How to Lower Cardiovascular Risks in Diabetes?

CME INDIA Presentation by Dr. N. K. Singh, MD, FICP, Diabetologist Physician, Director – Diabetes and Heart Research Centre (DHRC), Dhanbad, Chairman – RSSDI Jharkhand, Editor – CME INDIA.

22 Unique Ways to Proceed

1. Indian scenario is grim

• The overall diabetes prevalence of type 2 diabetes in India is increasing.
• It has been found that Indians progress faster from pre-diabetes to diabetes compared to other ethnic groups.
• It is also evident that pre-diabetes carries the inherent risk of cardiovascular diseases.
• In India, CVD attributes to nearly 25% of all deaths.
• According to the Global Burden of Disease study, age-standardized CVD mortality rate was 272 per 100000 population in India. It was higher than the global average of 235 per 100000 population.

2. Concept of Gluco-centric Approach is Weakening

• While tight glycaemic control is backbone of diabetes, management recent trials have focused on cardiovascular risk reduction as the primary objective. So, we find a contemporary shift in recommended strategy which extends beyond glycaemic control.
• But we must not forget that there are compelling and established data which support the benefit of long-term glycaemic control in reducing the risk of microvascular complications. Also, the importance of legacy effect is quite clear.
• Evidence from CVOTs demonstrating CV benefits with certain diabetes medications, in particular the SGLT-2 inhibitors and GLP-1RAs have major impact to formulate the strategy to risk reduction in type 2 diabetes.

3. Screening Recommendations ADA-2021

• In asymptomatic patients, routine screening for coronary artery disease is not recommended as it does not improve outcomes as long as atherosclerotic cardiovascular disease risk factors are treated. A
• Consider investigations for coronary artery disease in the presence of any of the following: atypical cardiac symptoms (e.g., unexplained dyspnea, chest discomfort); signs or symptoms of associated vascular disease including carotid bruits, transient ischemic attack, stroke, claudication, or peripheral arterial disease; or electrocardiogram abnormalities (e.g., Q waves). E

4. Assess Cardiovascular risk factors in all patients at diagnosis and annually

5. Assess who is at highest risk

6. Lifetime CVD risk and treatment benefit estimation

• Prevention of CVD by treating risk factors is usually done with a lifetime perspective.
• Lifetime CVD risk can be approximated by clinical experience with clinical criteria such as age, (change in) risk factor levels, risk modifiers, etc. or estimated in apparently healthy people, patients with established ASCVD, and persons with type 2 DM with specific lifetime CVD risk scores
• Lifetime benefit from risk factor management can be estimated by combining lifetime risk models with HRs (Hazard ratio) derived from RCTs, meta-analyses of RCTs, or Mendelian randomization studies, which may provide estimates of the effects of longer-term treatment of risk factors.
• Online calculators (such as the ESC CVD Risk app) can be used to estimate the average lifetime benefit of smoking cessation lipid lowering, and BP lowering on an individual patient level expressed as extra CVD-free life-years.

7. Accurate CVD risk estimation

• In people with T2DM without established CVD, we must identify patients at high risk of developing CVD. The risk assessment should be used to adapt the intensity and complexity of appropriate treatment.
• Although many risk calculators have been developed AHA and ACC risk score are more acceptable.
• To estimate the ten-year risk for the first ASCVD event (non-fatal myocardial infarction or CHD death, or fatal/non-fatal stroke) is usually used in clinical practice.(available online at tools.acc.org/ASCVD-Risk-Estimator-Plus)
• It must be appreciated that none of the risk calculators are perfect. To select appropriate therapeutic goals and interventions the importance of clinical judgement and consideration of cardiovascular risk factors cannot be overemphasised.
• Reducing CVD risk at the individual level begins with appropriate assessment of individual risk and effective communication of risk and anticipated risk reduction by risk factor treatment.
• Patient-doctor interactions are complex and communicating risk is challenging.
• There is no single ‘correct’ approach; rather, it will depend on the individual’s preferences and understanding, which may differ with education status and numeracy. Risk perception is also strongly affected by emotional factors such as fear, optimism, etc. (‘patients don’t think risk, they feel risk’).

8. Which Risk Calculator to use?

• Immigrants from South Asia (notably India and Pakistan) present higher CVD rates independent of other risk factors, whereas adjusted CVD risks appear lower in most other ethnic groups.
• Correction factors, based on data from the UK, could be applied when assessing CVD risk using risk calculators.
• Ideally, country and risk-calculator-specific RRs should be used, as the impact of ethnicity may vary between regions and risk calculators.
  • Southern Asian: multiply the risk by 1.3 for Indians and Bangladeshis, and 1.7 for Pakistanis.
  • Other Asian: multiply the risk by 1.1.
  • Black Caribbean: multiply the risk by 0.85.
  • Black African and Chinese: multiply the risk by 0.7.
• 2021-The way ESC tackles: SCORE2 = Systematic Coronary Risk Estimation 2; SCORE2-OP = Systematic Coronary Risk Estimation 2-Older Persons.

9. Indian Risk Calculator

• One Indian study showed that the FRS global CVD risk assessment model could stratify maximum number of patients into high risk for hard cardiovascular events.
• QRISK2, JBS3, FRS-CHD have performed intermediately.
• ACC/AHA-ASCVD risk score calculator and WHO risk score calculator could identify least number of patients to be in high risk so has performed the worst in our patient population considering 20% as cut off for high risk definition. (Indian Heart J. 2017 Jul-Aug; 69(4): 458–463.Published online 2017 Jan 31. doi: 10.1016/j.ihj.2017.01.015)

10. RSSDI (Research Society for Study of Diabetes in India) Input

• Current or previous CVD events, age, body weight, BP and pulse, of patients should be recorded during their first and subsequent visits
• UKPDS risk engine and QRISK3 are simple and effective tools for identifying and predicting CVD risks in patients with T2DM and should be recommended for identifying high risk individuals
• Patients with diabetes and CVD risk should follow the ABC treatment goals.

11. How to prioritize CV risk reduction in type 2 diabetes?

TOD (Target Organ damage)

• Persons with DM with severe TOD can be considered to be at very high CVD risk, similar to people with established CVD
•  Most others with DM are considered to be at high ASCVD risk.
• However, an exception can be made for patients with well-controlled short-standing DM (e.g. <10 years) no evidence of TOD, and no additional ASCVD risk factors, who may be considered as being at moderate CVD risk.

12. Commonly overlooked risks

13. Target to achieve

14. Miracle of Diet

New analysis from PURE (Prospective Urban and Rural Epidemiological study

• Glycaemic index as a key measure of dietary health.
• People with a diet in the highest quintile of glycaemic index had a significant 25% higher rate of combined total deaths and major CVD events during a median follow-up of nearly 10 years, compared with those with a diet in the lowest glycaemic index quintile.

PREDIMED study

• Mediterranean diet – 30% reduction in risk of cardiovascular events.
• In the prespecified diabetes subgroup of this trial 29% reduction in the primary three-point composite outcome.

On average, a 2% increase in energy intake from trans fatty acids is associated with a 23% higher CHD risk

ESC 2021

• Increase Fibre/Fruits/Nuts Intake,Lower Salt intake
• Each 7 g/day higher intake of total fibre is associated with a 9% lower risk of CAD (RR 0.91). A
• 10 g/day higher fibre intake was associated with a 16% lower risk of stroke (RR 0.84) and a 6% lower risk of type 2 DM (RR 0.94).
• A high fibre intake may reduce postprandial glucose responses after carbohydrate-rich meals and also lower triglyceride levels.
• In a meta-analysis, salt reduction of 2.5 g/day resulted in a 20% reduction of ASCVD events (RR 0.80)
• A meta-analysis reported an 11% lower risk for stroke associated with three to five daily servings of fruits and vegetables and of 26% with five servings a day compared with fewer than three servings
• Nuts. A meta-analysis of prospective cohort studies suggested that daily consumption of 30 g of (mixed) nuts was associated with a 30% lower risk of ASCVD.
• Fish and fish oil supplements. Studies indicate that eating fish, particularly fish rich in n-3 PUFA, at least once a week, is associated with a 16% lower risk of CAD,and eating fish two to four times a week is associated with a 6% lower risk of stroke.

15. Recent evidence suggests that adequate physical activity may reduce the risk by up to 27%

16. Antihypertensive therapy

• It is well known that the risk of stroke, myocardial infarction and all-cause mortality is directly proportional to blood pressure.
• One of the most important intervention is to achieve optimal blood pressure goal. Intensive control of blood pressure with appropriate drugs is a very important strategy.
• It is a unique fact that tight control of glucose decreases risk of microvascular complications but tight control of blood pressure reduces both micro-and macrovascular complications.

17. Do Remember

• Tight control of blood glucose decreases the risk of microvascular complications
• Tight control of BP reduces both micro-and macrovascular complications

18. Follow ADA 2021 Standard of Care/ Pearls in BP Management

• Patients with confirmed office based blood pressure >160/ 100 mmHg should, in addition to lifestyle therapy, have prompt initiation and timely titration of two drugs or a single-pill combination of drugs demonstrated to reduce cardiovascular events in patients with diabetes. A
• Treatment for hypertension should include drug classes demonstrated to reduce cardiovascular events in patients with diabetes. A
• ACE inhibitors or angiotensin receptor blockers are recommended first-line therapy for hypertension in people with diabetes and coronary artery disease. A
• Multiple-drug therapy is generally required to achieve blood pressure targets. However, combinations of ACE inhibitors and angiotensin receptor blockers and combinations of ACE inhibitors or angiotensin receptor blockers with direct renin inhibitors should not be used. A
• An ACE inhibitor or angiotensin receptor blocker, at the maximum tolerated dose indicated for blood pressure treatment, is the recommended first-line treatment for hypertension in patients with diabetes and urinary albumin-to-creatinine ratio >300 mg/g creatinine A or 30–299 mg/g creatinine. B
• If one class is not tolerated, the other should be substituted. B
• For patients treated with an ACE inhibitor, angiotensin receptor blocker, or diuretic, serum creatinine/estimated glomerular filtration rate and serum potassium levels should be monitored at least annually. B

19. लिपिड कथा Managing Lipids/Know the Gems

• Obtain a lipid profile at initiation of statins or other lipid lowering therapy, 4–12 weeks after initiation or a change in dose, and annually thereafter as it may help to monitor the response to therapy and inform medication adherence. E
• For patients with diabetes aged 40–75 years without atherosclerotic cardiovascular disease, use moderate-intensity statin therapy in addition to lifestyle therapy. A
• For patients with diabetes aged 20–39 years with additional atherosclerotic cardiovascular disease risk factors, it may be reasonable to initiate statin therapy in addition to lifestyle therapy.
• In patients with diabetes at higher risk, especially those with multiple atherosclerotic cardiovascular disease risk factors or aged 50–70 years, it is reasonable to use high-intensity statin therapy. B
• In adults with diabetes and 10-year atherosclerotic cardiovascular disease risk of 20% or higher, it may be reasonable to add ezetimibe to maximally tolerated statin therapy to reduce LDL cholesterol levels by 50% or more. C
• For patients of all ages with diabetes and atherosclerotic cardiovascular disease, high intensity statin therapy should be added to lifestyle therapy.A
• For patients with diabetes and atherosclerotic cardiovascular disease considered very high risk using specific criteria, if LDL cholesterol is >70 mg/dL on maximally tolerated statin dose, consider adding additional LDL-lowering therapy (such as ezetimibe or PCSK9 inhibitor). A
• Ezetimibe may be preferred due to lower cost.
• For patients who do not tolerate the intended intensity, the maximally tolerated statin dose should be used. E
• In adults with diabetes aged >75 years already on statin therapy, it is reasonable to continue statin treatment. B
• In adults with diabetes aged >75 years, it may be reasonable to initiate statin therapy after discussion of potential benefits and risks. C
• Statin therapy is contraindicated in pregnancy. B

TG (Triglyceride)Issues

• For patients with fasting triglyceride levels >500 mg/dL, evaluate for secondary causes of hypertriglyceridemia and consider medical therapy to reduce the risk of pancreatitis. C
• In adults with moderate hypertriglyceridemia (fasting or nonfasting triglycerides 175–499 mg/dL), clinicians should address and treat lifestyle factors (obesity and metabolic syndrome), secondary factors (diabetes, chronic liver or kidney disease and/or nephrotic syndrome, hypothyroidism), and medications that raise triglycerides. C
• In patients with atherosclerotic cardiovascular disease or other cardiovascular risk factors on a statin with controlled LDL cholesterol but elevated triglycerides (135–499 mg/dL), the addition of icosapent ethycan be considered to reduce cardiovascular risk. A
• Statin plus fibrate combination therapy has not been shown to improve atherosclerotic cardiovascular disease outcomes and is generally not recommended. A
• Statin plus niacin combination therapy has not been shown to provide additional cardiovascular benefit above statin therapy alone, may increase the risk of stroke with additional side effects, and is generally not recommended. A

20. Antiplatelets: When to use ADA 2021?

1. Use aspirin therapy (75–162 mg/day) as a secondary prevention strategy in those with diabetes and a history of atherosclerotic cardiovascular disease. A
2. For patients with atherosclerotic cardiovascular disease and documented aspirin allergy, clopidogrel (75 mg/day) should be used. B
3. Dual antiplatelet therapy (with low-dose aspirin and a P2Y12 inhibitor) is reasonable for a year after an acute coronary syndrome and may have benefits beyond this period. A
4. Long-term treatment with dual antiplatelet therapy should be considered for patients with prior coronary intervention, high ischemic risk, and low bleeding risk to prevent major adverse cardiovascular events.A
5. Combination therapy with aspirin plus low-dose rivaroxaban should be considered for patients with stable coronary and/or peripheral artery disease and low bleeding risk to prevent major adverse limb and cardiovascular events. A
6. Aspirin therapy (75–162 mg/ day) may be considered as a primary prevention strategy in those with diabetes who are at increased cardiovascular risk, after a comprehensive discussion with the patient on the benefits versus the comparable increased risk of bleeding. A
7. More contemporary primary prevention trials reported no or little benefit in patients without ASCVD and a consistent increase in bleeding.
8. An updated meta-analysis did not show a reduction in all-cause or CV mortality with aspirin, but did show a lower risk of non-fatal myocardial infarction (RR 0.82) and ischaemic stroke (RR 0.87).
9. Recommendations for using aspirin as primary prevention include both men and women
   • Aged >50 years with diabetes
   • At least one additional major risk factor (family history of premature ASCVD, hypertension, dyslipidemia, smoking, or chronic kidney disease/ albuminuria) who are not at increased risk of bleeding (e.g., older age, anemia, renal disease)
10. For primary prevention, the use of aspirin needs to be carefully considered and may generally not be recommended. Aspirin may be considered in the context of high cardiovascular risk with low bleeding risk, but generally not in older adults.
11. Aspirin therapy for primary prevention may be considered in the context of shared decision-making, which carefully weighs the cardiovascular benefits with the fairly comparable increase in risk of bleeding
12. Noninvasive imaging techniques such as coronary calcium scoring may potentially help further tailor aspirin therapy, particularly in those at low risk
13. Average daily dosages used in most clinical trials involving patients with diabetes ranged from 50 mg to 650 mg but were mostly in the range of 100–325 mg/ day. There is little evidence to support any specific dose, but using the lowest possible dose may help to reduce side effects.
14. Combination Antiplatelet and Anticoagulation Therapy Combination therapy with aspirin plus low dose rivaroxaban – May be considered for patients with stable coronary and/or peripheral artery disease to prevent major adverse limb and cardiovascular complications.

21. SGLT2 inhibitors / GLP-1RA  for CV Risk Reduction – चमत्कार को नमस्कार?

• The development of treatment strategies to improve CV outcomes in patients with T2D remains a major priority.
• The recent development of SGLT2 inhibitors and GLP-1RAs has for the first time, demonstrated that specific glucose-lowering therapies can directly improve CV outcomes.
• An SGLT2 inhibitor with demonstrated CV benefit is recommended for patients with T2D and HF, especially HF with reduced ejection fraction (HFrEF), or who are at high risk of developing HF, DKD, clinically evident ASCVD, or any combination of these conditions.
• A GLP-1RA with demonstrated CV benefit is recommended for patients with established or at very high risk for ASCVD. ACC
• It appears reasonable to use both an SGLT2 inhibitor and a GLP-1RA, with demonstrated CV benefit, concomitantly if clinically indicated, even though such combination therapy has not been studied for CV risk reduction. ACC

22. Lastly, do not forget to tackle Peripheral Arterial Disease as risk

CME INDIA Learning Points

• When we have a patient with diabetes, part of risk-factor management is of course glucose control. We want patients to know what their hemoglobin A1C is. But for macrovascular disease, it’s more important to manage other risk factors, such as keeping LDL [low-density lipoprotein] cholesterol levels very low, optimizing blood pressure, optimizing body weight, exercising, and avoiding tobacco products.
• Patients with diabetes have more rapid platelet turnover.They tend to have more platelet activation. And so in patients with diabetes and atherosclerotic vascular disease, patients are recommended to receive a single antiplatelet agent, generally aspirin. Although if someone is allergic to aspirin, they might receive clopidogrel monotherapy. 

(Based on the Presentation by Dr NK Singh at RSSDI Annual Conference 2021 at Ahmedabad)

CME INDIA Tail Piece

References:

1. Das SR, Everett BM, Birtcher KK, et al.2020 Expert Consensus Decision Pathway on Novel Therapies for Cardiovascular Risk Reduction in Patients With Type 2 Diabetes: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 2020;Aug 5:[Epub ahead of print].
2. Front. Cardiovasc. Med., 24 February2021  https://doi.org/10.3389/fcvm.2021.644189
3. Indian Heart J. 2017 Jul-Aug; 69(4): 458–463.Published online 2017 Jan 31. doi: 10.1016/j.ihj.2017.01.015
4. Glycemic Index, Glycemic Load, and Cardiovascular Disease and Mortality. April 8, 2021N Engl J Med 2021; 384:1312-1322
   DOI: 10.1056/NEJMoa2007123
5. Primary Prevention of Cardiovascular Disease with a Mediterranean Diet Supplemented with Extra-Virgin Olive Oil or NutsJune 21, 2018N Engl J Med 2018; 378:e34
   DOI: 10.1056/NEJMoa1800389
6. https://rssdi.in/newwebsite/pdfdata/Chawla2020_Article_RSSDI-ESIClinicalPracticeRecom.pdf
7. Standards of Medical Care in Diabetes—2021 Diabetes Care 2021 Jan; 44 (Supplement 1): S1-S2. https://doi.org/10.2337/dc21-Sint
8. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice: Developed by the Task Force for cardiovascular disease prevention in clinical practice with representatives of the European Society of Cardiology and 12 medical societies With the special contribution of the European Association of Preventive Cardiology (EAPC)European Heart Journal, Volume 42, Issue 34, 7 September 2021, Pages 3227–3337, https://doi.org/10.1093/eurheartj/ehab484

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