Management of Cardiovascular and Diabetes Risks Based on National Guidelines

Function

For cardiovascular disease, modifiable risk factor prevention is important, which includes the following:

1. Hypertension
2. Hyperlipidemia
3. Overweight and obesity
4. Glucose intolerance and diabetes
5. Smoking tobacco use.

Non-modifiable risk factors include male sex, certain races (Asian, African American), increased age, and family history of early CVD. After CVD is identified, the management involves a multifactorial approach to reducing the risk of further complications and mortality.

For diabetes, the most important preventative aspect is identifying the population at increased risk of developing diabetes based on weight, family history, presence of pre-diabetes, typical symptoms, and history of gestational diabetes. Early and frequent screening remains the most important factor for diabetes management. It is important to remember that 90% of adults (18+) with newly diagnosed diabetes are either overweight or obese.[2]

Issues of Concern

Screening

Diabetes can be diagnosed in either of four ways:

1. Random hemoglobin A1c (HbA1c) ≥6.5%
2. Fasting blood sugar ≥126 mg/dl
3. A 2-hr postprandial glucose ≥200 mg/dl after a 75 gm standard oral glucose load
4. Random blood sugar ≥200 mg/dl in a patient with classic symptoms of diabetes (polyuria, polydipsia, and/or polyphagia) or in the patient presenting with a hyperglycemic crisis

Any of the first three standard tests can be used to screen for type 1 or type 2 diabetes. For gestational diabetes, an oral glucose tolerance test is used with different glucose load and cut-off values than in non-pregnant adults. When HbA1c is being measured, it is noteworthy that some hemoglobin variants can interfere with certain essays of HbA1c and should be taken into account. If the patient was diagnosed with diabetes using lab testing (HbA1c or fasting/postprandial blood sugar) without having clinical symptoms, it is essential to send a second test to confirm the diagnosis.

If diabetes screening tests are negative, the first-degree family members of patients with type 1 diabetes may be offered screening for the risk of developing type 1 diabetes with one of the islet cell autoantibodies.[3] This testing should be coupled with diabetes symptoms education and close follow-up, which might help with early identification.

There is no clinical recommendation for screening for type 1 diabetes in asymptomatic low-risk individuals. For type 2 diabetes and prediabetes, adult screening should begin at age 45. It should be conducted earlier if BMI ≥25 (BMI ≥ 23 for Asian Americans) and at least one risk factor is present: hypertension, cardiovascular disease, dyslipidemia (low HDL or high triglycerides), polycystic ovary syndrome, physical inactivity, non-White race, severe obesity (BMI ≥40), first degree relative with type 2 diabetes.

If negative for prediabetes, it should be repeated at least every three years.[4] It might be repeated sooner if they develop symptoms or the risk profile is higher. Patients with prediabetes are tested yearly. Patients diagnosed with HIV should be tested as soon as possible. Women diagnosed with gestational diabetes mellitus must undergo lifelong screening at least every three years.

Prediabetes is not a clinical entity itself; however, it often serves to identify people at increased risk of developing diabetes and cardiovascular disease.[5] Prediabetes is diagnosed using one of the three methods:

1. Fasting plasma glucose 100 to 126 mg/dl
2. A 2-hr postprandial glucose 140 to 199 mg/dl after 75 gm glucose load
3. Hemoglobin A1C 5.7 to 6.4%

Some entities describe prediabetes as fasting plasma glucose between 110 to 126 mg/dl.[6] 

The diagnosis of hypertension (stage I) requires ambulatory blood pressure reading consistently. Systolic blood pressure (SBP) ≥ 130 mm Hg and/or diastolic blood pressure (DBP) ≥ 80 mm Hg. Patients with SBP 120 to 129 mm Hg and DBP <80 should be categorized as elevated BP and not hypertension. If there is a disparity in categorizing patients due to different values of SBP and DBP, the higher value should be used. For example, someone with BP 117/84 has stage I hypertension. Stage II hypertension is present if SBP ≥ 140 mm Hg and/or DBP ≥ 90 mm Hg. Screening for hypertension should be done at least annually in low-risk populations. For people whose SBP is 120 to 129 mm Hg or have risk factors for hypertension, blood pressure should be measured at least semi-annually. 

For people presenting with SBP ≥180 and/or DBP ≥120, hypertension can be diagnosed at the first measurement. Similarly, hypertension can be diagnosed if SBP ≥ 160 and/or DBP ≥ 100 PLUS evidence of end-organ damage (hypertensive retinopathy, ischemic cardiovascular disease, left ventricular hypertrophy).[7][8][9][10]

Hyperlipidemia screening is done using blood tests in either fasting or non-fasting state. Universal pediatric screening at age 9 to 11 and repeated at age 17 to 21 is important for diagnosing familial hypercholesterolemia. For patients with a history of smoking, hypertension, diabetes mellitus, and a family history of premature atherosclerotic disease, screening should begin at age 20 if they were not tested between ages 17 and 21 years as per the pediatric universal screening guidelines. For patients without the above risk factors, screening can begin at age 35 for men and 45 for women. For ASCVD risk stratification and intervention, LDL cholesterol values are most relevant. If screening results are normal, the testing can be repeated every five years. It can be repeated sooner (every year) in patients with abnormal values near the intervention threshold.

Screening is not routinely recommended in asymptomatic patients for coronary artery disease and peripheral arterial disease. For heart failure, the newest 2022 ACC/AHA guideline for heart failure recommends screening for asymptomatic patients at high risk for heart failure in those with either of the following risk factors:

1. Hypertension
2. ASCVD
3. Diabetes
4. Metabolic syndrome and obesity
5. Exposure to cardiotoxic agents
6. Genetic variant for cardiomyopathy
7. Positive family history of cardiomyopathy

These patients are classified as stage A: At risk for heart failure. The suggested screening uses BNP or NT-proBNP using cutoff values of 35 pg/mL or 125 pg/mL, respectively. If patients screen positive, patients are classified as Stage B: Pre-Heart failure and should be referred to a cardiovascular specialist (Class 2b recommendation). In addition, clinicians should ask patients about the symptoms of these diseases in routine visits.

Clinical Significance

Pre-Diabetes and diabetes

Patients with pre-diabetes should be referred to an intensive lifestyle modification program that includes a strategy for losing and maintaining 7% initial body weight and 150 minutes per week of moderate-intensity physical activity.[11] 

Changes in eating patterns with emphasis on a plant-based diet and reduction of animal products and processed foods have also shown benefits in preventing diabetes. ADA recommends metformin to be considered in pre-diabetics with age less than 60 years, history of gestational diabetes mellitus, or BMI ≥ 35 kg/m^2.

Once diabetes mellitus is identified, patients should be assessed for complications, and pharmacologic therapy should be started. Microvascular complications of diabetes include retinopathy, neuropathy, and diabetic kidney disease (DKD). Macrovascular complication includes atherosclerosis (predisposing to stroke, coronary artery disease, and peripheral arterial disease). Intensive glycemic control leads to reductions in both microvascular and macrovascular outcomes. Hyperglycemic complications include diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome. Any pharmacologic therapy for diabetes should ideally be coupled with lifestyle interventions.

For type 1 diabetes, insulin should be initiated, either with multiple daily injections of a basal-bolus regimen or continuous subcutaneous insulin infusion (CSII) with a pump. The amylin analog Pramlintide is the only other drug approved by the FDA to treat type 1 diabetes. Pramlintide may be helpful in patients who develop weight gain after initiation of insulin treatment as it acts to delay gastric emptying and increases satiety.[12] It might also help with better postprandial control of blood sugars. The addition of glucagon-like peptide-1 (GLP-1) agonists to insulin can also help lose weight, although they are not FDA approved for type 1 diabetes.[13] Adding metformin does not seem to provide any clinically significant benefit while adding sodium-glucose transport protein-2 (SGLT-2) inhibitors significantly increases the risk of diabetic ketoacidosis.

 For type 2 diabetes, metformin is always the first-line treatment unless it is contraindicated or not tolerated. Metformin is cheap, has a low risk of hypoglycemia, has proven mortality benefits in overweight individuals, and has potential mortality benefits in all patients with type 2 diabetes.[14] It should be started at a lower dose of 500 mg daily or twice daily and titrated up. The most common adverse effect is diarrhea or gastrointestinal upset. Other important adverse effects are lactic acidosis in those with reduced GFR <30 ml/min/1.73m^2, vitamin B12 deficiency, and worsening neuropathy with prolonged use. Metformin is contraindicated with eGFR <30 ml/min/1.73m^2, unstable heart failure, liver disease, active alcohol abuse, and history of lactic acidosis during metformin therapy. Metformin should not be initiated in those with eGFR < 45 ml/min/1.73m^2. However, in patients already on metformin, it can be continued until eGFR is <30.

Metformin should be temporarily discontinued before iodinated contrast exposure in patients with eGFR <60. The addition of other medications to metformin is dependent on co-morbidities and glycemic control after maximally tolerated metformin therapy. Generally speaking, the glycemic target is to achieve HbA1c < 7% in most patients with diabetes. However, there is increasing evidence that glycemic targets should be individualized. Glycemic targets can be higher (HbA1c <8%) in older people, people with limited life expectancy, and those with a significant risk of hypoglycemia. Conversely, lower glycemic targets might be appropriate and even beneficial in younger patients and those without risk of significant hypoglycemia.

Therapeutic options for attaining glycemic target in patients with type 2 diabetes are metformin, GLP-1 agonists, SGLT-2 inhibitors, insulin, DPP-4 inhibitors, sulfonylureas, and thiazolidinediones, meglitinides, alpha-glucosidase inhibitors, pramlintide, Dopamine-2 agonist bromocriptine, and bile acid sequestrant colesevelam. Insulin, Sulfonylureas, and metformin are the most effective antihyperglycemic agents, followed by GLP-1 agonists, meglitinides, and thiazolidinediones. When initial HbA1c is >10%, it is good to consider using long-acting insulin or GLP-1 agonists and metformin. It should be noted that liraglutide, injectable semaglutide, and dulaglutide are the only GLP-1 agonists with a reduction in CVD outcomes compared to placebo (beneficial in ASCVD and diabetic kidney disease driven by a reduction in albuminuria.)

The role of SGLT-2 inhibitors in the management of diabetes is being increasingly recognized. They have modest efficacy in reducing HbA1c; however, several drugs in this class have significant cardiovascular-renal benefits. There are four commercially available medications in this class: canagliflozin, empagliflozin, dapagliflozin, and ertugliflozin. Canagliflozin and empagliflozin provide benefits along all three spectrums, including ASCVD, heart failure, and DKD. Dapagliflozin only provides benefits for heart failure and DKD. Ertugliflozin is the newest drug and hasn’t been extensively studied. The latest 2022 ACC/AHA guideline for heart failure states that SGLT-2 inhibitors should be used in patients with type 2 diabetes and either established CVD or at high cardiovascular risk to prevent hospitalizations for heart failure (Class I recommendation). It is worth noting that these patients don’t need to have clinically diagnosed with heart failure.

Every patient with diabetes should be established with an ophthalmologist and podiatrist for an initial assessment. In addition, every patient with diabetes should establish care with the nutrition team and diabetes education team. All newly diagnosed diabetes patients should be assessed for albuminuria with spot urinary albumin to creatinine ratio (ACR). If albuminuria is present (urinary ACR > 30mg/g on spot sample), they should be started on angiotensin-converting enzyme inhibitors (ACEI) or Angiotensin receptor blockers (ARB) and titrated up to the maximally tolerated dose (based on blood pressure). An increase in creatinine up to 30% from baseline is expected and shouldn’t lead to discontinuation of ACEI/ARB.

It should be noted that there is high biological variability between measurements in ACR (up to 20%), and hence, repeat measurements are recommended in patients with borderline ACR. For patients with severely increased albuminuria (ACR > 300mg/g), addition of SGLT-2 inhibitors should be considered if eGFR ≥ 30 ml/min/1.73m^2. In patients with normal ACR, it should be repeated annually in patients with type 2 diabetes. For patients with type 1 diabetes, an initial waiting period of 5 years (after presumed diagnosis) is suggested to assess for nephropathy.

If patients have albuminuria with the absence of retinopathy (in type 1 diabetes), active sediment including WBC, RBC or casts, rapidly rising albuminuria, or nephrotic syndrome, an alternative diagnosis should be sought after, and patients should be referred to a nephrologist. In addition, every DKD patient with eGFR <30 ml/min/1.73m^2 or ACR >300 mg/g must be established with a nephrologist. 

All patients with diabetes (of any age) should have evaluation and management of hyperlipidemia based on their risk. Details are provided under the hyperlipidemia section of this article.

Hypertension

Hypertension can be classified based on etiology: if the hypertension is idiopathic, it is termed primary hypertension. If any cause can be identified for hypertension (except obesity), it is classified as secondary hypertension. The most common causes of secondary hypertension are obstructive sleep apnea, primary hyperaldosteronism, renovascular disease, chronic kidney disease, and drug/substance-induced. It is not mandatory to rule out secondary hypertension in every patient with elevated blood pressure, but the treating clinician should be aware of the possibility of secondary hypertension.

For all patients with elevated blood pressure and hypertension, the first-line treatment is always lifestyle interventions. The decision to treat pharmacologically (in addition to lifestyle interventions) depends on the blood pressure itself and/or the presence of comorbidities and/or 10-year ASCVD risk. Lifestyle interventions effective at lowering blood pressure are dietary approaches to stop hypertension (DASH) diet, weight loss to BMI < 25 kg/m^2 and ideally to <23 kg/m^2, physical activity and exercise, reducing sodium intake, reducing alcohol use and increasing potassium intake. For overweight patients, weight loss through a combination of exercise and reduced caloric intake is most effective. For patients with normal body weight, the DASH diet is most effective.

For low-risk patients without current cardiovascular disease or diabetes with a 10-year ASCVD risk of <10%, pharmacological treatment is only recommended if stage II hypertension is present, i.e., BP ≥ 140/90. When treating hypertension, generally, the goal is to lower blood pressure to <130/80 mm Hg; however, the goal should be individualized to a lower value based on the presence of co-morbidities and/or patient tolerance/preference.

The 2017 ACC/AHA guidelines recommend treating hypertension with the following first-line agents: ACEI/ARB, thiazide/thiazide-type diuretic, or calcium channel blockers (both dihydropyridines DHP and non-DHP). If blood pressure is more than 20/10 mmHg above the goal, therapy with two agents from two different classes is recommended. Fixed-dose combination products seem to help increase patient compliance. For older adults, caution is advised when starting therapy with two antihypertensives at the same time due to the risk of hypotension and orthostatic hypotension. It is always important to consider secondary hypertension as the cause of hypertension if the age at first diagnosis is <30 years or ≥65 years or hypertensive urgency/emergency is the presentation.

Second-line agents for treating hypertension include diuretics (loop, potassium-sparing, and aldosterone antagonist type), beta-blockers, direct renin inhibitors (e.g., aliskiren), alpha-1 blockers, central alpha-2 agonists, and direct vasodilators (hydralazine and minoxidil). The angiotensin receptor II blocker - neprilysin inhibitor (ARNI), sacubitril-valsartan, has an established role in the treatment of patients with HF with reduced ejection fraction (HFrEF). Some of these second-line agents in the presence of specific comorbidities may be used as first-line agents (e.g., beta-blockers and spironolactone in the presence of symptomatic heart failure with reduced ejection fraction [HFrEF]). Spironolactone is the recommended addition for patients whose blood pressure is not well controlled on three first-line antihypertensives.

Atherosclerosis and aspirin/statin use

Aspirin is an irreversible inhibitor of platelet cyclooxygenase enzyme with the resultant effect of halting thromboxane A2 production and hence is effective for preventing platelet aggregation. Due to this property, low-dose aspirin has been commonly used for primary and secondary prevention of atherosclerotic disease. Treatment with low-dose aspirin (75 to 162 mg daily) should be started and continued indefinitely in patients with presumed or diagnosed coronary artery disease or stroke/TIA.[15] 

In patients with peripheral arterial disease, aspirin or clopidogrel use is recommended to prevent the risk of cardiovascular death, especially in symptomatic PAD (Class I indication). In asymptomatic PAD (ABI ≤0.9), aspirin/clopidogrel use is recommended as a class IIa indication. There is no added benefit of dual antiplatelet agents in symptomatic or asymptomatic PAD.[16] However, dual antiplatelet agents might be reasonable in patients with symptomatic PAD who underwent revascularization (Class IIb indication). All of the above patients should receive statin therapy.

Hyperlipidemia

When discussing hyperlipidemia, the values of LDL-C and triglycerides matter the most, not the total cholesterol levels. Statins are always the first-line treatment for dyslipidemia because they confer the highest cardiovascular protection. Statins are classified as low intensity (<30% reduction of LDL from baseline), moderate-intensity (30 to 49%), and high intensity (>50%). Only two commercially available statins are high-intensity statins, atorvastatin 40 to 80 mg and rosuvastatin 20-40mg. The addition of ezetimibe, bile acid sequestrant, or PCSK-9 inhibitors to statins reduces LDL-C values by a further 15%, 25%, and 50%, respectively.[17] Ezetimibe is typically added to statins because of its safety and cost-efficacy.

There are three major high-risk categories when it comes to hyperlipidemia and ASCVD. They are patients with diabetes, those with severe hypercholesterolemia (LDL-C ≥190 mg/dl), and adults aged 40-75 years.

Patients of any age with LDL-C ≥ 190 mg/dl should receive treatment with high-intensity statin therapy to reduce LDL-C levels to <100 mg/dl. Ezetimibe is typically added if the goal is not achieved.

For patients aged 40 to 75 years with LDL between 70 and 189 mg/dl AND without diabetes or clinical/established ASCVD, the ASCVD Risk Estimator Plus tool should be used, and patients should be risk-stratified. The stratification is as follows: Low risk (<5%), Borderline risk (5 to 7.4%), Intermediate risk (7.5 to 19.9%), and high risk (≥20%). The physician and patient should engage in a risk-benefit discussion and mutually agree on lifestyle modification and/or statin initiation. Patients with low risk will likely benefit from lifestyle modification only (Class I recommendation).

Patients with borderline risk (5 to 7.4%) should also undergo intensive discussion regarding ASCVD risk and can be offered statin treatment in addition to lifestyle modifications. Those at intermediate and high risk will likely benefit from adding statin therapy, preferably of moderate intensity and high intensity, respectively (Class I recommendation). Discussion can be more informed with the interpretation of risk-enhancing factors, especially in patients who are reluctant to start statin therapy. In intermediate-risk patients (7.5 to 19.9%) reluctant to start statin treatment, Coronary artery calcium (CAC) scoring can be done to further clarify risk status, and those with a score of more than zero should be started on statin therapy.[17]

All diabetes patients aged 40 to 75 should be started on moderate/high-intensity statin and titrated upwards based on tolerance, other risk factors, and LDL cholesterol levels. In diabetes patients without established ASCVD, however, with other risk factors, the LDL-C goal is < 70 mg/dl, and the statin dose should be titrated upwards to achieve that goal. In those with diabetes and established cardiovascular disease, the high-intensity statin should be used, ideally to lower LDL-C to <55 mg/dl. If LDL goals are not achieved with the highest dose of statin tolerated, an ezetimibe/PCSK-9 inhibitor should be added.

For patients who have a clinical history of ASCVD and/or high risk for ASCVD who are already on statin therapy and LDL-C is well controlled, persistent hypertriglyceridemia (TG >135 mg/dl) should be treated with the addition of icosapent ethyl. Icosapent ethyl has been shown to reduce cardiovascular events in hypertriglyceridemic patients on statin therapy.[18] Adding niacin or fibrate to statin therapy does not seem to provide any benefit and may cause harm. 

Congestive Heart Failure

The ACC/AHA guideline 2022 defines 'heart failure as a complex clinical syndrome with symptoms and signs that result from structural or functional impairment of ventricular filling or pumping of blood.' Asymptomatic stages are considered at risk for HF (stage A) and pre-HF (stage B). Patients who are currently experiencing symptoms/signs or had symptoms/signs in the past are classified as stage C HF. It is important to note that according to new guidelines, the terms HFpEF, HFmrEF, and HFrEF should only be used for stage C heart failure.

For patients with stage B HF (who have never had symptoms/signs), the only recommended GDMT includes ACEi/ARB and BB for patients with LVEF ≤40%. SGLT-2 inhibitor should be used (for either stage A or stage B) if the patient has concurrent type 2 diabetes.

An implantable cardioverter-defibrillator (ICD) should be used to prevent sudden cardiac death in patients who fulfill the following criteria: 1. 40 days post-MI, have LVEF ≤30% and have a reasonable expectation of meaningful survival for >1 year. 2. 90 days of maximally tolerated medical therapy for heart failure, EF ≤35%, and have a reasonable expectation of meaningful survival for >1 year. If heart failure patients have hypertension, it should be treated with ACEi/ARB, and treatment of diabetes should include SGLT-2 inhibitors. Clinicians should avoid using non-dihydropyridine CCB and/or Thiazolidinediones in patients with LVEF <50% as they might induce harm.[19]

For patients with Stage C HF, management should be classified by the severity of symptoms, ejection fraction, and presence of fluid congestion. In those with fluid congestion, loop diuretics should be used. The addition of thiazides should only be considered if patients don’t respond to a moderate-high dose of loop diuretics.

ARNI is the preferred RAAS drug for patients with HFrEF and NYHA II-III symptoms. If ARNI is not tolerated or affordable, ACEi should be used. If ACEi is not tolerated due to cough or angioedema, ARB should be used. Angioedema with ARNI or ACEi is an absolute contraindication to using either of these drugs. Beta-blockers with proven mortality benefits (bisoprolol, metoprolol succinate, carvedilol) are another recommended class of drugs in HFrEF. Similarly, spironolactone or eplerenone should be used in HFrEF NYHA II-IV, provided eGFR >30 ml/min/1.73m^2 and K <5 mEq/L.

The newest recommendation adds SGLT-2 inhibitor in patients with HFrEF, regardless of diabetes (Class I indication). The combination of hydralazine-isosorbide combination can be added to usual medical management in African American patients with NYHA III-IV symptoms. If symptomatic HFrEF patients of any race cannot tolerate ACE/ARB, hydralazine-isosorbide is a reasonable alternative and should be started. In patients with HFrEF, dihydropyridine calcium channel blockers do not provide any mortality or hospitalization benefit (in contrast with non-DHP CCB, which might cause harm). Disopyramide, flecainide, propafenone, dronedarone, sotalol, doxazosin, thiazolidinediones, saxagliptin, alogliptin, and NSAIDs induce harm in HFrEF and should not be used.

Additional therapies that can be added for heart failure include ivabradine, vericiguat (oral soluble guanylate cyclase stimulator), digoxin, omega-3 fatty acids, implantable cardioverter-defibrillator, and cardiac resynchronization therapy. They are outside the scope of this article.

Other Issues

When managing diabetes and cardiovascular diseases using the latest guidelines, the most common issue encountered involves patients’ ability to afford therapies. Therapies like SGLT-2 inhibitors, ARNI, PCSK-9 inhibitors & GLP-1 agonists are expensive, and patients might not be able to afford them. Hence it is always a good idea to be aware of cost-effective alternatives.

Enhancing Healthcare Team Outcomes

For effective management of cardiovascular diseases and diabetes, a multidisciplinary approach is needed. Lifestyle modifications including a healthy diet, exercise, weight loss, smoking cessation, and reduction of alcohol intake are the cornerstone of this approach. Ensuring medication compliance is another issue to be addressed. Dietary education, diabetes education, physical therapy, specialist physicians, primary care doctors, and social workers should work in tandem to improve outcomes.