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Prevention and management of cardiovascular disease in patients with diabetes: current challenges and opportunities

Bruemmer, Dennis; Nissen, Steven E.

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Cardiovascular Endocrinology & Metabolism: April 17, 2020 - Volume 9 - Issue 3 - p 81-89
doi: 10.1097/XCE.0000000000000199
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Currently, more than 100 million USA adults have overt diabetes or prediabetes [1]. The number of patients diagnosed with type 2 diabetes in the USA has steadily increased over the past decade and is expected to triple over the next several decades [2]. Among the one-third of the USA adult population with prediabetes, 90% are unaware of their diagnosis [1]. This increased prevalence of diabetes is associated with the rising rates of obesity [3], and mechanisms underlying this close relationship have been well defined [4]. Currently, two-thirds of the USA population are either overweight or obese [3]. Of great concern, the rate of childhood obesity is increasing rapidly with more than half of the children in the USA now either overweight or obese [5]. Therefore, it is not surprising that currently one in five adolescents has prediabetes [6]. This increase in childhood obesity and the ensuing increased rates of type 2 diabetes are expected to increase the future prevalence of cardiovascular disease in adulthood [7].

The major contribution of diabetes as a risk factor for cardiovascular is well established [8]. Consequently, patients with diabetes comprise an increasingly large proportion of the cardiovascular disease population [9]. Patients with type 2 diabetes have at least a two-fold increase in cardiovascular risk and subsequent mortality [10,11] Cardiovascular disease is the most frequent cause of mortality in patients with diabetes [12]. Patients with diabetes have worse outcomes after acute coronary syndromes [13]. Mortality from coronary heart disease and all-cause mortality are higher than in patients without diabetes [11]. Even in patients with prediabetes, the risk for a cardiovascular event is substantially higher compared with a population without prediabetes [14]. Although the prevalence of cardiovascular disease and associated mortality have consistently decreased in the USA over the past decades, it remains the leading cause of morbidity and mortality [15]. This decrease in cardiovascular disease has been attributed to a decline in hypertension, hypercholesterolemia, and tobacco use as a result of evidence-based preventive treatments. However, the rate in the decline of cardiovascular disease has decreased in the past years, and there is concern for stagnation or even an increase, largely owing to the increased prevalence of obesity and associated type 2 diabetes in the USA [16]. Particularly in younger patients with diabetes, recent national statistics demonstrate a concerning 25% increase in diabetic complication rates over only the past 5 years, including hyperglycemia, myocardial infarction, stroke, and limb amputation [17].

Evidence supporting multifactorial intervention in patients with diabetes

Among various cardiovascular risk factors, diabetes represents a challenge, not only because it constitutes one of the major risk factors for cardiovascular disease and is highly prevalent but also due to multiple associated comorbidities. In addition to the high prevalence of microvascular complications (18.8%)[18] and all manifestations of cardiovascular disease (32.2%) [19], the prevalence of obesity (87.5%) [1], hypertension (73.6%) [1], dyslipidemia (58.2%) [1], and smoking (25.7%)[20] remains surprisingly high in patients with type 2 diabetes. These traditional risk factors are associated with an increased cardiovascular risk, thereby amplifying the underlying risk of diabetes. In association with obesity and diabetes, insulin resistance results in a clustering of hypertension, a proinflammatory state, and a pattern of diabetic dyslipidemia that includes hypertriglyceridemia and decreased high density lipoprotein (HDL) cholesterol. All of these factors likely contribute to the increased risk of cardiovascular disease [21]. Finally, hyperglycemia is well established as a cause of both microvascular and macrovascular complications [22], and treatment of hyperglycemia decreases diabetic complications [23]. In the landmark United Kingdom Prospective Diabetes Study trial, intensive lowering of HbA1c from 7.9% to 7.0% reduced any diabetes-related endpoint and microvascular disease [24]. In addition, metformin treatment in 342 overweight patients with type 2 diabetes decreased the incidence of myocardial infarction and all-cause mortality, which provided the rationale for use of metformin as first-line treatment in current guidelines for the management patients with type 2 diabetes [25]. Long-term follow-up of these patients confirmed the cardiovascular benefit of early intensive glucose management [26], similarly as seen in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications patient population with type 1 diabetes [27]. From follow-up studies targeting near-normal HbA1c levels (to less than 6.0% in one trial), including the Action to Control Cardiovascular Risk in Diabetes [28], the Action in Diabetes and Vascular Disease-Preterax and Diamicron Controlled Evaluation [29], and the Veterans Affairs Diabetes Trial [30], we have learned the importance of individualized diabetes care and the risk of mandating near-normal glucose levels, if these cannot be safely achieved [23]. However, it is important to consider the traditional glucocentric treatment approach for diabetes in these studies in the perspective of real-world diabetes care. In the USA, guideline-recommended HbA1c testing has been as low as 20% in primary care physician settings [31], 30% percent of Medicare patients with diabetes receive insufficient HbA1c testing [32], and 30% of Medicaid patients have a HbA1c above 9% [33].

As noted, a therapeutic approach focused on the treatment of hyperglycemia alone has been proven effective in patients with type 2 diabetes only for microvascular complications but not for cardiovascular disease [23]. Instead, reducing atherosclerotic cardiovascular risk in patients with diabetes requires a multifactorial approach and aggressive management of all risk factors. Because of the common risk factor clustering in patients with type 2 diabetes and inherent treatment complexity [34], therapeutic focus has shifted from glucocentric treatment to comprehensive, multifactorial risk factor management. In the Steno-2 trial, intensive multifactorial risk intervention led to a 53% relative risk reduction of cardiovascular outcomes in patients with advanced type 2 diabetes [35]. In the Bypass Angioplasty Revascularization Investigation 2 Diabetes trial, control of multiple risk factors through guideline-driven therapy improved survival and correlated to the number of risk factors at target [36]. Further encouraging results are from a Swedish Registry, which revealed that diabetic patients with comprehensive risk factor control [elevated HbA1c level, elevated low density lipoprotein (LDL) cholesterol level, albuminuria, smoking, and elevated blood pressure] have no increased mortality compared to matched controls [37]. Therefore, current major society guidelines recommend comprehensive treatment of risk factors in patients with cardiovascular disease [38–42], which is feasible, reduces cardiovascular morbidity and mortality, and is cost-effective [35,43].

Due to the increased cardiovascular risk of patient with diabetes and safety concerns of prior antihyperglycemic agents, novel agents developed specifically for glycemic treatment now require cardiovascular outcome trials to establish safety and are mandated to include multifactorial risk factor management [44]. Since the addition of glucagon-like peptide 1 receptor agonists (GLP1-RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) to the repertoire of antihyperglycemic agents, we have for the first time conclusive evidence to support the use of these two drug classes to reduce cardiovascular events and mortality in patients with type 2 diabetes and established cardiovascular disease [45]. Currently, empagliflozin [46], canagliflozin [47], and liraglutide [48] have received Food and Drug Administration approval for an indication to reduce cardiovascular events. Therefore, recent guideline updates recognize their benefit and focus on these two classes of medications as either first-line therapy [41] or addition to metformin [42]. However, since the evidence for metformin monotherapy from the United Kingdom Prospective Diabetes Study is less compelling compared to that of GLP1-RA and SGLT2i, metformin use as first-line therapy in type 2 diabetic patients with established cardiovascular may ultimately become questionable. In current USA guidelines, metformin remains first-line therapy [42], partly because of its long-term availability and costs. Conversely, European Guidelines have already accepted GLP1-RA and SGLT2i as first-line therapy with a class I indication for patients with type 2 diabetes and cardiovascular disease or at high risk [41].

Current quality of diabetes health care

While randomized controlled trials demonstrated that treatment of hyperglycemia, multifactorial management of risk factors, and new treatment agents, including SGLT2 inhibitors and GLP1-RA, improve cardiovascular outcomes, the vast majority of patients in the USA with diabetes and established cardiovascular disease receive suboptimal treatment [49]. Although over 74 medications are approved by the Food and Drug Administration to treat hyperglycemia in patients with diabetes, the number of patients achieving the recommended target HbA1c remained unchanged over the past decade in the USA [50]; yet healthcare spending for diabetes has tripled [51]. At least 80% of patients with type 2 diabetes do not achieve guideline-recommended goals for optimal medical therapy [49,52]. In the Diabetes Collaborative Registry, among 574 972 patients with diabetes from 259 USA practices, optimal, comprehensive therapy according to current guidelines was only achieved in 17% [49]. In the recent Getting to an imprOved Understanding of Low-Density Lipoprotein Cholesterol and Dyslipidemia Management Registry, multifactorial medical therapy according to current treatment guidelines for secondary prevention of cardiovascular disease in patients with type 2 diabetes was merely 6.9% [52]. Only one-third of diabetic patients admitted with an acute coronary syndrome is even tested for HbA1c, a frequently missed opportunity to improve care [53]. Similarly, observations from the National Cardiovascular Disease Registry Practice Innovation and Clinical Excellence confirmed that only 13% of outpatients in the USA with coronary artery disease are screened for diabetes [54].

The reasons for the overall inadequate management of patients with diabetes and cardiovascular disease are complex and multifactorial. Barriers are not limited to but frequently occur at the levels of healthcare systems, the individual provider, and patients (Table 1). Diabetes is one of the most frequent chronic medical conditions and associated with multiple comorbid illnesses, requiring coordinated continuity of care. However, the well-described fragmentation of care in the USA is not only associated with worse outcomes and poor patient satisfaction but leads to important gaps in coordination, failure of treatment, and a lack of ownership responsibilities [55]. The vast majority of patients with diabetes receive routine care from primary care providers, who are faced with the important task of implementing standards of care recommendations for patients with diabetes. This is further complicated by frequent changes in primary care physicians. In a recent analysis, more than half of patients with diabetes changed primary care providers within 2 years [56]. Given the overwhelming number of patients with diabetes, less than 15% of all diabetes care in the USA is provided by endocrinologists [57]. The average wait time to see an endocrinologist in the USA is 37 days, and the demand for endocrinology expertise by far outweighs the supply as the Endocrinology work-force and fellowship training opportunities continue to decline [57]. Conversely, approximately 60–70% of patients admitted with acute myocardial infarction to cardiology care have prediabetes or diabetes [9]. Cardiologists frequently encounter the high-risk patient with diabetes. In fact, cardiologists see about 5 times more patients with diabetes and comorbid cardiovascular disease than do Endocrinologists [58]. However, cardiologists are rarely involved in managing diabetes [53], and endocrinology consultations after acute myocardial infarction occur only in 40% of diabetic patients with poor glycemic control [59]. Moreover, even discontinuation of antihyperglycemic agents is common in patients hospitalized for acute myocardial infarction [60]. Although current guidelines recommend a multidisciplinary treatment approach, delivery of care is insufficient. Major gaps are evident between recommended diabetes care, and the care patients are currently receiving, calling for an improvement in quality and system-based approaches.

Table 1
Table 1:
Barriers to optimal diabetes management

‘Therapeutic inertia’ has become a major concern leading to delayed treatment intensification in patients with diabetes not achieving recommended goals [61,62]. Estimates in a retrospective patient cohort suggest that patients spend on average 5 years with an HbA1c of above 8% and 10 years with an HbA1c of above 7% until treatment is intensified [63]. Inertia to intensify therapy has been recognized in up to 75% of patients with uncontrolled diabetes [64]. This reported lack of advancing treatment in patients with uncontrolled diabetes appears to be similar between primary care physicians and specialty providers [65]. In high-risk patients admitted with acute coronary syndrome, almost 70% of patients with uncontrolled diabetes are ultimately discharged without further adjustment in their antidiabetic medication regimen [53]. When followed over 2 decades, a 1-year delay in treatment intensification in patients with poor control, already significantly increases the risk of cardiovascular complications[66]. Providers are likely to accept mild HbA1c elevations, assume that diet and exercise recommendations suffice for achieving target goals, fear hypoglycemia side effects, and delay referral to an Endocrinologist until complications have occurred [67,68]. In addition, the most frequently used addition to first-line metformin remains sulfonylureas, which lack long-term efficacy and may even cause adverse cardiovascular outcomes [69,70]. Novel agents, including SGLT2 inhibitors and GLP1-RA, are often cost-prohibitive for patients if covered at all by payers. Advancing therapy to insulin regimens requires considerable time, education, and resources on the provider side, who may lack confidence in using complex insulin regimens and recommended treatment algorithms [71].

While providers appear to accept a degree of responsibility for inertia, physicians frequently provide explanations for inertia related to patient and system-level barriers, including physician time constraints, resources for appropriate diabetes teaching, complexity of comorbidities, and costs [72]. In addition, 80% of physicians perceive reluctance to insulin initiation, nonadherence, and poor self-management skills from patients as key barriers [73]. A major contributing factor to poor glycemic control in earlier disease states is poor adherence to lifestyle behavior [74]. However, 30% of new diabetes prescriptions are not filled [75], and half of the patients discontinue their diabetes medications within the first year of treatment [76]. This nonadherence combined with missed clinic visits is associated with increased mortality [77]. Moreover, the costs associated with poor compliance for medications for diabetes, hypertension, and hyperlipidemia in the USA are estimated to be about 100 billion USA dollars per year [78]. Socioeconomic factors are associated with compliance, as older age, higher education level, higher income, and presence of comorbid chronic conditions are all factors which increase compliance [79]. A major concern is that patients who perceive to be healthy, including younger patients with a new diagnosis, are those who are frequently noncompliant [79]. Particularly, these younger patients with diabetes may be at risk for increased mortality and could derive long-term benefit if treated early in the disease process [80]. In addition to the perceived harmlessness of early diabetes, a general misconception about the benefit and the efficacy of medications is highly prevalent [81]. In general, patients are more likely to be compliant using patient-centered approaches and patient empowerment to self-care [80]. A key element to improve care is the communication between the provider and the patient leading to an accurate education about the gravity and consequence of the disease.

Opportunities and models for diabetes care improvement

There is a compelling imperative to explore and define new management paradigms for patients with diabetes and associated cardiovascular disease. Diabetes is a high risk and chronic disease, which requires multifactorial intervention and a high degree of patient engagement and self-management. There is a wide discrepancy between the potential benefits seen in cardiovascular outcomes trials and the real-world care that patients with diabetes currently receive. Opportunities for improvement in the quality of care exist at every level of care to improve the implementation of current guidelines standards. Several major societies, including the American Heart Association, American College of Cardiology, and American Diabetes Association, have recognized the need for collaborative efforts and initiated cardiometabolic programs to improve care for patient with diabetes and cardiovascular disease [39,82–84]. Important strategies include, but are not limited to, the following concepts:

1. Multidisciplinary care teams: Current treatment guidelines endorse a multidisciplinary approach to treat cardiovascular risk in patients with diabetes [38–42]. Because of the large proportion of diabetic patients presenting with cardiovascular disease, there is a clear need for cardiologists to collaborate with primary care providers and Endocrinologists in managing patients with diabetes. Such collaborative efforts are already established in many major USA health care systems. Cardiologists frequently encounter the patient with a first diagnosis of diabetes, which represents a window of opportunity to initiate multidisciplinary care. Additional members of the care team should include diabetes educators, nutritionists, pharmacists, and behavioral therapists. Ideally, primary care and subspecialty providers will share clinic space to integrate care, which improves outcomes, increases quality, and patient satisfaction [85]. The treatment team should work systematically and use standardized algorithms, set clear goals, intensify therapy timely according to current guidelines, and avoid therapeutic inertia [82]. Patients not achieving HbA1c goals should be referred early to Endocrinologists, including all patients requiring multiple daily injection insulin management or medically supervised weight management. Ideally, care teams will share clinic space to integrate health care and communication between providers. Finally, the development of multidisciplinary care models will require novel education pathways for future physicians. Specialized, combined training in Endocrinology and Cardiology in form of a 3-year training program in cardiometabolic medicine has previously been proposed [86]. The cardiometabolic physician would care for the needs of a very large patient population, whose treatment is currently insufficiently addressed by primary care physicians, endocrinologists, and cardiologists.

2. Simplified treatment algorithms for comprehensive care: Due to the complexity of diabetes treatment and the associated comorbidities, management frequently requires individualization. Therefore, current treatment algorithms are complex and convoluted. There is a need for simplified treatment approaches to comprehensive risk factor management, including lifestyle and behavioral therapy, weight management (i.e., surgical and medical therapy of obesity), and pharmacological treatment of hyperglycemia, dyslipidemia, and hypertension. Using simplified treatment algorithms at the healthcare system level has been demonstrated to improve cardiovascular outcomes [87]. In addition, current guidelines need to be consistent among specialties and provide focused recommendations on new agents for cardiovascular risk reduction, including SGLT2 inhibitors and GLP1-RA. Figure 1 outlines a potential comprehensive and succinct algorithm adapted from current guidelines [38–42,88–90].

Fig. 1
Fig. 1:
Multifactorial treatment algorithms for patients with type 2 diabetes: (a) Overview of comprehensive treatment of patients with type 2 diabetes. Step 1: When evaluating patients with diabetes, anthropometric measurements should be obtained, and the clinical components of the medical, obesity, and diabetes history should be assessed. Providers should screen for complications of diabetes using additional testing as needed. Step 2: The next step includes the assessment of cardiometabolic risk and diabetes-associated comorbidities. Provider-patient discussions should focus on education about risk and the definition of treatment goals. Step 3: Evidence-based, multifactorial treatment algorithms are used to treat patients to the appropriate goals, avoiding therapeutic inertia. At all three steps, primary care physicians, endocrinologists, and cardiologists collaborate and include additional team members based on clinical judgment (i.e., bariatric surgery, pharmacists, nutritionists, diabetes educators, behavioral therapists, and exercise physiologists). (b) Lifestyle therapy algorithms use evidence-based approaches and are emphasized to all patients to focus on nutritional therapy, physical activity, behavioral interventions, smoking cessation, and sleep hygiene as well as screening for OSA. (c) The obesity treatment algorithm uses risk stratification based on the presence and the severity of complications, which could be treated by weight loss. The algorithm emphasizes nutritional therapy, weight management programs, early medical therapy of obesity, and metabolic surgery, specifically in patients with a BMI ≥ 35 kg/m2 and severe complications. In patients with obesity-associated complications (stage 1 and 2), the algorithm combines obesity therapy with treatment of the specific complications. (d) The first step of the diabetes algorithm includes lifestyle therapy (including medically assisted weight therapy) plus metformin, followed by either a GLP1-RA or SGLT2i in patients with established ASCVD. SGLT2i are preferred as second-line agents in patients with CHF or CKD if the glomerular filtration rate is adequate. Therapy is intensified every three months until the goal HbA1c is achieved. If adequate glucose control is not achieved with triple therapy consisting of metformin, GLP1-RA, and SGLT2i, the next step may include the addition of a DPP-4i, pioglitazone, or basal insulin, considering side effects and current contraindications. The HbA1c target for most patients is <7.0%. For patients with an HbA1c > 7.5%, initiation of dual therapy is encouraged. Patients with an HbA1c > 9.0% should be referred to endocrinology for initiation of insulin therapy. (e) The dyslipidemia algorithm targets an LDL cholesterol of < 55 mg/dl in patients with diabetes and established ASCVD. If the target LDL is not achieved, statin therapy should be intensified, ezetimibe should be added, or PCSK9 inhibitor therapy should be initiated. (f) The blood pressure goal for patients with diabetes is less than 130/80 mmHg. ACEi and ARB are first-line therapies. In patients with an initial blood pressure above 150/100 mmHg, CCB, β-blocker, or thiazide diuretics are added as second medication. Treatment is intensified every 2–3 months until the goal blood pressure of <130/80 mmHg is achieved. ACEi, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blocker; ASCVD, atherosclerotic cardiovascular disease; CCB, calcium-channel blocker; CHF, congestive heart failure; CKD, chronic kidney disease; DPP-4i, dipeptidyl-peptidase 4 inhibitor; GLP1-RA, glucagon-like peptide 1 receptor agonists; OSA, obstructive sleep apnea; PSCK9, proprotein convertase subtilisin/kexin type 9; SGLT2i, sodium-glucose cotransporter-2 inhibitors. Adapted and modified from [38–42,88–90].

3. Patient-centered care and empowerment: Effective patient self-management constitutes a critical aspect of diabetes care. Providers need to encourage patients and actively support collaborative and informed decision making. Physicians combined with managed efforts of health care organization should encourage patients to participate in evidence-based systems for lifestyle intervention program, including for example weight loss programs, diabetes prevention programs, and diabetes self-management program [91,92]. Managing diabetes mandates considerable patient education, which includes discussion of the associated complications, including increased risk for cardiovascular disease. Goals and models of care require detailed consideration of the patients’ socioeconomic background and health literacy. Medication cost and access to care are major limitations for many patients. Providers should leverage on novel technology, including, for example, mobile health tools for the review of glucose logs and virtual visits to increase access to care.

4. Performance measures of health care quality: Care team members should leverage on new capabilities of electronic medical record systems to monitor treatment performance. In addition, system-based approaches, including quality of care measures and performance-based incentives, should be developed. For example, registries have been established to track multidisciplinary care of patients with diabetes and facilitate the measurement of care quality, including, for example, the Diabetes Collaborative Registry [49]. These allow for a documentation and improvement in quality of achieving guideline-recommended goals for patients with diabetes.

5. Community engagement and education: The increasing prevalence of diabetes and prediabetes in the USA combined with the required high degree of self-management provide key opportunities for education and community engagement. Increasing patient awareness about diabetes and cardiometabolic risk play an integral role to produce partnerships, patient trust, and preventive approaches [93]. Introducing patients to the emerging diabetes online community facilitates support and education. National organizations, including the American Diabetes Association and the American Heart Association, launched multiple initiatives and have partnered to increase awareness of cardiovascular risk in patients with diabetes and drive community education, advocacy, and physician education efforts [83,84]. To recognize therapeutic inertia, the American Diabetes Association recently launched a new education campaign investigating the causes in the delay of implementing effective care for patients with diabetes [94]. At the provider level, continued education on diabetes management, individualized care, and provider partnerships to bridge care are needed.


The evidence to support multifactorial therapy of cardiometabolic risk in patients with diabetes is unequivocal. Pharmacological therapies are now available to effectively reduce cardiovascular risk in patients with diabetes. However, the majority of patients remain insufficiently treated, and the impact of novel treatment options with proven cardiovascular benefit in the real-world population has been minimal. Particularly, patients with prediabetes and early diabetes are at risk to forego treatment due to perceived harmlessness and physician inertia. Our current care for diabetes is far from optimal and limited by access and the dissemination of available therapies with effective cardiovascular benefit. In addition to medical therapy, diabetes represents a unique and challenging chronic condition, probably if not likely the disease which requires the most attentive and persistent self-management. Goals for improvement include the development of multidisciplinary, collaborative teams between primary care physicians, cardiologists, and endocrinologist to enhance provider focus on achieving treatment goals and quality measures. Care teams should leverage on multifactorial support by nutritionists, diabetes educators, pharmacists, and behavioral therapists. Structured programs are required to educate patients and empower self-management to improve patient outcomes and quality of life. Finally, there is a need for physicians to shift from traditional diabetes treatment approaches to contemporary management and to translate the cardiovascular benefit of novel diabetes medications, including SGLT2 inhibitors and GLP1-RA, to the broad patient population.


Conflicts of interest

There are no conflicts of interest.


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