Primary Prevention of Cardiovascular Disease in Diabetes Mellitus

Abstract

Type 2 diabetes mellitus (T2D) is a major risk factor for cardiovascular disease (CVD), the most common cause of death in T2D. Yet, <50% of U.S. adults with T2D meet recommended guidelines for CVD prevention. The burden of T2D is increasing: by 2050, approximately 1 in 3 U.S. individuals may have T2D, and patients with T2D will comprise an increasingly large proportion of the CVD population. The authors believe it is imperative that we expand the use of therapies proven to reduce CVD risk in patients with T2D. The authors summarize evidence and guidelines for lifestyle (exercise, nutrition, and weight management) and CVD risk factor (blood pressure, cholesterol and blood lipids, glycemic control, and the use of aspirin) management for the prevention of CVD among patients with T2D. The authors believe appropriate lifestyle and CVD risk factor management has the potential to significantly reduce the burden of CVD among patients with T2D.

CLINICAL VIGNETTE

A 58-year-old Caucasian woman with a 7-year history of type 2 diabetes mellitus (T2D) is seen by a cardiologist in clinic for cardiovascular (CV) risk factor management and counseling. There is no history of early-onset CV or cerebrovascular disease in her family. Her only regular medication is 1,000-mg daily extended-release metformin. She is a sedentary, lifelong nonsmoker with minimal alcohol intake and no illicit drug use. On examination, her blood pressure (BP) is 135 mm Hg systolic (SBP) and 80 mm Hg diastolic (DBP); she has a body mass index (BMI) of 30 kg/m². Distal pulses are brisk, and monofilament testing of lower extremity sensation is normal. Laboratory testing is notable for a glycosylated hemoglobin (HbA_1c) of 7.5%, a total cholesterol of 200 mg/dl, high-density lipoprotein cholesterol (HDL-C) of 40 mg/dl, low-density lipoprotein cholesterol (LDL-C) of 100 mg/dl, and triglycerides of 300 mg/dl. Routine chemistries including serum creatinine and complete blood count are normal. Spot urinary albumin-to-creatinine ratio is 40 mg/g Cr (normal <30 mg/g Cr). The patient and her husband are wondering what options are available to reduce her future risk of cardiovascular disease (CVD).

THE CLINICAL PROBLEM

T2D is a major risk factor for CVD, which remains the most common cause of death for adults with T2D (1). Yet, less than one-half of adults with T2D in the United States meet recommended clinical guidelines for the prevention of CVD (2). Despite improvements in CVD mortality, the incidence of obesity, metabolic syndrome, and T2D continues to rise, and it is estimated that by 2050, approximately 1 in 3 U.S. individuals will have T2D (3). Our goal was to synthesize the current evidence and scientific statements from the American Diabetes Association (ADA), American Heart Association (AHA) and American College of Cardiology (ACC) applicable to CVD prevention for a patient with T2D and risk factors for CVD. This summation may be broadly useful for clinicians, including cardiologists, and other physician specialties caring for patients with diabetes (1,4). The increasingly recognized important relationship between T2D and congestive heart failure is beyond the scope of this review and is covered in depth elsewhere (4). This clinical review focuses on 2 major domains for the prevention of atherosclerotic risk in T2D: lifestyle management and management of CVD risk factors. Lifestyle management reviews the roles of exercise, nutrition, weight management, and smoking cessation. CVD risk factor management reviews the role of aspirin, glycemic control, management of blood pressure and cholesterol, and new directions for risk stratification and primary prevention of CVD in patients with T2D.

STRATEGIES AND EVIDENCE

LIFESTYLE MANAGEMENT

Lifestyle management, including increased physical activity and diet control, is the cornerstone of clinical care for patients with T2D. Diet and physical activity are often evaluated together as part of a comprehensive lifestyle intervention. We first review evidence from lifestyle intervention studies, and then consider evidence from studies of exercise/physical activity and nutrition/diet alone for CVD prevention among patients with T2D.

Lifestyle

The largest and most extensive trial of exercise and CV morbidity and mortality among patients with T2D was the Look AHEAD (Action for Health in Diabetes) trial, which randomized 5,145 patients with T2D to an intensive lifestyle intervention including caloric restriction, pre-specified caloric intake of fats and protein, meal replacement, and ≥175 min/week of moderate intensity physical activity by week 26 or to usual care with diabetes support and education (5). Mean weight loss from baseline was greater at 1 year in the intervention (8.6%) versus usual care (0.7%) groups, a difference that was attenuated, but sustained, throughout the trial (5). In addition to differences in mean weight loss from baseline, patients in the intervention arm had greater improvements in fitness and HDL-C levels, and greater reduction in waist circumference and requirements for medication to lower blood glucose, pressure, and cholesterol (5). Despite these benefits, after nearly 10 years of follow-up, the trial was stopped early for futility to reduce CVD events (403 CVD events in intervention vs. 418 for usual care; hazard ratio [HR]: 0.95; 95% confidence interval [CI]: 0.83 to 1.09; p = 0.51) (5). Compared with usual care, the intervention group had decreased use of cardioprotective medications, especially statins, which may have confounded the potential benefits of the intensive intervention (1,6).

The Steno-2 study randomized a total of 160 participants with T2D and albuminuria (30 to 300 mg urinary albumin in 4 of 6 of the 24-h urine samples) to either conventional multiple CV risk factor treatments from their general practitioner or to a multi-factorial intervention overseen by a project team at the trial diabetes center that included smoking cessation courses, restrictions in total and saturated fat intake, light-to-moderate exercise 3 to 5 days/week, and a stepwise intensive regimen that included more stringent control of blood glucose (target HbA_1c <6.5%) and BP (target <140/85 mm Hg for most of the study), along with angiotensin-converting enzyme (ACE) inhibitor regardless of BP and lipid-lowering therapy (7,8). Participants randomized to the intensive treatment arm had a 53% (HR: 0.47; 95% CI: 0.24 to 0.73) reduction in the composite outcome of CV death, nonfatal myocardial infarction (MI) or stroke, revascularization, or amputation. Intensive treatment was also associated with a significant reduction in microvascular endpoints (nephropathy, retinopathy, and autonomic neuropathy) (7).

Although both the Look AHEAD trial and the Steno-2 study used multidimensional lifestyle interventions for CVD prevention among T2D patients, the Diabetes Prevention Project (DPP) provided important data on diabetes prevention by comparing a lifestyle intervention to metformin or placebo (9). Among >3,200 nondiabetic participants with impaired fasting and post-load plasma glucose followed for nearly 3 years, randomization to an intensive lifestyle intervention with weight reduction of at least 7% initial body weight through a low-calorie, low-fat diet and moderate intensity physical activity (≥150 min/week), was associated with approximately 60% (HR: 0.42; 95% CI: 0.44 to 0.52) and 40% (HR: 0.61; 95% CI: 0.49 to 0.76) lower incidence of diabetes compared with placebo and metformin, respectively (9). There have not been sufficient events in the DPP Outcomes study to permit examination by treatment group, but similar improvements in multiple CVD risk factors have been observed in all treatment groups after 10 years of follow-up (10).

Exercise

The Look-AHEAD trial, the Steno-2 study, and the DPP all combined different lifestyle parameters, including weight loss, physical activity and exercise, and a dietary intervention (5,7,9). Studies focused on exercise interventions have also demonstrated improvements in CV risk factors (BP, dyslipidemia, and body composition) among T2D patients (11). However, no clinical trial of exercise in T2D patients has demonstrated a reduction in major CVD endpoints or mortality. Current guidelines for exercise and CVD risk reduction in diabetes are displayed in Table 1. In addition to exercise quantity, limited evidence suggests exercise type may be important for cardiovascular prevention. A study of 262 sedentary patients with type 2 diabetes and an HbA_1c ≥6.5% were randomized to either aerobic exercise, resistance exercise, a combination of both, or none for 9 months; the outcome was a reduction in HbA_1c and improved fitness as defined by increases in peak and lean VO₂ (oxygen consumption), treadmill time, and other measures (12). There was a trend toward a decreased HbA_1c for all groups, but the decrease in HbA_1c was significant only in the combined aerobic-resistance exercise group (−0.34%; 95% CI: 0.64% to 0.03%). Participants in the aerobic-resistance exercise group also experienced significant increases in VO₂ max and decreases in waist circumference (12).

TABLE 1.

Guideline-Based Care for CVD Prevention for Patients With Diabetes Mellitus

Risk Factor	Specific Recommendation	Level of Evidence (Ref. #)
Physical activity	≥150 min/week moderate intensity (50%–70% MPHR) over ≥3 days/week with ≤2 consecutive days without exercise	ADA LOE: A (13)
Nutrition	Mediterranean style diet may improve glycemic control and CVD risk factors Consumption of fruits, vegetables, legumes, whole grains, and dairy in place of other carbohydrate sources Carbohydrate monitoring as an important strategy for glycemic control	ADA LOE: B (13)
Weight management	Counsel overweight and obese patients that lifestyle changes can lead to a sustained 3%–5% rate of weight loss and clinically meaningful health benefits	ACC/AHA Class I, LOE: A (20)
Cigarette Smoking	Advise all patients not to use cigarettes, other tobacco products, or e-cigarettes Include smoking cessation counseling and other forms of treatment as a routine component of care	ADA LOE: A (13)
Glycemic control	Lower HbA1c ≤7% in most patients to reduce risk of microvascular disease	ADA LOE: B (13)
	Consider HbA1c <6.5% for patients with diabetes of short duration, long life expectancy, and no significant CVD if can be achieved safely	ADA LOE: C (13)
	HbA1c <8% or higher for patients with severe hypoglycemia, limited life expectancy, and/or comorbid conditions	ADA LOE: B (13)
Blood pressure	Achieve a goal of <140/90 mm Hg for most diabetic patients	ADA LOE: A, JNC-8 LOE: E (13,43)
	A goal of <130/80 mm Hg may be appropriate for younger diabetic patients with cerebrovascular disease or multiple CV risk factors,* assuming target can be safely achieved	ADA LOE: B/C (13)
	Pharmacotherapy should include either an ACE inhibitor or an ARB; if intolerant to one, substitute the other	ADA LOE: B/C (13,40)
Cholesterol	Diabetic patients 40–75 yrs of age with LDL 70–189 mg/dl should receive at least moderate-intensity statin†	ACC/AHA Class I, LOE: A; ADA LOE: A (13,54)
	If age 40–75 yrs with CV risk factors,* high-intensity statin‡ should be given	ACC/AHA Class IIa, LOE: B (54)
Antiplatelet therapy	Aspirin 75–162 mg is reasonable for diabetic patients ≥50 yrs of age with at least 1 CV risk factor§ without increased GI bleeding risk||	ACC/AHA Class IIa, LOE: B; ADA LOE: C (1,13,30)
	Aspirin 75–162 mg might be reasonable for diabetic patients <50 yrs of age with 1 or more CV risk factors¶	ACC/AHA Class IIb, LOE: C; ADA LOE: E (1,13,30)

^*One or more of the following major CV risk factors: smoking, hypertension, dyslipidemia, family history of premature CVD or albuminuria.

^†Moderate-intensity statin therapy lowers LDL cholesterol on average by 30% to 50%.

^‡High-intensity statin lowers LDL cholesterol on average by >50%.

^§Corresponds to a 10-year ASCVD risk >10% (http://tools.acc.org/ASCVD-Risk-Estimator/).

^||Prior GI bleed, peptic ulcer disease, or concurrent use of medications that increase bleeding risk (e.g., nonsteroidal anti-inflammatory drugs or warfarin).

^¶Corresponds to a 5% to 10% 10-year ASCVD risk.

ACC/AHA = American College of Cardiology/American Heart Association; ACE = angiotensin-converting enzyme; ADA = American diabetes Association; ARB = angiotensin II receptor blocker; ASCVD = atherosclerotic cardiovascular disease; CV = cardiovascular; CVD = cardiovascular disease; GI = gastrointestinal; HbA_1c = glycosylated hemoglobin; JNC-8 = Eighth Joint National Committee; LDL = low density lipoprotein; LOE = Level of Evidence; MPHR = maximum predicted heart rate.

Nutrition

Each landmark lifestyle intervention trial for CVD prevention in T2D has included a nutritional component (5,7,9). Nutritional interventions have also been examined independently for CVD prevention in T2D. According to a recent position statement from the ADA, a holistic approach to nutrition and diet should be used for counseling patients with diabetes to obtain individualized glycemic, BP, and lipid goals; to achieve and maintain body weight; and to delay or prevent complications of diabetes (13). These guidelines for patients with T2D emphasize increased fruit, vegetable, and low-fat dairy consumption, and decreased consumption of saturated fat (13). Multiple options for dietary control in patients with diabetes exist, including the DASH (Dietary Approaches to Stop Hypertension) diet (14), Mediterranean, low-fat, or controlled carbohydrate diets are all effective in reducing CVD risk factors (13). The PREDIMED (Prevención con Dieta Mediterránea) trial is the largest dietary (RCT) to date for CVD risk reduction. The PREDIMED trial randomized nearly 7,500 participants at high risk of CVD, almost 50% of whom had T2D, to a Mediterranean diet supplemented with either extra-virgin olive oil or mixed nuts, or to a control diet (15). The trial was stopped early because of a 30% reduction in the primary composite outcome of CV death, MI, or stroke observed with the Mediterranean diet (15). Patients with prevalent diabetes (a pre-specified subgroup, n = 3,614) had results similar to the main trial population, suggesting that a Mediterranean diet may prevent cardiovascular events in patients with T2D (15). Data from the nondiabetic subgroup of the PREDIMED study also indicates a Mediterranean diet may reduce the risk of developing diabetes among persons with high cardiovascular risk (16). There is also additional evidence that diets with low carbohydrate and low glycemic index foods may improve glycemic control and CVD risk factors (17,18), and may lower future diabetes risk (16). The importance of low carbohydrate diets and use of the glycemic index for CVD risk factor control in T2D warrants further investigation.

Weight management

The primary approach to weight management in patients with T2D includes dietary change focused on caloric restriction; increased energy expenditure through daily physical activity and regular aerobic activity; and behavior changes related to lifestyle (1). The Look AHEAD trial employed these strategies for a trial of intensive lifestyle management compared with usual care for patients with T2D (5). In addition to the previously described intervention for physical activity (5), the intensive management arm of the Look AHEAD trial also employed multiple dietary strategies (5). At 4 years, participants in the intensive intervention arm lost nearly 5% of their initial weight, compared with 1% of initial weight among participants in the usual care group (5). Despite the sustained weight loss and improvement in CVD risk factors observed in the intensive treatment group, the Look AHEAD trial did not demonstrate a reduction in CVD events for T2D patients assigned to the intensive lifestyle intervention (5). Other clinical trials have also demonstrated salutary effects of intensive lifestyle interventions, dietary counseling and caloric restriction on CV risk factor control for patients with T2D, but without improvements in CVD outcomes (19). However, many patients with T2D have difficulty achieving weight loss goals with lifestyle interventions alone. In line with current ACC/AHA/The Obesity Society guidelines (20), pharmacotherapy is indicated for weight loss among individuals with a BMI of 25 to 30 kg/m² with additional risk factors for CVD, including T2D or pre-diabetes, or a BMI >30 kg/m², regardless of comorbidities. A more complete review of pharmacotherapy for weight loss among patients with T2D is included elsewhere (1).

In contrast to the lifestyle intervention, bariatric surgery for severe obesity (BMI ≥35 kg/m²) improves control of glycemia and CV risk factors (1,20). Moreover, compared with nonsurgical management in the Swedish Obese Subjects study, bariatric surgery reduces CVD mortality after nearly 15 years of follow-up (adjusted HR: 0.47; 95% CI: 0.29 to 0.76; p = 0.002).

Smoking cessation

There is robust evidence to support the causal links between cigarette smoking and multiple poor health outcomes, including CVD (13). A routine and thorough assessment of tobacco use with cessation counseling and pharmacotherapy, where appropriate, is strongly recommended for CVD prevention among patients with and without T2D (Table 1). Although some patients may gain weight in the period after smoking cessation, recent research indicates this weight gain does not significantly attenuate the substantial CVD benefit from smoking cessation (13,21).

The multifaceted approach

As summarized in Figure 1, programs combining lifestyle interventions and medical therapy for CVD risk reduction are more efficacious than either therapy alone. However, only a few trials have evaluated the effect of multiple simultaneous intensive interventions (5,7,22). Some (7), but not all (5,22), have demonstrated an improvement in CV outcomes with multifactorial interventions. Taken together, these trials suggest that multifactorial interventions targeting several important risk factors simultaneously result in greater CV risk factor control and likely greater reduction in CVD risk compared with single risk factor interventions. An individually tailored aggressive management program to control multiple CVD risk factors simultaneously represents the best potential to prevent CVD morbidity and mortality among patients with T2D (23).

FIGURE 1.

Primary Prevention of CVD Events in Patients With T2D

CVD events are defined as cardiovascular death, myocardial infarction, or stroke and: *all-cause mortality; †revascularization or amputation; ‡hospitalization for angina. CI = confidence interval; CVD = cardiovascular disease; SBP = systolic blood pressure; T2D = type 2 diabetes; TX = treatment.

CVD RISK FACTOR MANAGEMENT

The major domains of CVD prevention and risk reduction for patients with T2D include the use of aspirin, and the control of blood pressure, cholesterol, and glycemia.

Aspirin

Despite a clear benefit of aspirin for the secondary prevention of CVD among patients with and without T2D (24), the use of aspirin for primary prevention among patients with T2D remains controversial.

Three trials to date specifically examined CVD prevention with aspirin among patients with T2D (25–27), only 1 of which (JPAD [Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes]) (25) was a primary prevention study. The ETDRS (Early Treatment of Diabetic Retinopathy Study) randomized over 3,700 participants 18 to 70 years of age with either type 1 diabetes (T1D) or T2D and retinopathy, approximately one-third of whom had prior CVD, to 650 mg of aspirin daily versus placebo. With a 5-year combined event rate of 20% in the placebo group, aspirin use was associated with a significant 17% reduction in fatal or nonfatal MI (HR: 0.83; 95% CI: 0.65 to 1.03; p = 0.04) and a nonsignificant increase in stroke (27).

The POPADAD (Prevention of Arterial Disease and Diabetes) trial used a factorial design to investigate whether daily aspirin 100 mg with or without antioxidant therapy was more effective than placebo in reducing incident CVD in 1,276 U.K. participants >40 years of age with diabetes and asymptomatic peripheral artery disease, defined by an ankle brachial index ≤0.99 (26). After a median follow-up of 6.7 years, the primary cardiovascular composite outcome was 18.2% in patients randomized to aspirin or to placebo, respectively (26).

The JPAD study was an open label, primary prevention study of 81 to 100 mg of aspirin among 2,539 Japanese participants with T2D (25), 26% of whom were also taking statins (25). Despite a broad composite outcome that included angina, multiple forms of peripheral vascular disease, and other outcomes not included in the secondary prevention ETDRS and POPADAD trials (26,27), the annual event rate was nearly 50% lower in the JPAD trial compared with the ERDRS and POPADAD trials (25). After 4.4 years of follow-up, there was no difference in the primary CV composite between participants in the aspirin group (68 events, 5.4%) versus no aspirin group (86 events, 6.7%; HR: 0.80; 95% CI: 0.58 to 1.10). The incidence of fatal coronary and cerebrovascular events, a pre-specified secondary endpoint, was significantly reduced in the low-dose aspirin group (p = 0.0037).

Through 2012, a number of meta-analyses have synthesized data on the effects of aspirin for the prevention of CVD patients in patients with diabetes (28–30). Although these meta-analyses differ in the included trials, the overall results suggest a modest 10% relative reduction in CVD events and ≥2-fold relative increase in the risk of bleeding, predominantly gastrointestinal (GI) in origin, with low-dose (75 to 162 mg) daily aspirin (1). In summary, low-dose aspirin is reasonable for diabetic patients with increased CVD risk (10-year risk >10%), without an increased risk of GI bleeding (Table 1) (1,13,30). This includes most diabetic men and women, ≥50 years of age, with at least 1 major CVD risk factor. Low-dose aspirin might be reasonable for patients at intermediate CVD risk (5% to 10% 10-year risk) (Table 1) (1,13,30).

BP control

BP control, in particular control of systolic blood pressure (SBP) is a major objective of CV risk reduction for patients with T2D. Seventy percent to 80% of T2D patients have comorbid hypertension, the presence of which increases the risk of many adverse health outcomes, including MI, stroke, and all-cause mortality, in addition to heart failure, nephropathy, and other microvascular outcomes (1). Epidemiological studies have demonstrated a progressive increase in micro- and macrovascular disease risk among patients with T2D with increasing SBP from approximately 115 mm Hg (31). Trials such as the UKPDS (United Kingdom Prospective Diabetes Study), HOT (Hypertension Optimal Treatment), and the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation) studies have unequivocally demonstrated that antihypertensive drug therapy for hypertensive diabetic patients reduces CVD risk (32–34). Despite the abundance of clinical studies, the appropriate threshold for initiating medical therapy and treatment goals for BP reduction for T2D patients remains much less clear.

RCTs have demonstrated the benefit (reduced coronary heart disease, stroke, and diabetic nephropathy) associated with lowering BP in diabetic patients to <140 mm Hg systolic and <90 mm Hg diastolic (35). Evidence supporting lower BP targets is limited. The ACCORD trial examined whether a SBP of <120 mm Hg provided greater CV risk reduction compared with a SBP of 130 to 140 mm Hg (36), and found no reduction in the primary composite endpoint (nonfatal MI, nonfatal stroke, and CV death) with intensive compared with standard BP control (36). Intensive versus standard SBP reduction in the ACCORD trial was associated with a 1% absolute decrease in stroke, but this benefit was outweighed by a 2% absolute increase in significant adverse events, including hypotension, bradycardia, and hyperkalemia (36). In contrast to a strategy of targeting a specific BP, the ADVANCE trial randomized patients with diabetes to either a single-pill, fixed-dose combination ACE inhibitor and diuretic or placebo, regardless of baseline blood pressure. Diabetic participants in the ADVANCE trial randomized to active treatment demonstrated significant reductions in the primary composite of macro- and microvascular events, along with significant reductions in all-cause and CV mortality (34). Although both SBP and DBP were lower with active treatment compared with placebo, the ADVANCE trial was not intended to be a comparison of CV risk reduction with more versus less intensive BP targets (34). In addition to the SBP targets of the ACCORD trial, there are earlier studies evaluating “lower” versus “standard” DBP targets in diabetic patients (33,37–39). There are limitations in these earlier studies that, taken together, do not clearly demonstrate a benefit with lower versus standard DBP targets in patients with diabetes (35).

Although differing in analytic structure, recent meta-analyses are largely in agreement and confirm the protective effect of BP treatment for SBP >140 mm Hg in diabetic patients, and show that this benefit decreases with decreasing BP (40,41). There may be a cerebrovascular benefit to commencement of antihypertensive therapy below an initial SBP <140 mm Hg and treatment to a SBP <130 mm Hg, but uncertainty remains around these estimates (40–42). Current recommendations are a goal BP of <140/90 mm Hg for most diabetic patients (Table 1) (13,43), but recognize that lower targets (e.g., SBP <130 mm Hg) may be appropriate for younger patients with diabetes and a history of cerebrovascular disease or multiple CV risk factors, assuming this lower target can be reached safely (13,40,44).

Some trials have indicated ACE inhibitor or angiotensin II receptor blocker (ARB) use may have unique CV benefits for the treatment of hypertension in patients with diabetes (45–47). However, evidence is more consistent that the achieved BP, rather than the specific drug or drug class used, is the principal determinant of this benefit (43). Despite this, an ACE inhibitor or ARB may still be preferred as initial therapy in the hypertensive diabetic patient due to the renal-protective effects and benefits for CVD risk reduction and risk factor control (13). Angiotensin inhibition with either an ACE inhibitor or ARB should be considered for patients with T2D and an abnormal urinary albumin excretion (urinary albumin-to creatinine ratio ≥30 mg/g Cr) (13), even if SBP is <140 mm Hg (46).

Control of blood cholesterol

Patients with diabetes have a number of lipoprotein abnormalities, including increased triglycerides, low HDL-C, and low, normal, or elevated LDL-C, with increased numbers of dense LDL particles (48). Multiple clinical trials and meta-analyses have demonstrated the benefits of statins for primary and secondary prevention of CVD (49). Subgroup analyses of patients with diabetes in larger lipid-lowering statin trials (50), and trials restricted to patients with diabetes (51,52), demonstrate significant reductions in CV events and death with statin use. A large meta-analysis including >18,000 patients with diabetes (>95% T2D) from 14 randomized trials of statin therapy followed for a mean of 4.3 years demonstrated about a 9% proportional reduction in all-cause mortality and a 13% reduction in vascular mortality per 1 mmol/l (39 mg/dl) reduction in LDL-C (53). Outcomes were similar to those achieved in patients without diabetes mellitus. Moreover, the outcomes of proportionate LDL reduction were similar for patients with T2D with and without a history of vascular disease (53).

Consistent with the ACC/AHA guidelines on the management of blood cholesterol (54), the ADA has revised its treatment guidelines for the use of statin therapy in patients with diabetes (13), a summary of which is presented in Table 1. Current guidelines indicate that all patients with diabetes 40 to 75 years of age with an LDL-C >70 mg/dl should be treated with a statin (13,54). Patients with diabetes and an LDL-C <70 mg/dl may still benefit from primary prevention statin use if the 10-year risk of atherosclerotic CVD is ≥7.5% (54). In general, the statin dose should be at least of moderate intensity (30% to 50% LDL-C reduction), unless clinical CVD or CV risk factors are present, in which case high-intensity statin (>50% LDL-C reduction) therapy should be considered (13,54). Lowering other lipoproteins such as triglycerides for CVD risk reduction in patients with diabetes has not proven beneficial (1), although subgroup analyses of diabetic patients with hypertriglyceridemia and low HDL-C may benefit from fibrate use on a background of statin therapy (55). Current ACC/AHA guidelines continue to endorse the treatment of patients with fasting triglycerides >500 mg/dl to prevent more severe hypertriglyceridemia and pancreatitis (54).

Glycemic control

T2D is associated with a 2- to 4-fold increased risk of CVD, with event rates correlating with the degree of hyperglycemia (1). After adjustment for other CVD risk factors, a 1% increase in HbA_1c was associated with a 21% increased risk of CVD events, including MI (56). However, the correlation between glycemia and microvascular disease is stronger than for macrovascular disease, with a 37% increase in retinopathy or nephropathy per 1% increase in HbA_1c (57).

Earlier RCTs of patients with T1D and T2D demonstrated a 25% to 70% reduction in microvascular disease along with nonsignificant reductions in macrovascular disease (58,59), that required 10+ years of follow-up to reach statistical significance for CVD risk reduction (60). Three major RCTs of diabetes and macrovascular disease studied middle age or older (mean age 60 to 68 years) participants with established T2D for 8 to 11 years, with either CVD or multiple CVD risk factors (61–63). These studies compared intensive glucose control with an HbA_1c of 6.4% to 6.9% versus 7.0% to 8.4% in the standard glucose control groups. None of the 3 studies could demonstrate a benefit on macrovascular outcomes with intensive therapy compared with standard glycemic control (61–63). The ACCORD trial was stopped early because of a 22% increase in all-cause mortality (HR: 1.22; 95% CI: 1.01 to 1.46), driven by predominantly CV mortality (62). Reasons for the increased mortality associated with intensive glucose control in the ACCORD trial are unclear and are discussed in detail elsewhere (64,65).

Current recommendations emphasize individualization of glycemic goals and suggest that for most patients with T2D, an HbA_1c of <7% is a reasonable target to reduce future risk of microvascular disease events (AHA/ACC Class IIb, Level of Evidence: A; ADA Level of Evidence: B) (13,64). More (e.g., HbA_1c <6.5%) or less (HbA1c <8% or slightly higher) may be appropriate depending on patient characteristics and medical history (13).

Glucose-lowering agent selection for CV risk reduction

Based on improved primary prevention of macrovascular disease in a subset of patients (n = 342) from the UKPDS trial, metformin is generally considered to be first-line therapy for glycemic control (66). Recent trials have suggested other pharmacological strategies may also reduce vascular risk for patients with diabetes. In particular, a sodium glucose cotransporter-2 (SGLT2) inhibitor (empagliflozin) and glucagon-like peptide (GLP)-1 analogues (liraglutide and semaglutide), have recently demonstrated a reduction in mortality (67,68) and CVD events (67–69) among patients with diabetes and pre-existing CVD or multiple CVD risk factors. Further study in primary prevention populations are needed to demonstrate whether these agents are superior or additive to the CVD risk reduction reported with the use of metformin.

AREAS OF UNCERTAINTY

Initiation and goals of BP reduction

Although the evidence is most robust to initiate pharmacotherapy when BP is >140/90 mm Hg, and to treat to a goal of <140/90 mm Hg for most patients with diabetes (43), other evidence supports initiating BP lowering below a SBP of 140 mm Hg and treating to a SBP <130 mm Hg (40,44). More aggressive BP goals could be considered in diabetic patients with a history of cerebrovascular and/or microvascular disease, such as retinopathy or nephropathy (40). A recent meta-analysis suggests the reduction in major CV events, MI, and stroke among patients at high CV risk, including diabetes, with early treatment and intensive BP reduction may outweigh the increased risk of adverse events with intensive therapy (44). Further study in high-risk stroke populations, with or without microvascular disease, is necessary to validate these findings and to determine whether a lower BP target is beneficial in this subpopulation of patients with diabetes mellitus (1,70).

T1D vs. T2D

Management of CV risk for patients with T1D relies largely on the evidence base for CV risk in T2D, despite the longer duration of disease in T1D vs. T2D and notable differences in the underlying pathophysiology (71). Following the results of landmark trials in T1D including the DCCT (Diabetes Control and Complications Trial) and its follow-up observational study EDIC (Epidemiology of Diabetes Interventions and Complications), intensive glycemic control became the standard of care (72,73). However, the basis of our understanding of CV risk factors and disease in T1D predates widespread intensive glycemic control in T1D. There is growing interest to better understand the effects of intensive glycemic control and weight gain on blood lipids in patients with T1D, the types of lipid abnormalities in T1D, and the prognostic role of albuminuria and renal function and BP control in T1D (71). Future study will help determine whether CV risk reduction strategies differ between patients with T1D versus T2D.

Triglyceride lowering

Lipid guidelines indicate the efficacy of statin treatment to lower LDL-C concentrations and reduce CV events in patients with T2D (54). However, the efficacy of treating other lipoprotein abnormalities remains unproven. Low levels of HDL, often in association with elevated triglycerides, are the most prevalent pattern of dyslipidemia in patients with T2D (13). Triglyceride-rich lipoproteins are often elevated in patients with T2D, appear to be atherogenic, and may be a secondary target for lipid-lowering therapy (1). The most selective of the triglyceride-lowering drugs are the fibrates. Clinical trials of fibrates conducted to date do not support triglyceride reduction in the presence or absence of T2D as a means to reduce CV risk. Unfortunately, these trials are few in number and have methodological limitations rendering the overall findings hypothesis generating (1). The definitive trial of triglyceride lowering among patients with T2D and elevated triglycerides, with or without low HDL-C, on a background of statin therapy, has yet to be conducted. Although combination therapy with a statin/fibrate is generally not recommended, it may be considered for men with elevated triglycerides and a low HDL-C (1,13).

CONCLUSIONS AND RECOMMENDATIONS

The patient discussed in the Clinical Vignette was referred to a nutritionist for dietary counseling and weight loss planning, along with a combined resistance and aerobic exercise training program. She was amenable to treating her borderline BP with lifestyle modification, including the DASH diet. Because of the variability in urinary albumin excretion (13), she was advised to repeat a urine collection in 3 months, and if persistently elevated, to begin either an ACE inhibitor or an ARB. Moderate-intensity statin therapy was prescribed (atorvastatin 20 mg), and the patient was counseled that if her BP increases or persistent albuminuria is confirmed, a high-intensity statin would be recommended. Because she has no history of GI bleeding, peptic ulcer disease, or use of medications increasing bleeding risk, she was also started on 81 mg of aspirin daily. The patient was counseled to increase her metformin dose and/or initiate other glucose-lowering therapies, but she preferred to discuss these options with her endocrinologist. Additional use of an SGLT-2 inhibitor or a GLP-1 analogue could be considered, even though the benefit in recent trials favored participants with established CVD at baseline (67–69).

CV risk reduction is critically important for the care of patients with diabetes, with or without known CVD and CV risk factors (Central Illustration). Use of statins, aspirin, glucose-lowering therapies, and BP reduction should be considered on a background of intensive lifestyle management including exercise, nutrition, and weight management, in all patients with T2D. The uniform use of proven medical therapies could meaningfully impact the morbidity and mortality for the diabetic patient over his or her lifetime.

CENTRAL ILLUSTRATION.

Pathways of Cardiovascular Risk in Patients With T2D

CVD = cardiovascular disease; T2D = type 2 diabetes.

ABBREVIATIONS AND ACRONYMS

ACC

American College of Cardiology

ACE

angiotensin-converting enzyme

ADA

American Diabetes Association

AHA

American Heart Association

ARB

angiotensin II receptor blocker

BMI

body mass index

BP

blood pressure

CI

confidence interval

CV

cardiovascular

CVD

cardiovascular disease

DBP

diastolic blood pressure

DPP

Diabetes Prevention Project

GI

gastrointestinal

HbA_1c

glycosylated hemoglobin

HDL-C

high-density lipoprotein cholesterol

HR

hazard ratio

LDL-C

low-density lipoprotein cholesterol

MI

myocardial infarction

RCT

randomized clinical trial

SBP

systolic blood pressure

T1D

type 1 diabetes

T2D

type 2 diabetes