Secondary Logo

Journal Logo

Reviews

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

Bruemmer, Dennis; Nissen, Steven E.

Author Information
Cardiovascular Endocrinology & Metabolism: April 17, 2020 - Volume 9 - Issue 3 - p 81-89
doi: 10.1097/XCE.0000000000000199
  • Free

Abstract

Introduction

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.

Conclusion

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.

Acknowledgements

Conflicts of interest

There are no conflicts of interest.

References

1. Centers for Disease Control and Prevention. National Diabetes Statistics Report A. 2017, GA: Centers for Disease Control and Prevention, US Department of Health and Human Services
2. Boyle JP, Thompson TJ, Gregg EW, Barker LE, Williamson DF. Projection of the year 2050 burden of diabetes in the US adult population: dynamic modeling of incidence, mortality, and prediabetes prevalence. Popul Health Metr. 2010; 8:29
3. Hales CM, Fryar CD, Carroll MD, Freedman DS, Ogden CL. Trends in obesity and severe obesity prevalence in US youth and adults by sex and age, 2007-2008 to 2015-2016. JAMA. 2018; 319:1723–1725
4. Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature. 2006; 444:840–846
5. Skinner AC, Ravanbakht SN, Skelton JA, Perrin EM, Armstrong SC. Prevalence of obesity and severe obesity in US children, 1999-2016. Pediatrics. 2018; 141e20173459
6. Andes LJ, Cheng YJ, Rolka DB, Gregg EW, Imperatore G. Prevalence of Prediabetes Among Adolescents and Young Adults in the United States, 2005-2016. JAMA Pediatr. 2020; 174e194498
7. Baker JL, Olsen LW, Sørensen TI. Childhood body-mass index and the risk of coronary heart disease in adulthood. N Engl J Med. 2007; 357:2329–2337
8. Low Wang CC, Hess CN, Hiatt WR, Goldfine AB. Clinical update: cardiovascular disease in diabetes mellitus: atherosclerotic cardiovascular disease and heart failure in type 2 diabetes mellitus - mechanisms, management, and clinical considerations. Circulation. 2016; 133:2459–2502
9. Arnold SV, Lipska KJ, Li Y, McGuire DK, Goyal A, Spertus JA, Kosiborod M. Prevalence of glucose abnormalities among patients presenting with an acute myocardial infarction. Am Heart J. 2014; 168:466–470.e1
10. Sarwar N, Gao P, Seshasai SR, Gobin R, Kaptoge S, Di Angelantonio E, et al.; Emerging Risk Factors Collaboration. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010; 375:2215–2222
11. Rawshani A, Rawshani A, Franzén S, Eliasson B, Svensson AM, Miftaraj M, et al. Mortality and cardiovascular disease in type 1 and type 2 diabetes. N Engl J Med. 2017; 376:1407–1418
12. Baena-Díez JM, Peñafiel J, Subirana I, Ramos R, Elosua R, Marín-Ibañez A, et al.; FRESCO Investigators. Risk of cause-specific death in individuals with diabetes: a competing risks analysis. Diabetes Care. 2016; 39:1987–1995
13. Donahoe SM, Stewart GC, McCabe CH, Mohanavelu S, Murphy SA, Cannon CP, Antman EM. Diabetes and mortality following acute coronary syndromes. JAMA. 2007; 298:765–775
14. Vistisen D, Witte DR, Brunner EJ, Kivimäki M, Tabák A, Jørgensen ME, Færch K. Risk of cardiovascular disease and death in individuals with prediabetes defined by different criteria: the whitehall II study. Diabetes Care. 2018; 41:899–906
15. Benjamin EJ, Muntner P, Alonso A, Bittencourt MS, Callaway CW, Carson AP, et al.; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics-2019 update: a teport from The American Heart Association. Circulation. 2019; 139:e56–e528
16. Sidney S, Quesenberry CP Jr, Jaffe MG, Sorel M, Nguyen-Huynh MN, Kushi LH, et al. Recent trends in cardiovascular mortality in the united states and public health goals. JAMA Cardiol. 2016; 1:594–599
17. Gregg EW, Hora I, Benoit SR. Resurgence in diabetes-related complications. JAMA. 2019; 321:1867–1868
18. Kosiborod M, Gomes MB, Nicolucci A, Pocock S, Rathmann W, Shestakova MV, et al.; DISCOVER investigators. Vascular complications in patients with type 2 diabetes: prevalence and associated factors in 38 countries (the DISCOVER study program). Cardiovasc Diabetol. 2018; 17:150
19. Einarson TR, Acs A, Ludwig C, Panton UH. Prevalence of cardiovascular disease in type 2 diabetes: a systematic literature review of scientific evidence from across the world in 2007-2017. Cardiovasc Diabetol. 2018; 17:83
20. Clair C, Meigs JB, Rigotti NA. Smoking behavior among US adults with diabetes or impaired fasting glucose. Am J Med. 2013; 126:541.e15–541.e18
21. Shulman GI. Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease. N Engl J Med. 2014; 371:1131–1141
22. Bornfeldt KE, Tabas I. Insulin resistance, hyperglycemia, and atherosclerosis. Cell Metab. 2011; 14:575–585
23. Brown A, Reynolds LR, Bruemmer D. Intensive glycemic control and cardiovascular disease: an update. Nat Rev Cardiol. 2010; 7:369–375
24. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998; 352:837–853
25. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998; 352:854–865
26. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008; 359:1577–1589
27. Nathan DM, Cleary PA, Backlund JY, Genuth SM, Lachin JM, Orchard TJ, et al.; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005; 353:2643–2653
28. Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, et al.; Action to Control Cardiovascular Risk in Diabetes Study G. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008; 358:2545–2559
29. Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, et al.; ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008; 358:2560–2572
30. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, et al.; VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009; 360:129–139
31. Kirkman MS, Williams SR, Caffrey HH, Marrero DG. Impact of a program to improve adherence to diabetes guidelines by primary care physicians. Diabetes Care. 2002; 25:1946–1951
32. Goodney PP, Newhall KA, Bekelis K, Gottlieb D, Comi R, Chaudrain S, et al. Consistency of hemoglobin A1c testing and cardiovascular outcomes in medicare patients with diabetes. J Am Heart Assoc. 2016; 5e003566
33. Cole MB, Galárraga O, Wilson IB, Wright B, Trivedi AN. At federally funded health centers, medicaid expansion was associated with improved quality of care. Health Aff (Millwood). 2017; 36:40–48
34. Brunzell JD, Davidson M, Furberg CD, Goldberg RB, Howard BV, Stein JH, Witztum JL. Lipoprotein management in patients with cardiometabolic risk: consensus conference report from the american diabetes association and the american college of cardiology foundation. J Am Coll Cardiol. 2008; 51:1512–1524
35. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008; 358:580–591
36. Bittner V, Bertolet M, Barraza Felix R, Farkouh ME, Goldberg S, Ramanathan KB, et al.; BARI 2D Study Group. Comprehensive cardiovascular risk factor control improves survival: the BARI 2D trial. J Am Coll Cardiol. 2015; 66:765–773
37. Rawshani A, Rawshani A, Franzén S, Sattar N, Eliasson B, Svensson AM, et al. Risk factors, mortality, and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2018; 379:633–644
38. Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA, et al. Consensus statement by the American Association Of Clinical Endocrinologists And American College Of Endocrinology on the comprehensive type 2 diabetes management algorithm - 2019 executive summary. Endocr Pract. 2019; 25:69–100
39. Arnett DK, Blumenthal RS, Albert MA, Buroker AB, Goldberger ZD, Hahn EJ, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: executive summary: a report of the american college of cardiology/american heart association task force on clinical practice guidelines. J Am Coll Cardiol. 2019; 74:1376–1414
40. American Diabetes A. 10. Cardiovascular disease and risk management: standards of medical care in diabetes-2020. Diabetes Care. 2020; 43:S111–S134
41. Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V, et al.; Group ESCSD. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J. 2020; 41:255–323
42. American Diabetes A. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2020. Diabetes Care. 2020; 43:S98–S110
43. Gaede P, Valentine WJ, Palmer AJ, Tucker DM, Lammert M, Parving HH, Pedersen O. Cost-effectiveness of intensified versus conventional multifactorial intervention in type 2 diabetes: results and projections from the steno-2 study. Diabetes Care. 2008; 31:1510–1515
44. U.S. Food and Drug Administration Guidance Document Type 2 Diabetes Mellitus: Evaluating the Safety of New Drugs for Improving GLycemic Control - Guidance for Industry March 2020.. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/type-2-diabetes-mellitus-evaluating-safety-new-drugs-improving-glycemic-control-guidance-industry. [Accessed March 2020]
45. Lupsa BC, Inzucchi SE. Diabetes medications and cardiovascular disease: at long last progress. Curr Opin Endocrinol Diabetes Obes. 2018; 25:87–93
46. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al.; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015; 373:2117–2128
47. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, et al.; CREDENCE Trial Investigators. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019; 380:2295–2306
48. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al.; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016; 375:311–322
49. Arnold SV, Goyal A, Inzucchi SE, McGuire DK, Tang F, Mehta SN, et al. Quality of care of the initial patient cohort of the diabetes collaborative registry((R). J Am Heart Assoc. 2017; 6:e005999
50. Kazemian P, Shebl FM, McCann N, Walensky RP, Wexler DJ. Evaluation of the Cascade of Diabetes Care in the United States, 2005-2016. JAMA Intern Med. 2019; 179:1376–1385
51. Squires E, Duber H, Campbell M, Cao J, Chapin A, Horst C, et al. Health care spending on diabetes in the U.S., 1996-2013. Diabetes Care. 2018; 41:1423–1431
52. Arnold SV, de Lemos JA, Rosenson RS, Ballantyne CM, Liu Y, Mues KE, et al.; GOULD Investigators. Use of guideline-recommended risk reduction strategies among patients with diabetes and atherosclerotic cardiovascular disease. Circulation. 2019; 140:618–620
53. Stolker JM, Spertus JA, McGuire DK, Lind M, Tang F, Jones PG, et al. Relationship between glycosylated hemoglobin assessment and glucose therapy intensification in patients with diabetes hospitalized for acute myocardial infarction. Diabetes Care. 2012; 35:991–993
54. Chan PS, Oetgen WJ, Buchanan D, Mitchell K, Fiocchi FF, Tang F, et al. Cardiac performance measure compliance in outpatients: the american college of cardiology and national cardiovascular data registry’s PINNACLE (practice innovation and clinical excellence) program. J Am Coll Cardiol. 2010; 56:8–14
55. Frandsen BR, Joynt KE, Rebitzer JB, Jha AK. Care fragmentation, quality, and costs among chronically ill patients. Am J Manag Care. 2015; 21:355–362
56. Liu CW, Einstadter D, Cebul RD. Care fragmentation and emergency department use among complex patients with diabetes. Am J Manag Care. 2010; 16:413–420
57. Vigersky RA, Fish L, Hogan P, Stewart A, Kutler S, Ladenson PW, et al. The clinical endocrinology workforce: current status and future projections of supply and demand. J Clin Endocrinol Metab. 2014; 99:3112–3121
58. Patel RB, Al Rifai M, McEvoy JW, Vaduganathan M. Implications of specialist density for diabetes care in the united states. JAMA Cardiol. 2019; 4:1174–1175
59. Green Conaway DL, Enriquez JR, Barberena JE, Jones PG, O’Keefe JH Jr, Spertus JA. Assessment of and physician response to glycemic control in diabetic patients presenting with an acute coronary syndrome. Am Heart J. 2006; 152:1022–1027
60. Lipska KJ, Wang Y, Kosiborod M, Masoudi FA, Havranek EP, Krumholz HM, Inzucchi SE. Discontinuation of antihyperglycemic therapy and clinical outcomes after acute myocardial infarction in older patients with diabetes. Circ Cardiovasc Qual Outcomes. 2010; 3:236–242
61. Lin J, Zhou S, Wei W, Pan C, Lingohr-Smith M, Levin P. Does clinical inertia vary by personalized a1c goal? A study of predictors and prevalence of clinical inertia in a u.s. Managed-care setting. Endocr Pract. 2016; 22:151–161
62. Khunti K, Wolden ML, Thorsted BL, Andersen M, Davies MJ. Clinical inertia in people with type 2 diabetes: a retrospective cohort study of more than 80,000 people. Diabetes Care. 2013; 36:3411–3417
63. Brown JB, Nichols GA, Perry A. The burden of treatment failure in type 2 diabetes. Diabetes Care. 2004; 27:1535–1540
64. Davis J, Chavez B, Juarez DT. Adjustments to diabetes medications in response to increases in hemoglobin a1c: an epidemiologic study. Ann Pharmacother. 2014; 48:41–47
65. Pantalone KM, Wells BJ, Chagin KM, Ejzykowicz F, Yu C, Milinovich A, et al. Intensification of diabetes therapy and time until A1C goal attainment among patients with newly diagnosed type 2 diabetes who fail metformin monotherapy within a large integrated health system. Diabetes Care. 2016; 39:1527–1534
66. Paul SK, Klein K, Thorsted BL, Wolden ML, Khunti K. Delay in treatment intensification increases the risks of cardiovascular events in patients with type 2 diabetes. Cardiovasc Diabetol. 2015; 14:100
67. Blonde L, Aschner P, Bailey C, Ji L, Leiter LA, Matthaei S; Global Partnership for Effective Diabetes Management. Gaps and barriers in the control of blood glucose in people with type 2 diabetes. Diab Vasc Dis Res. 2017; 14:172–183
68. Marrett E, Zhang Q, Kanitscheider C, Davies MJ, Radican L, Feinglos MN. Physician reasons for nonpharmacologic treatment of hyperglycemia in older patients newly diagnosed with type 2 diabetes mellitus. Diabetes Ther. 2012; 3:5
69. Douros A, Dell’Aniello S, Yu OHY, Filion KB, Azoulay L, Suissa S. Sulfonylureas as second line drugs in type 2 diabetes and the risk of cardiovascular and hypoglycaemic events: population based cohort study. BMJ. 2018; 362:k2693
70. Cook MN, Girman CJ, Stein PP, Alexander CM, Holman RR. Glycemic control continues to deteriorate after sulfonylureas are added to metformin among patients with type 2 diabetes. Diabetes Care. 2005; 28:995–1000
71. Williamson C, Glauser TA, Burton BS, Schneider D, Dubois AM, Patel D. Health care provider management of patients with type 2 diabetes mellitus: analysis of trends in attitudes and practices. Postgrad Med. 2014; 126:145–160
72. Zafar A, Stone MA, Davies MJ, Khunti K. Acknowledging and allocating responsibility for clinical inertia in the management of type 2 diabetes in primary care: a qualitative study. Diabet Med. 2015; 32:407–413
73. Ratanawongsa N, Crosson JC, Schillinger D, Karter AJ, Saha CK, Marrero DG. Getting under the skin of clinical inertia in insulin initiation: the translating research into action for diabetes (TRIAD) insulin starts project. Diabetes Educ. 2012; 38:94–100
74. LeBlanc ES, Rosales AG, Kachroo S, Mukherjee J, Funk KL, Schneider JL, Nichols GA. Provider beliefs about diabetes treatment have little impact on glycemic control of their patients with diabetes. BMJ Open Diabetes Res Care. 2015; 3:e000062
75. Fischer MA, Stedman MR, Lii J, Vogeli C, Shrank WH, Brookhart MA, Weissman JS. Primary medication non-adherence: analysis of 195,930 electronic prescriptions. J Gen Intern Med. 2010; 25:284–290
76. Farr AM, Sheehan JJ, Curkendall SM, Smith DM, Johnston SS, Kalsekar I. Retrospective analysis of long-term adherence to and persistence with DPP-4 inhibitors in US adults with type 2 diabetes mellitus. Adv Ther. 2014; 31:1287–1305
77. Currie CJ, Peyrot M, Morgan CL, Poole CD, Jenkins-Jones S, Rubin RR, et al. The impact of treatment noncompliance on mortality in people with type 2 diabetes. Diabetes Care. 2012; 35:1279–1284
78. Nasseh K, Frazee SG, Visaria J, Vlahiotis A, Tian Y. Cost of medication nonadherence associated with diabetes, hypertension, and dyslipidemia. Am J Pharm Benefits. 2012; 4:e41–e47
79. Kirkman MS, Rowan-Martin MT, Levin R, Fonseca VA, Schmittdiel JA, Herman WH, Aubert RE. Determinants of adherence to diabetes medications: findings from a large pharmacy claims database. Diabetes Care. 2015; 38:604–609
80. Ho PM, Rumsfeld JS, Masoudi FA, McClure DL, Plomondon ME, Steiner JF, Magid DJ. Effect of medication nonadherence on hospitalization and mortality among patients with diabetes mellitus. Arch Intern Med. 2006; 166:1836–1841
81. Rubin RR. Adherence to pharmacologic therapy in patients with type 2 diabetes mellitus. Am J Med. 2005; 118Suppl 5A27S–34S
82. Association AD. 1. Improving care and promoting health in populations: standards of medical care in diabetes-2020. Diabetes Care. 2020; 43:S7–S13
83. Sasson C, Eckel R, Alger H, Bozkurt B, Carson A, Daviglus M, et al. American heart association diabetes and cardiometabolic health summit: summary and recommendations. J Am Heart Assoc. 2018; 7:e009271
84. Sanchez EJ, Cefalu WT. Know diabetes by heart. Circulation. 2019; 140:526–528
85. Elrashidi MY, Mohammed K, Bora PR, Haydour Q, Farah W, DeJesus R, et al. Co-located specialty care within primary care practice settings: A systematic review and meta-analysis. Healthc (Amst). 2018; 6:52–66
86. Eckel RH, Blaha MJ. Cardiometabolic medicine: a call for a new subspeciality training track in internal medicine. Am J Med. 2019; 132:788–790
87. Dudl RJ, Wang MC, Wong M, Bellows J. Preventing myocardial infarction and stroke with a simplified bundle of cardioprotective medications. Am J Manag Care. 2009; 15:e88–e94
88. Garvey WT, Mechanick JI, Brett EM, Garber AJ, Hurley DL, Jastreboff AM, et al.; Reviewers of the AACE/ACE Obesity Clinical Practice Guidelines. American Association Of Clinical Endocrinologists And American College Of endocrinology comprehensive clinical practice guidelines for medical care of patients with obesity. Endocr Pract. 2016; 22Suppl 31–203
89. Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Dennison Himmelfarb C, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APHA/ASH/ASPC/NMA/PCNA Guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary: a report of the American College Of Cardiology/American Heart Association Task Force On Clinical Practice Guidelines. Circulation. 2018; 138:e426–e483
90. Jellinger PS, Handelsman Y, Rosenblit PD, Bloomgarden ZT, Fonseca VA, Garber AJ, et al. American Association of Clinical Endocrinologists and American College of Endocrinology Guidelines for management of dyslipidemia and prevention of cardiovascular disease - executive summaryComplete Appendix to Guidelines. Endocr Pract. 2017; 23:479–497. available at http://journals.aace.com/
91. Knowler WC, Fowler SE, Hamman RF, Christophi CA, Hoffman HJ, Brenneman AT, et al.; Diabetes Prevention Program Research Group. 10-year follow-up of diabetes incidence and weight loss in the diabetes prevention program outcomes study. Lancet. 2009; 374:1677–1686
92. Powers MA, Bardsley J, Cypress M, Duker P, Funnell MM, Fischl AH, et al. Diabetes self-management education and support in type 2 diabetes: a joint position statement of the american diabetes association, the american association of diabetes educators, and the academy of nutrition and dietetics. Clin Diabetes. 2016; 34:70–80
93. Gopalan A, Lorincz IS, Wirtalla C, Marcus SC, Long JA. Awareness of prediabetes and engagement in diabetes risk-reducing behaviors. Am J Prev Med. 2015; 49:512–519
94. American Diabetes Association. Overcoming Therapeutic Inertia.. https://professional.diabetes.org/meeting/other/overcoming-therapeutic-inertia. [Accessed March 2020]
Keywords:

diabetes; cardiovascular disease; quality of care

Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.