The global prevalence of diabetes mellitus (DM) has quadrupled over the past few decades, from an estimated 108 million adults living with diabetes in 1980 to 422 million adults living with diabetes in 2014.¹ Just as worrying, the global burden of diabetes is projected to further increase by 10% in 2040.² This poses a major challenge to societies and health care authorities as diabetes increases the risk for several diseases, including cardiovascular disease (CVD).³ Indeed, the total economic cost associated with DM was $327 billion in 2017 in the US alone.⁴ Clear and evidence-based recommendations for how to manage patients with diabetes have never been more important.

The European Society of Cardiology (ESC), in collaboration with the European Association for the Study of Diabetes (EASD) released 2019 guidelines for the prevention and management of CVD in patients with prediabetes and diabetes.⁵ Since the prior ESC guidelines published in 2013, there has been an unprecedented increase in new evidence indicating cardiovascular benefits from the use of novel glucose-lowering drugs based on large-scale cardiovascular outcome trials (CVOTs). CVOTs such as EMPA-REG OUTOME, CANVAS, CREDENCE, REWIND, PIONEER 6 and LEADER reported significant reduction in CVD events with sodium-glucose cotransporter-2 (SGLT2) inhibitor or glucagon-like peptide-1 receptor agonist (GLP1-RA) in patients with DM. These new treatment options provide important opportunities for improving care of patients with DM.

Risk Stratification

In general, risk scores that were developed for general populations are not recommended for CVD risk assessment in patients with diabetes. The current categorization of CVD risk in patients with diabetes was developed from the 2016 ESC guidelines on CVD prevention in clinical practice. CV risk categories are summarized below (Table 1).

Table 1: Cardiovascular Risk Classification

Very high risk	High risk	Moderate risk
Patients with DM and CVD or DM with target organ damage.* Patients with DM with three or more major risk factors or with type 1 DM duration of >20 years	Patients with DM duration of ≥10 years without target organ damage plus any other additional risk factor	Young patients (type 1DM aged <35years or type 2DM aged <50years) with DM duration of <10 years without other risk factors

Pharmacological Management

The 2019 ESC guidelines provide specific recommendations for glucose treatment:

Glucose Lowering Management
In general, the new 2019 ESC recommendations for glucose lowering treatments are closely linked to recent results from the CVOTs. Thus, an SGLT-2 inhibitor or GLP1-RA should be immediately initiated or added to existing metformin treatment in patients with DM and CVD, or in patients at high or very high risk to reduce CV events.

The guideline also provides specific recommendations for SGLT2 and GLP1-RA based on results from individual CVOTs. Accordingly:

• SGLT2 inhibitors such as empagliflozin, canagliflozin, or dapagliflozin are recommended to lower the risk of heart failure hospitalization and to reduce the progression of diabetic kidney disease. Empagliflozin is recommended in patients with prevalent CVD, to reduce the risk of death.
• GLP1-RAs such as liraglutide, semaglutide and dulaglutide are recommended in patients with DM and CVD, or who are at very high/high CVD risk, to reduce CVD events. In addition, liraglutide has shown to significantly reduce CV death in DM and CVD, or for patients at very high/high CV risk.

The choice of drug to reduce CV events should be prioritized and individualized based on the presence of risk factors and CVD in patients with DM. For glycemic control, HbA1c level of < 7% is advised for most patients, while a target of 8% or ≤9% may be adequate for elderly patients.

Lipid Management
The 2019 ESC diabetes guidelines endorse the same principle for management of blood cholesterol as the 2019 dyslipidemia guidelines, that is, by providing differentiated treatment targets for low-density lipoprotein cholesterol (LDL-C) based on estimated risk for CVD. These LDL-C targets have been lowered compared to the preceding guideline:

• Moderate risk: LDL-C <2.6 mmol/L (<100mg/dL)
• High risk: LDL-C <1.8 mmol/L (<70mg/dL)
• Very high risk: LDL-C <1.4 mmol/L (<55mg/dL)

To reach these targets, most patients will qualify for statin treatment. Currently, a PCSK9 inhibitor is recommended in very high-risk patients who have persistently high LDL-C levels even with maximal dose of statin and ezetimibe therapy or in patients who have statin intolerance.

Blood Pressure Management
As with lipid targets, the targets for blood pressure levels have been lowered in the new guidelines. Thus, a systolic blood pressure (SBP) goal of 130 mmHg (<130 mmHg if well tolerated), and a diastolic blood pressure (DBP) goal of <80 mmHg is recommended, compared to a previous target of <140/85 mmHg for all patients. In older adults aged >65 years, SBP target range of 130-139 mmHg is recommended. The guidelines emphasize an individualized approach for hypertension management. Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker is recommended as first line therapy for BP control in DM patients.

Antiplatelet Therapy
The 2019 ESC guideline does not provide strong recommendations for antiplatelet therapy in DM patients without CVD. However, aspirin (75-100 mg/day) may be considered in high risk or very high risk patients in the absence of contraindications (IIb).

Imaging

Screening for coronary artery disease (CAD) in asymptomatic patients with DM remains debatable. According to the new guidelines, screening of CAD with computed tomography coronary angiography (CTCA) or functional imaging such as radionuclide myocardial perfusion imaging, stress cardiac magnetic resonance imaging, or exercise or pharmacological stress echocardiography may be considered (IIb). Additionally, coronary artery calcium (CAC) score may be considered as a risk modifier in the CVD risk assessment of asymptomatic patients at moderate risk (IIb).

Differences and Similarities between the ESC and ADA Guidelines

As in Europe, diabetes is also an increasing problem in the US due to the obesity epidemic. In US, an estimated 30.3 million adults or 9.4 % of the population had diagnosed diabetes and 84.1 million or 33.9% of the adult population had prediabetes.⁷

The American Diabetes Association (ADA), Standards of Medical Care in Diabetes-2020 provide recommendations for management of diabetes that are like those from the 2019 ESC guidelines. However, some differences in treatment targets and treatment intensity is demonstrated below (Table 2).

Table 2: 2019 ESC vs. 2020 ADA Guidelines

Management	2019 ESC	ADA 2020
HbA1c	<7% for most adults (6-6.5% and <8% or ≤ 9% as individualized targets)	<7% for most adults (<6.5% and <8% as individualized targets)
Blood pressure	<130/80 mmHg for most adults	<130/80 mmHg if high risk and <140/90 mmHg if lower risk
Lipid targets	Differentiated LDL-C targets (<1.4, <1.8 and <2.6 mmol/L) according to risk	No specific targets, but instead recommendations for treatment intensity
Antithrombotic	No strong recommendations for primary prevention but may be considered in high or very risk patients. A proton pump inhibitor may be considered to prevent GI bleeding (IIa)	No strong recommendations for primary prevention, but may be considered in high or very risk patients
Imaging	Routine screening for asymptomatic coronary artery disease (CAD) remains controversial. Calcium score may be considered as a risk modifier in the CVD risk assessment of asymptomatic patients at moderate risk (IIb).	Routine screening for asymptomatic CAD remains controversial.

ADA recommends HbA1c level of <7% for most patients.⁸ The ADA recommends a BP target of <130/80 mmHg for individuals with diabetes and hypertension at higher cardiovascular risk such as those with known ASCVD or 10-year ASCVD risk ≥15%.⁹ Whereas, for individuals with diabetes and hypertension at lower risk with 10-year ASCVD risk <15%, a BP target of <140/90 mmHg is recommended. Additionally, the ADA also recommends individualized treatment targets rather than treating all diabetic patients through shared decision-making. For primary prevention, aspirin (75–162 mg/day) may be considered in DM patients who are at increased CVD risk and low bleeding risk after a comprehensive discussion with the patient. While 2019 ESC guideline provide differentiated LDL-C targets based on ASCVD risk, ADA recommends a simpler approach of moderate-intensity statin therapy for patients with DM aged 40–75 years in primary prevention and a high-intensity statin for those with multiple ASCVD risk factors or aged 50–70 years. In DM adults with very high risk (10-year ASCVD risk ≥20%), non-statin therapy such as ezetimibe may be added to maximally tolerated statin dose to reduce LDL-C levels by 50% or more. For patients with DM and ASCVD considered very high risk (which includes a history of multiple major ASCVD events or one major ASCVD event and multiple high-risk conditions),¹⁰ if LDL cholesterol is ≥70 mg/dL on maximally tolerated statin dose, ezetimibe or PCSK9 inhibitor may be considered, however, ezetimibe may be preferred due to lower cost.

Metformin is the preferred initial glucose-lowering agent for the treatment of type 2 DM.¹¹ For patients with established ASCVD or high ASCVD risk (patients aged ≥55 years, with coronary, carotid, or lower-extremity artery stenosis >50% or left ventricular hypertrophy), established kidney disease, or heart failure, an SGLT2 inhibitor or GLP1-RA with demonstrated CVD benefit is recommended as part of glycemic management independent of HbA1C.¹¹ Using noninvasive screening methods, such as CT calcium scoring, is not routinely recommended in asymptomatic patients with DM. The current ESC guidelines underscore the significance of a patient centered approach to facilitate shared decision-making in DM management. Similarly, the 2018 consensus report by the ADA/EASD, and more recently, the 2020 ADA Standards of Medical Care in DM continue to emphasize a patient-centered approach to guide appropriate pharmacologic treatment.¹² Key factors to consider include the presence of comorbidities, hypoglycemia risk, chronic kidney disease (CKD), cost, risk for side effects, and most importantly, patient preferences. A comparison of the average monthly cost of some of the old and new glucose-lowering agents in the US is presented in Table 3.

Table 3: Comparison of average monthly cost of old and new glucose-lowering agents in the US

Drug	Dose	Median Average Cost	Maximum Approved Daily Dose	Median NADAC
Biguanides
Metformin	500 mg	$84 ($4-$85)	2,000mg	$2
Sulfonylureas
Glimepiride	4 mg	$71 ($71-$198)	8mg	$4
Glipizide	10 mg	$75 ($67-$97)	40mg	$5
Thiazolidinediones
Pioglitazone	45 mg	$348 ($283-$349)	45 mg	$4
Rosiglitazone	4 mg	$407	8 mg	$330
SGLT2 inhibitors
Empagliflozin	25 mg	$591	25mg	$473
Dapagliflozin	10 mg	$591	10mg	$473
Canagliflozin	300 mg	$593	300mg	$475
GLP1-RAs
Exenatide	10 µg pen	$876	20 µg	$730
Semaglutide	1 mg pen	$927	1 mg*	$745
	14 mg (tablet)	$927	14 mg	N/A
Liraglutide	18mg/ 3ml pen	$1,106	1.8mg	$886

Conclusion

The 2019 ESC guidelines feature compelling evidence from important CVOTs highlighting the role of newer anti-diabetic medications in reducing CVD events in patients with DM. Both American and European guidelines recommend the use of SGLT-2 inhibitor and GLP1-RAs for CVD prevention in DM patients at high or very high risk. While the trials data looks favorable, new information and increased costs for the newer drugs may impact decision making in routine clinical practice. The burden of diabetes continues to increase in the US and worldwide, and the resulting adverse health and economic implications warrant improved cost-effective management strategies for DM and the resulting CVD complications. In recent years, several large observational studies consistently showed a markedly lower risk of CVD in asymptomatic patients with diabetes, and absence of coronary artery calcium (CAC) has been identified as a favorable prognostic marker in DM patients.^13-15 Future guidelines may consider strengthening recommendations for CAC testing for strategizing individualized preventive and treatment decisions in patients with DM. Ultimately, optimal lifestyle intervention measures along with strong risk factor control and tighter treatment targets continue to remain central to reduce the risk of CVD events in patients with DM.

References

1. Global Report on Diabetes. (World Health Organization website). 2016. Available at: https://apps.who.int/iris/handle/10665/204871. Accessed 01/03/2020.
2. Ogurtsova K, da Rocha Fernandes JD, Huang Y, et al. IDF Diabetes Atlas: global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res Clin Pract 2017;128:40-50.
3. Liu L, Simon B, Shi J, Mallhi AK, Eisen HJ. Impact of diabetes mellitus on risk of cardiovascular disease and all-cause mortality: evidence on health outcomes and antidiabetic treatment in United States adults. World J Diabetes 2016;7:449-61.
4. American Diabetes Association. Economic costs of diabetes in the U.S. in 2017. Diabetes Care 2018;41:917-28.
5. Cosentino F, Grant PJ, Aboyans V, et al. 2019 ESC Guidelines on diabetes, prediabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J 2020;41:255-323.
6. Piepoli MF, Hoes AW, Agewall S, et al. 2016 European guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J 2016;37:2315-81.
7. Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2017. Atlanta, GA: Centers for Disease Control and Prevention, US Department of Health and Human Services; 2017.
8. American Diabetes Association. 6. Glycemic Targets: Standards of Medical Care in Diabetes -- 2020. Diabetes Care 2020;43:S66-S76.
9. American Diabetes Association. 10. Cardiovascular Disease and Risk Management: Standards of Medical Care in Diabetes -- 2020. Diabetes Care 2020;43:S111-S134. 
10. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019;73:3168-3209.
11. American Diabetes Association. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes -- 2020. Diabetes Care 2020;43:S98-S110.
12. Davies MJ, D'Alessio DA, Fradkin J, et al. Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2018;61:2461-98.
13. Agarwal S, Cox AJ, Herrington DM, et al. Coronary calcium score predicts cardiovascular mortality in diabetes: Diabetes Heart Study. Diabetes Care 2013;36:972-77.
14. Malik S, Zhao Y, Budoff M, et al. Coronary artery calcium score for long-term risk classification in individuals with type 2 diabetes and metabolic syndrome from the multi-ethnic study of atherosclerosis. JAMA Cardiol 2017;2:1332-40.
15. Silverman MG, Blaha MJ, Budoff MJ, et al. Potential implications of coronary artery calcium testing for guiding aspirin use among asymptomatic individuals with diabetes. Diabetes Care 2012;35:624-26.

Clinical Topics: Anticoagulation Management, Cardiovascular Care Team, Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Prevention, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Nonstatins, Novel Agents, Statins, Acute Heart Failure, Interventions and Coronary Artery Disease, Interventions and Imaging, Angiography, Computed Tomography, Echocardiography/Ultrasound, Magnetic Resonance Imaging, Nuclear Imaging, Hypertension

Keywords: Diabetes Mellitus, Metabolic Syndrome, Angiotensin Receptor Antagonists, Angiotensin-Converting Enzyme Inhibitors, Aspirin, Benzhydryl Compounds, Calcium, Blood Pressure, Cardiovascular Diseases, Constriction, Pathologic, Cholesterol, LDL, Consensus, Coronary Angiography, Coronary Artery Disease, Decision Making, Diabetes Mellitus, Type 2, Diabetic Nephropathies, Dyslipidemias, Echocardiography, Stress, Factor XII, Fibrinolytic Agents, Glipizide, Glomerular Filtration Rate, Glucagon-Like Peptides, Glucose, Glucosides, Heart Failure, Goals, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hospitalization, Hypertension, Hypertrophy, Left Ventricular, Immunoglobulin Fc Fragments, Life Style, Lower Extremity, Magnetic Resonance Imaging, Myocardial Perfusion Imaging, Hypoglycemia, Metformin, Obesity, Patient Preference, Patient-Centered Care, Platelet Aggregation Inhibitors, Prediabetic State, Prevalence, Primary Prevention, Radioisotopes, Proton Pump Inhibitors, Prognosis, Proteinuria, Recombinant Fusion Proteins, Renal Insufficiency, Renal Insufficiency, Chronic, Risk Factors, Risk Assessment, Sodium-Glucose Transporter 2, Sulfonylurea Compounds, Tablets, Thiazolidinediones, Tomography, Tomography, X-Ray Computed

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