≤35%, despite treatment with an ACE-I (or, if not tolerated, an ARB) and a beta-blocker (16). Diuretics are useful for the relief of dyspnoea and oedema in patients with fluid overload, with preference of loop diuretics rather than thiazides, which could promote hyperglycaemia.  Addition of ivabradine to an ACE-I, beta-blocker and MRA may be considered in patients in sinus rhythm with T2DM with heart failure and LVEF <40%, who have persisting symptoms (NYHA Class II–IV) and a heart rate >70 b.p.m. Recommendations for nonpharmacolic therapy of heart failure are the same as for non diabetic patients. The use of metformin has been associated with lower mortality, lower hospital admission, and fewer adverse events. Thiazolidinediones should not be used in patients with heart failure and T2DM since water retention may worsen or provoke heart failure (17).

Atrial fibrillation

Individuals with atrial fibrillation (AF) are at significantly increased risk of stroke and have twice the mortality rate from CVD, compared with those in sinus rhythm. Screening for AF can be recommended in selected patient groups where there is any suspicion of paroxysmal or permanent AF by pulse palpation, routine 12-lead ECG, or Holter recordings. The simplest scheme with "CHA2DS2VASc" score is recommended for stroke risk stratification, based on updated 2012 ESC Guidelines for the management of AF. 
Antithrombotic therapy in diabetes patients: Oral anticoagulation with vitamin K antagonists (VKAs) or one of the new oral anticoagulants  is recommended in patients with AF, and should be used in DM patients with AF unless contra-indicated and if accepted by the patient. With the use of VKA, an international normalized ratio (INR) of 2.0–3.0 is the optimal range for prevention of stroke and systemic embolism in patients with DM. A lower target INR (1.8–2.5) has been proposed for the elderly, but this is not based on evidence. Combinations of VKA with antiplatelet therapy do not offer added benefits and lead to more bleeding and such combinations should be avoided. Two new classes of anticoagulants oral direct thrombin inhibitors and oral factor Xa inhibitors have the potential to be used as an alternative to warfarin, especially in patients intolerant to, or unsuitable for, VKAs. An assessment of bleeding risk should be carried out before starting anticoagulation using simple bleeding score known as (HAS-BLED). A score ≥3 indicates high risk and some caution and regular review of the patients is needed following initiation of antithrombotic therapy (18).

Sudden cardiac death

Screening for risk factors for sudden cardiac death should be considered in patients with DM. T2DM patients with congestive heart failure or previous MI should have LVEF measured in order to identify candidates for prophylactic implantable cardioverter defibrillator therapy. Secondary prophylaxis with implantable cardioverter defibrillator therapy is indicated in DM patients resuscitated from ventricular fibrillation or sustained ventricular tachycardia, as recommended in the Guidelines (19). 

Lower extremity artery disease

Diabetes mellitus is a risk factor for the development of lower extremity artery disease (LEAD). Duration and severity of DM are important risks factors for gangrene and ulceration development. Medical history and physical examination are the basics of diagnostic workup and should include a review of the different vascular beds and their specific symptoms. Clinical screening for PAD should be performed annually with advices for lifestyle changes. An objective measure of LEAD is the ankle–brachial index (ABI), with an ABI <0.8 indicating PAD, regardless of symptoms. All patients with PAD should receive adequate lipid-lowering, antihypertensive and antiplatelet treatment, with optimal glycaemic control and stop smoking (20). It is recommended that LDL-C should be lowered to <1.8 mmol/L (<70 mg/dL) or by ≥50% when the target level cannot be reached and blood pressure controlled to <140/85 mm Hg. Antiplatelet therapy is recommended in all patients with symptomatic PAD and DM without contraindications. If conservative therapy is unsuccessful, revascularisation should be considered in each individual case. In patients with critical limb ischemia comprehensive management requires multidisciplinary care to control atherosclerotic risk factors, provision of revascularisation where possible, optimization of wound care, appropriate shoe wear, treatment of infection, and rehabilitation (20). 

Carotid artery disease

Diabetes mellitus is an independent risk factor for ischaemic stroke with an incidence 2.5–3.5 times higher than in non-DM. Patients who have suffered a stroke or TIA within the past six months are considered symptomatic. Duplex ultrasonography, computed tomography angiography, and magnetic resonance imaging are indicated to evaluate carotid artery stenosis. Carotid endarterectomy seems to offer a clear advantage over conservative treatment in patients with symptomatic carotid artery disease, however the role of revascularization in asymptomatic patients remains less clear. 

Conclusions

Multifactorial risk assessment and lifestyle management in the prevention and treatment of DM and CVD should be a major goal in everyday clinical practice. Patient-oriented care is advised for better disease control and decision-making respecting patient priorities and goals. Comprehensive care of DM patients requires multidisciplinary collaboration between different specialties in cardiology, diabetology, primary care physicians and several other subspecialties. Current lifestyle and living in the era of limited health care resources, place cardiovascular prevention and diabetes screening as main priorities of nation oriented health care strategy.