Macrovascular Disease

Introduction

The long-term macrovascular complications that may co-exist with or develop in patients with type 2 diabetes (T2D) include:

• Hypertension
• Dyslipidemia
• Cerebrovascular disease
• Cardiovascular disease (CVD)
• Renovascular disease, including chronic kidney disease (CKD)
• Peripheral vascular disease

The long-term, chronic complications of diabetes have a great impact on the health of individuals with diabetes as well as on the health care system. According to the Centers for Disease Control (CDC), diabetes and its associated complications were the seventh leading cause of death in the United States in 2013, with the leading cause being heart disease. In individuals with diabetes, CVD is the major cause of morbidity and mortality, making early detection and aggressive treatment of these complications essential.

The currently recommended strategies for reducing the risk of long-term complications use a multifactorial treatment approach, focusing on controlling blood glucose and lowering low-density lipoprotein and blood pressure (BP). Evidence for the efficacy of this approach was demonstrated in the Steno-2 study, which enrolled patients with T2D and persistent albuminuria. Patients in this trial were randomized to receive either conventional treatment or treatment aimed at multifactorial risk reduction (glycosylated hemoglobin (A1C) ≤6.5%, and cholesterol and blood pressure (BP) targets). Compared with conventional treatment, multifactorial treatment reduced the risk of death and cardiovascular (CV) events by 50% and 60%, respectively. Given these findings, the American Diabetes Association (ADA) recommended striving for the best possible glycemic control in patients with type 1 diabetes (T1D) and T2D, with the following treatment goals:

• Preprandial capillary plasma glucose level of 80 mg/dL to 130 mg/dL
• Peak postprandial capillary plasma glucose of <180 mg/dL
• A1C <7%.

Diabetes and the conditions that commonly coexist with it (e.g., hypertension and dyslipidemia) are all risk factors for cerebrovascular, CV, renovascular and peripheral vascular disease. The incidence of these major macrovascular diseases is greater in individuals with diabetes than in nondiabetic individuals, accounting for up to 80% of mortality in adult diabetics. Atherosclerotic cardiovascular disease (ASCVD) also develops at an earlier age, accelerates more rapidly and is more extensive in patients with diabetes than in nondiabetics matched by age, weight and sex. Controlling individual CV risk factors is effective at slowing or preventing ASCVD, with the largest benefits arising when multiple risk factors are addressed during treatment. Smoking and lack of exercise contribute to an increased risk of ASCVD in both diabetics and nondiabetics alike. Renal insufficiency can also increase the risk of and accelerate macrovascular disease in diabetic individuals with albuminuria or gross proteinuria.

Weight control and exercise are safe and effective methods for modifying macrovascular risk and should form the basis to which all other treatments are added. The following treatments for hypertension and dyslipidemia should be applied when appropriate.

Hypertension

Hypertension is a risk factor for CV events and mortality in patients with diabetes, in addition to being a risk factor for microvascular complications. The ADA recommends treating individuals with diabetes to a systolic blood pressure (SBP) of <130 mm Hg and a diastolic blood pressure (DBP) of <80 mm Hg, if this target can be safely attained. In clinical trials, including the Strategy of Blood Pressure Intervention in the

Elderly Hypertensive Patients (STEP) trial and the ACCORD (Action to Control Cardiovascular Risk in Diabetes) blood pressure trial (ACCORD BP), lowering BP to these goals has been shown to reduce the risk of CHD events, diabetic kidney disease, and stroke. Although these trials were not designed to specifically demonstrate a decreased incidence of adverse cardiovascular events with a target of <130/80 mm Hg), the ADA recommendation aligns with the guidelines issued by the American College of Cardiology and American Heart Association, the International Society of Hypertension, and the European Society of Cardiology.

The Systolic Blood Pressure Intervention Trial (SPRINT) was a randomized study that compared standard (<140 mm Hg systolic) and intensive (<120 mm Hg systolic) pressure-reducing strategies in non-diabetic patients, with primary efficacy outcome measures of stroke, heart failure (HF), MI, acute coronary syndrome and death due to CVD. Intensive therapy resulted in significantly lower rates of CV events and death, including a lower relative risk of 25% for the primary endpoint, 38% for HF, 43% for death from CV causes and 27% for death from any cause. The benefits of intensive therapy warranted halting the study early.

Patients with BP >120/80 mm Hg should be encouraged to make lifestyle changes to control their BP, whereas patients with confirmed BP >140/90 mm Hg should additionally initiate prompt pharmacologic therapy. Recommended lifestyle changes include increased exercise, weight loss (if overweight or obese), moderation of alcohol intake and a DASH-style diet that reduces sodium and increases potassium intake.

Discrepancies can exist between office and home BP measurements. White coat hypertension is a phenomenon where a patient’s anxiety in the medical environment can lead to abnormally high BP readings. Conversely, masked hypertension occurs when office BP is measured to be <140/90 mm Hg, but home measurements are in the hypertensive range. Occasional home self-monitoring is encouraged to reveal such discrepancies.

Several different agents have been shown to effectively reduce the risk of CV events by lowering BP, including angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), β-blockers, diuretics and CCBs. The 2018 European Society of Hypertension/European Society of Cardiology (ESH/ESC) guidelines on the management of hypertension conclude that it is not the choice of the antihypertensive drug, but rather the degree of BP reduction that is the major determinant in reducing CV risk in patients. Meta-analysis has determined that ARBs are equivalent to ACE inhibitors in reducing mortality and CV events in diabetic patients. The 2024 ADA Standards of Medical Care recommend that initial pharmacologic therapy in patients with diabetes include drug classes shown to reduce CV events. Options include ACE inhibitors, ARBs, thiazide-like diuretics, or dihydropyridine calcium channel blockers. In patients with diabetes and a urinary albumin-to-creatinine ratio of greater than or equal to 300 mg/g creatinine, an ACE inhibitor or ARB at maximum tolerated dose is the recommended first-line treatment.

Because patients with diabetes can be uniquely impacted by certain side effects of antihypertensives, physicians must be familiar with the potential complications with the various classes of antihypertensive drugs (Table 23-1). In general, reductions in systolic or DBP of 5% to 10% occur with most antihypertensives. The potential benefits of the commonly prescribed antihypertensives are shown in Table 23-2. Sodium glucose cotransporter type (SGLT2) inhibitors are approved glucose-lowering medications and although they are not approved as antihypertensive agents, these agents have the added benefit of reducing BP in patients with diabetes, in part, by inducing osmotic diuresis.

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Angiotensin Inhibitors: Angiotensin-Converting Enzyme (ACE) Inhibitors and Angiotensin II Receptor Blockers (ARBs)

ACE inhibitors and the ARBs are commonly the first choices for therapy because they are effective and have a low incidence of side effects. In the UKPDS, the ACE inhibitor captopril was equally efficacious as the β-blocker atenolol in reducing microvascular and CV complications of T2D. ACE inhibitors have also been shown to be cardioprotective in addition to having beneficial effects on the diabetic kidney.

The Heart Outcomes Prevention Evaluation (HOPE) trial studied >3500 subjects with diabetes who had documentation of previous CV events and were >55 years of age. Subjects were randomized to either ramipril (10 mg/day) or placebo and vitamin E or placebo. Within 4.5 years, the ramipril-treated group experienced a 22% reduction in MI, 33% reduction in stroke, 37% reduction in any CV event and a 24% reduction in the development of overt nephropathy when compared with the placebo group. These benefits occurred despite minor reductions in BP, raising the possibility that ACE inhibitors have benefits for diabetic patients independent of BP lowering. ACE inhibitors have since been shown to slow the rate of progression of proteinuria in diabetic nephropathy, reduce declining renal function, prevent progression of retinopathy and have no negative impact on carbohydrate or lipid metabolism.

Caution should be used in patients with peripheral occlusive disease because renal artery stenosis may be present, which could lead to a decline in eGFR with ACE inhibitors. Serum potassium should be monitored during therapy with ACE inhibitors in patients with suspected hyporeninemic hypoaldosteronism (type IV renal tubular acidosis) to prevent severe hyperkalemia. One complication of ACE inhibitors, although rare, is hypoglycemia in patients with normal glycemic control.

In addition to lowering BP, ARBs have been shown to have the same cardioprotective benefits as ACE inhibitors. The safety and efficacy of combination renin-angiotensin system inhibition were assessed in several clinical trials. The ONTARGET, ALTITUDE and VA-NEPHRON D trials found that combination therapy produced more side effects than ACE inhibitor monotherapy. For this reason, combination treatment using an ACE inhibitor with an ARB or with a direct renin inhibitor is not recommended.

β-Blockers

β-blockers were used more frequently as antihypertensive agents following the beneficial effects reported with atenolol in the UKPDS. Besides equal efficacy to the ACE inhibitor captopril, treatment with atenolol did not result in an increased incidence of hypoglycemic episodes. However, in the LIFE diabetic parallel study, the ARB losartan provided significantly more protection against adverse CV outcomes than atenolol.

Worsening glycemic control has been observed in studies with β-blockers. The Atherosclerosis Risk In Communities study (ARIC) demonstrated that β-blockers are associated with an increased incidence of new onset diabetes in nondiabetic patients. In this trial, hypertensive nondiabetic patients were at 28% increased risk of developing T2D with β-blockers but not thiazides, calcium channel blockers, or ACE inhibitors compared with no antihypertensive therapy. However, the GEMINI study has since demonstrated that ACE inhibitor or ARB treatment also increases the risk of new onset diabetes.

α-Blockers

α-blockers (eg, doxazosin) are not used as primary therapy for hypertension, despite being as effective as ACE inhibitors and calcium channel blockers in lowering BP. This is due to side effects such as orthostatic hypotension and because patients receiving doxazosin were at an increased risk of new onset HF compared with patients receiving the thiazide diuretic chlorthalidone.

Calcium Channel Blockers (CCBs)

There are two main subclasses of CCBs: the dihydropyridine group (DHP) and the non-dihydropyridine group (the benzothiazepines and phenylalkylamines). The non-dihydropyridine calcium channel blockers (eg, verapamil) have similar efficacy to ACE inhibitors and similarly have no adverse events related to lipid or carbohydrate metabolism. However, ACE inhibitors are still preferred since they have been shown to superior to verapamil in the prevention of diabetic nephropathy in patients with T2D. Conflicting results exist from clinical trials studying CV risk associated with dihydropyridine calcium channel blockers, with some smaller trials suggesting increased CV complications associated with nisoldipine or amlodipine compared with ACE inhibitors. The large ALLHAT trial observed comparable rates of rates of coronary mortality and nonfatal MI between patients treated with amlodipine and the ACE inhibitor lisinopril. Also, in the same trial, treatment with amlodipine was found to result in a higher rate of HF among diabetic patients compared with patients receiving the thiazide diuretic chlorthalidone.

Thiazide Diuretics

Low-dose thiazide diuretics have been shown to be effective in treating hypertensive diabetic patients, in part by reversing volume expansion. They also have benefits in combination with other antihypertensive agents: they increase the antihypertensive effect of the angiotensin inhibitors, and ACE inhibitors can reduce some of the metabolic complications that occur with higher doses of diuretic, including hyperlipidemia, hypokalemia and hyperuricemia.

Summary

ACE inhibitors, ARBs, β-blockers, CCBs and thiazide diuretics are all considered first-line treatment choices for controlling hypertension. The choice of anti-hypertensive agent should be selected based on several factors, including the presence of CVD or albuminuria, history of HF and medication safety profiles.

Dyslipidemia

Lipid Profile Abnormalities in Diabetic Patients

Lipid abnormalities that accelerate atherosclerosis and increase the risk of CV disease are significantly more common in patients with T2D than in nondiabetic individuals. In addition, central obesity associated with T2D is also a risk factor for CV disease. These combined factors have resulted in CV disease becoming a major cause of morbidity and mortality in T2D. The characteristic lipid abnormalities in T2D are:

• Hypertriglyceridemia usually due to elevated triglyceride-rich, very low-density lipoprotein (VLDL) levels and sometimes increased chylomicrons
• Decreased high-density lipoprotein cholesterol levels (HDL-C)
• Phenotype B pattern (excessive amounts of small, dense LDL and intermediate-density lipoprotein particles), which contributes to an increased CV risk.

Other common components of dyslipidemia associated with T2D are shown in Table 23-3. In the United States, the Framingham Study found that elevated triglyceride levels (above the 90th percentile) were present in 19% of men and 17% of women with T2D, compared with 9% and 8% of non-diabetic men and women, respectively. Another study, the UKPDS, found a 50% increase in triglyceride levels among patients with T2D compared with non-diabetics. For high-density lipoprotein (HDL), the Heart Protection Study (HPS) found that low HDL-C levels (below the 10th percentile) were two times more prevalent in diabetics than in non-diabetics.

A common lipid pattern among patients with T2D is the increased atherogenicity of low-density lipoprotein cholesterol (LDL-C). The United States National Health and Nutritional Examination Survey (NHANES) 1999-2000 found that the prevalence of elevated LDL-C was similar between diabetics and non-diabetics (25.3% compared with 24.3%). However, the qualities of the LDL-C particles are altered in diabetic patients: they are typically smaller, denser, more numerous and more susceptible to oxidation and glycosylation. This is especially pronounced in individuals with elevated triglyceride (>200 mg/dL), or in chronic hyperglycemia, which promotes LDL-C glycosylation. These changes in LDL-C are proposed to enhance the atherogenicity of the particles, even in diabetics with normal lipid profiles. Reductions in CVD events correlate closely to lowering of LDL-C.

The ADA recommends screening the lipid profile of adult patients with diabetes when they are first diagnosed, at the initial medical evaluation and once yearly thereafter, or more frequently if indicated. Lipid screening profiles should be measured for total cholesterol, LDL cholesterol, HDL cholesterol and triglycerides.

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Cholesterol Measurements

Total Cholesterol

Measuring total cholesterol is simple, inexpensive and does not require patient fasting for accurate results. Levels <200 mg/dL are considered good, whereas ≥240 mg/dL puts patients at risk of heart disease. Although easy to obtain, total cholesterol measurements are misleading, since HDL-C, LDL-C and VLDL-C are all included in a single value. This means that patients with apparently normal total cholesterol levels could still have unhealthy levels of any of the component values.

HDL

HDL measurement is both informative by itself and in relation to total cholesterol. By itself, HDL levels lower than 40 mg/dL are a risk factor for heart disease and levels greater than 60 mg/dL are protective. HDL can also be used to determine the total cholesterol-to-HDL ratio. A ratio of 5 puts individuals at average risk of heart disease and this risk halves or doubles as the ratio decreases to 3.4 or increases to 9.6, respectively. Since women tend to have higher HDL levels, a ratio of 4.4 signifies average risk of heart disease. In conjunction with total cholesterol, HDL can also be used to calculate the level of non-HDL-C, which is discussed below.

LDL

LDL-C is considered the most important measurement when determining a patient’s risk of developing heart disease. Many practice guidelines, including the ADA, consider LDL-C the primary target of therapy. LDL-C is usually measured indirectly using the Friedewald equation in fasting patients:

LDL = total cholesterol – HDL – (triglycerides ÷ 5)

Triglycerides increase after a meal or alcohol consumption, so patients need to fast and avoid alcohol for approximately 12 and 24 hours prior to this test, respectively. Additionally, this calculation becomes less accurate as triglycerides increase above 250 mg/dL. An alternative way to measure LDL-C is directly by ultracentrifugation.

A major limitation of only measuring LDL-C is that other lipoproteins, including VLDL and IDL, are also atherogenic, so an LDL-C measure may not accurately capture patient risk. Supporting this, many patients with ASCVD have optimal LDL-C levels and complications of ASCVD can still develop in patients who meet LDL-C goals goals of <70 mg/dL (referred to as residual risk).

ApoB and LDL-P

One reason why LDL-C may not be an ideal measure of ASCVD risk is that the amount of cholesterol contained within individual LDL particles can vary greatly, by >2-fold between individuals. LDL particles that are more cholesterol-enriched may deposit more cholesterol in artery walls, and could be considered more atherogenic in this regard. However, as particle number increases, so does the probability that a particle will contribute its cholesterol to a developing atheroma. Variation in LDL-C content means that measures of LDL-C can either overestimate or underestimate the number of circulating atherogenic particles. This means that patients with mostly cholesterol-depleted particles could have LDL-C within the normal range, while having an unusually high number of circulating atherogenic particles (a situation that can arise in patients with elevated triglycerides).

Due to the variability in LDL-C content between individuals, it has been proposed that ApoB or LDL particle (LDL-P) number be measured in conjunction with LDL-C. Since ApoB is a major component of all atherogenic lipoproteins, with each carrying a single copy, ApoB accurately measures the total number of circulating atherogenic lipoprotein particles. Since VLDL-P contributes only a small proportion of the total number of atherogenic particles (approximately 5%), an alternative is quantifying only LDL-P by nuclear magnetic resonance.

The Framingham Offspring Study found that as LDL-C decreases, LDL particles become progressively cholesterol-depleted, independent of triglycerides or LDL particle size. When lipid levels were measured, most patients in the study with low LDL-C had a correspondingly low LDL-P level and CVD risk. However, 21% of patients with low LDL-C had a discordantly high level of LDL-P, along with a higher CVD event rate. The study concluded that if LDL-C and LDL-P levels do not agree, then CVD is more strongly associated with LDL-P; a similar conclusion was made about ApoB. These results are of clinical importance, since it indicates that therapy that successfully lowers LDL-C may not necessarily bring LDL-P or ApoB within the target range.

Overall, using only LDL-C levels to guide treatment and evaluate response may mask a requirement to further reduce circulating atherogenic particles. Although there is some evidence that either LDL-P, ApoB or non-HDL-C measurements are superior to LDL-C in determining a patient’s risk for ASCVD, there is no consensus on which measure is most accurate.

Shown in Table 23-4 are AACE lipid targets for high and very-high risk patients with T2D. If pharmacologic therapy does not bring a patient’s lipid levels to desirable levels, the AACE recommends that patients intensify lifestyle therapy and consider therapeutic intensification:

• To lower LDL-C, intensify statin therapy and add ezetimibe, a PCSK9 inhibitor, colesevelam, or niacin
• To lower non-HDL-C or TG, intensify statin therapy and/or add pharmaceutical grade omega-3 fatty acid, a fibrate and/or niacin
• To lower ApoB or LDL-P, intensify statin therapy and/or add ezetimibe, a PCSK9 inhibitor, colesevelam and/or niacin.

Non–HDL-C

Another proposed alternative to LDL-C is a measure of non-HDL-C, which is calculating by subtracting HDL-C from total cholesterol. This measure represents all cholesterol in all atherogenic lipoprotein particles.

Although there is some evidence that either LDL-P, ApoB and non–HDL-C measurements are superior to LDL-C in determining a patient’s risk for ASCVD, there is no consensus on whether LDL-P, ApoB, or non–HDL-C are more accurate. Shown in Table 23-4 are AACE lipid targets for patients with T2D.

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Lifestyle Modifications

Because lipid abnormalities often reflect poor glycemic control, the first treatment approach to dyslipidemia in T2D should be optimizing diabetes control with diet and exercise.

The ADA recommends lifestyle changes and optimizing glycemic control in patients with elevated triglyceride levels (≥150 mg/dL) and/or low HDL cholesterol (<40 mg/dL for men, <50 mg/dL for women). Glycemic control through lifestyle can improve overall lipid profiles and reduce the risk of CVD, particularly in individuals with high triglycerides and poor glycemic control. Possible lipid management strategies include:

• Weight loss in overweight individuals
• Achievement of ideal aerobic activity level
• Individualized medical nutrition therapy
• Adoption of a well-balanced diet
• Cessation of smoking
• Moderate alcohol consumption.

Nutrition is an important modifiable risk factor that contributes to ASCVD. Past guidelines have focused on recommending ideal proportions of dietary components (eg, fat, protein, carbohydrates). However, such guidelines are difficult to follow since different foods, each with different proportions of dietary components, are consumed in combination rather than individually. Nutritional guidelines now focus on dietary patterns, by recommending types of food to avoid or consume. The 2020-2025 Dietary Guidelines for Americans published jointly by the US Department of Health and Human Services (HHS) and the US Department of Agriculture (USDA) recommend an eating pattern for individuals ages 2 years and older that includes:

• A variety of vegetables from all of the subgroups (eg, starchy, dark green, red and orange, legumes)
• A variety of protein-containing foods (e.g., lean meats and poultry, seafood, legumes, eggs, seeds, nuts, soy)
• Fat-free or low-fat daily (e.g., milk, yogurt, cheese, fortified soy beverages)
• Grains, at least half of which being whole grains
• Fruits, especially whole fruit
• Oils.

The 2020-2025 Dietary Guidelines for Americans recommend that individuals should limit consumption of:

• Saturated fats to <10% of daily calories
• Trans fats (avoid or reduce as much as possible without compromising the nutritional adequacy of the diet)
• Added sugars to <10% of daily calories
• Sodium to <2300 mg per day
• Alcohol (up to one drink per day for women and up to two drinks per day for men).

In controlled trials enrolling adults, for every 1% of energy from trans monounsaturated fatty acids replaced by energy from monounsaturated fatty acids (MUFAs), or polyunsaturated fatty acids (PUFAs):

• LDL-C was lowered by approximately 1.5 mg/dL and 2.0 mg/dL, respectively
• HDL-C was increased by approximately 0.4 mg/dL and 0.5 mg/dL, respectively
• Triglycerides were decreased by approximately 1.2 mg/dL and 1.3 mg/dL, respectively.

In 2013, the American Heart Association (AHA) and the American College of Cardiology (ACC) published lifestyle guidelines for reducing CV risk. Patients who would benefit from LDL-C lowering are encouraged to adapt a DASH-dietary pattern, which emphasizes an intake of vegetables, fruits and whole grains, low-fat dairy products, poultry, fish, legumes, non-tropical vegetable oils and nuts, while limiting sweets, sugar-sweetened beverages and red meats. Adopting a DASH dietary pattern has been demonstrated to improve BP and lipid profiles in men and women of all ages. The benefits of adopting such a dietary pattern persist as long as it is maintained. The AHA/ACC has insufficient evidence to recommend lowering dietary cholesterol as a means to reduce LDL-C, although some individual studies indicate that dietary cholesterol can contribute up to 15% of serum cholesterol levels.

Nutritional interventions should be tailored to the individual patient, taking into consideration their age, pharmacologic treatment regimen, lipid levels and underlying medical conditions.

Pharmacologic Therapy

Lipid-lowering pharmacologic agents are usually necessary when the lipid profile does not normalize in response to diet, exercise and other efforts to improve glycemic control. The ADA follows an order of priority for the treatment of diabetic dyslipidemia, with LDL-C considered the first priority. Commonly used pharmacologic agents for the treatment of dyslipidemia are listed in Table 23-5.

HMG-CoA reductase inhibitors (atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin) reduce cholesterol synthesis and are useful as monotherapy for the familial forms of hypercholesterolemia and are an effective therapeutic option for combined dyslipidemia. LDL cholesterol can be reduced up to 60% and triglycerides up to 40% with an HMG-CoA reductase inhibitor.

Several clinical trials have demonstrated statins have significant effects on CVD prevention and on CVD outcomes in individuals with coronary heart disease. Meta-analysis of data from 14 randomized trials enrolling 18,000 patients has demonstrated that statin therapy decreases all-cause mortality by 9% and vascular mortality by 13%, for each mmol/L reduction in LDL-C. These benefits of statin therapy are especially pronounced in individuals with high baseline CVD risk. Statins are therefore the drug of choice for lowering LDL-C and reducing the risk of CVD. The 2024 ADA recommendations for statin therapy based on the risk profile of patients with T2D are shown in Table 23-6.

The ADA recommends that hypertriglyceridemia be managed with dietary and lifestyle changes. Severe hypertriglyceridemia (>1000 mg/dL) may merit prompt pharmacologic therapy to reduce the risk of acute pancreatitis. The most effective therapy is a no/very low fat diet. Other possible treatment options include a fibric acid derivative or fish oil. If severe hypertriglyceridemia is not present, then there is insufficient evidence supporting HDL-C or triglyceride-targeted therapy.

Some patients do not achieve an LDL-C of <70 mg/dL on maximal tolerated statin or are intolerant to statin treatment and might benefit from an alternative treatment option. Additional effective add-on therapies would also benefit patients who fail to achieve clinically significant lipid control with statins alone. The proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors may have the greatest potential to meet these clinical needs. This class of drugs includes the monoclonal antibodies evolocumab and alirocumab, and the siRNA inclisiran. The PCSK-9 inhibitors have been studied in over 20 short-term clinical trials and are associated with mean LDL-C reductions of approximately 50% to 60%. These reductions were observed across different doses, patient populations, and in patients with or without maximally tolerated background statin therapy. PCSK-9 treatment also decreases triglycerides (~23%) and lipoprotein(a) (~31%), and increases HDL-C (~7%). Longer-term outcome trials evaluating their effectiveness in reducing ASCVD event rates are currently ongoing. The ADA recommends PCSK-9 inhibitor therapy as an alternative to statin therapy for the secondary prevention of ASCVD events in patients who are unable to tolerate statins.

Bempedoic acid and the ANGPTL3 (angiopoietin-like 3) inhibitor evinacumab are two novel types of lipid-lowering drugs recently approved for use together with other LDL-C-lowering medications. Bempedoic acid is an inhibitor of adenosine triphosphate-citrate lyase (ACL), an important enzyme in the cholesterol biosynthesis pathway. Bempedoic acid is indicated as an adjunct to diet, exercise, and a maximally-tolerated statin therapy for the treatment of adult patients with heterozygous familial hypercholesterolemia or established ASCVD; however, a direct benefit of bempedoic acid on CV outcomes has not yet been established. A meta-analysis of 10 randomized controlled trials has found that bempedoic acid reduces LDL-C levels by ~23% compared to the placebo. The 2024 ADA Standards of Medical Care state that bempedoic acid may be considered for patients who are unable to use or statin therapy (for primary or secondary prevention of ASCVD), or for whom those other therapies are ineffective. Evinacumab is a recombinant human monoclonal antibody currently approved for the treatment of adult and pediatric patients with homozygous familial hypercholesterolemia as an adjunct to other LDL-C therapies. It inhibits ANGPTL3 – itself an inhibitor of lipoprotein lipase (LPL) and endothelial lipase (EL) – which leads to a decrease in triglyceride and HDL-C levels; evinacumab also promotes the processing and clearance of VLDL, which also reduces LDL-C levels.

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Cardioprotective Benefits of Antihyperglycemic Agent Pharmacologic Therapy

Landmark clinical trials have successfully demonstrated the cardioprotective benefits of certain antihyperglycemic agents in patients with T2D at high CV risk, including SGLT2 inhibitors and GLP-1 receptor agonists. The first CV outcome trial, EMPA-REG OUTCOME, demonstrated the cardioprotective effects of empagliflozin compared to the placebo. CV benefits were also demonstrated for canagliflozin in the CANVAS trial (Figure 11-5) and dapagliflozin in DECLARE-TIMI 58 (Figure 11-9). In addition to improvements in the composite CV outcomes, all three SGLT2 inhibitors also demonstrated significant benefits in the reduction of hospitalization for HF, as did ertugliflozin, which however failed to demonstrate a benefit in the overall CV composite outcome. Significant cardioprotective effects were demonstrated for several GLP-1 receptor agonists, including liraglutide (the LEADER trial; Figure 19-10), dulaglutide (the REWIND trial; Figure 19-12) and semaglutide in both its subcutaneous (the SUSTAIN-6 trial; Figure 19-13) and oral formulation (PIONEER-6).

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Renoprotective Benefits of Antihyperglycemic Agent Pharmacologic Therapy

Chronic kidney disease is defined as the presence of either an estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m² or of at least one marker of kidney damage in a contiguous time period of at least 3 months. CKD is common in the general population (~15%), but even more common in patients with T2D (25-40%) and HF (20-67%); it is rarely present without comorbidities. In patients with T2D, CKD is driven both by CVD, which causes vasoconstriction and endothelial dysfunction in the kidneys (glomerulosclerosis, tubulointerstitial fibrosis) and by hyperglycemia, which causes metabolic dysregulation and increased inflammation, resulting in hyperfiltration, albuminuria and interstitial cell infiltration. All of these mechanisms ultimately reduce eGFR and result in a progressive loss of kidney function. CKD is a major risk factor for end-stage kidney disease (ESKD) and for early death. Although few pharmacological interventions to prevent disease progression in patients with CKD and T2D used to be available, the armamentarium has recently expanded with the approval of two SGLT2 inhibitors and a nonsteroidal, selective mineralocorticoid receptor (MR) antagonist.

SGLT2 Inhibitors for the Treatment of Chronic Kidney Disease

The SGLT2 inhibitors canagliflozin and dapagliflozin demonstrated significant renoprotective effects in patients with CKD in two large, double-blind trials: CREDENCE and DAPA-CKD. Since only patients with T2D were recruited into CREDENCE while DAPA-CKD enrolled both patients with and without T2D, canagliflozin received approval for the treatment of patients with T2D and diabetic nephropathy with albuminuria, while dapagliflozin is approved in all patients with CKD, regardless of T2D. Canagliflozin and dapagliflozin inhibit the SGLT2 transporter which is responsible for ~90% of renal glucose reabsorption, and is upregulated in T2D. This prevents kidney hypertrophy and CKD progression. In the EMPA-KIDNEY trial, empagliflozin also demonstrated positive results in CKD and the trial was terminated early; results have not yet been published.

Finerenone (Kerendia) for the Treatment of Chronic Kidney Disease

The MR antagonist finerenone is the first agent in its class to receive FDA approval for the prevention of CKD progression. Finerenone is indicated to reduce the risk of sustained eGFR decline, ESKD, CV death, non-fatal myocardial infarction and hospitalization for HF in adult patients with CKD associated with T2D. One of the major mechanisms of CKD progression in patients with T2D is increased aldosterone signaling. Aldosterone binds MR to promote sodium retention and potassium loss, causing increased inflammation and fibrosis in the kidneys. Finerenone exerts its renoprotective effects by blocking MR and preventing aldosterone signaling.

The safety and efficacy of finerenone in patients with CKD and T2D was investigated in FIDELIO-DKD, a large, double-blind trial. Finerenone demonstrated superior efficacy compared to the placebo with respect to both the primary endpoint (a composite of kidney failure, a sustained decrease of at least 40% in the eGFR from baseline, or death from renal causes; HR = 0.82; P = 0.001; Figure 23-1) and the key secondary endpoint (a composite of death from CV causes, nonfatal myocardial infarction, nonfatal stroke, or HHF; HR = 0.86; P = 0.03). The safety profile of finerenone was comparable to that of the placebo. Serious adverse reactions occurred in 32% of patients treated with finerenone, compared to 34% of patients receiving placebo. Of the adverse reactions that occurred in 1% or more of patients, three were more common in the finerenone group than in the placebo group: hyperkalemia (18.3% vs 9.0%), hypotension (4.8% vs 3.4%), and hyponatremia (1.4% vs 0.7%).

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