Clinical Update: Cardiovascular Disease in Diabetes Mellitus: Atherosclerotic Cardiovascular Disease and Heart Failure in Type 2 Diabetes Mellitus - Mechanisms, Management, and Clinical Considerations

Abstract

Cardiovascular disease remains the principal cause of death and disability among patients with diabetes mellitus. Diabetes mellitus exacerbates mechanisms underlying atherosclerosis and heart failure. Unfortunately, these mechanisms are not adequately modulated by therapeutic strategies focusing solely on optimal glycemic control with currently available drugs or approaches. In the setting of multifactorial risk reduction with statins and other lipid-lowering agents, antihypertensive therapies, and antihyperglycemic treatment strategies, cardiovascular complication rates are falling, yet remain higher for patients with diabetes mellitus than for those without. This review considers the mechanisms, history, controversies, new pharmacological agents, and recent evidence for current guidelines for cardiovascular management in the patient with diabetes mellitus to support evidence-based care in the patient with diabetes mellitus and heart disease outside of the acute care setting.

Keywords: cardiovascular diseases; diabetes mellitus; drugs; heart failure; trials.

Figure 1. Rates of vascular diseases are decreasing in persons with diabetes but are still higher than in persons without diabetes: Twenty years of surveillance

Age-standardized rates of selected vascular diseases in individuals with or without diabetes in the years 1990, 2000, and 2010. A: Acute myocardial infarction; B: Stroke; C: Amputation; D: End-stage renal disease. Red: Individuals with diabetes. Blue: Individuals without diabetes. Error bars indicate 95% confidence intervals. Data from Gregg EW, Li Y, Wang J, Burrows NR, Ali MK, Rolka D, Williams DE, Geiss L. New Engl J Med. 2014;370;1514–1523.

Figure 2. Development and progression of atherosclerosis in diabetes

Insulin resistance is present before the onset of pre-diabetes or diabetes, and increases progressively over time, while hyperglycemia develops in pre-diabetes and worsens with development of diabetes. Insulin resistance with impairment of insulin signaling, hyperinsulinemia and hyperglycemia contribute to multiple processes including elevated free fatty acids (FFA), advanced glycation end product (AGE) production, protein kinase C (PKC) activation, oxidative stress, mitochondrial dysfunction, and epigenetic modifications, which together contribute to endothelial dysfunction and inflammation resulting in activation of vascular smooth muscle cells (VSMC), endothelial cells (EC), and monocytes. Concentrations of modified (oxidized) LDL are higher in diabetes, and are retained in the subendothelial layer of vulnerable sections of the vasculature. Circulating leukocytes attach and migrate through the endothelial wall into the VSMC layer of the intimal media. These monocytes engulf retained lipoproteins and transform into lipid-laden foam cells/macrophages producing proteinases and inflammatory mediators including tumor necrosis factor alpha (TNF-α) and interleukins. Stress responses including inflammasome complex formation and endoplasmic reticulum (ER) stress result in macrophage proliferation and inflammatory activation with resultant macrophage and VSMC phenotypic switch (proliferation, migration, and dedifferentiation). In response to vascular injury, VSMC secrete collagen to form a fibrous cap, which promotes atherosclerotic plaque stability. However, when stable lesions remodel inward, progressive stenosis of arteries occurs. Plaques can become vulnerable with thinning of the fibrous cap and apoptosis of macrophages in advanced atherosclerotic lesions, where impaired efferocytosis (phagocytic clearance) of lipid laden macrophages results in formation of a necrotic core accelerating vascular inflammation, necrosis, thrombosis. The resulting unstable atherosclerotic lesion complex is prone to sudden expansion from acute thrombus formation forming a nidus for platelet thrombosis, hemorrhage of atherosclerotic plaque microvessels, and rupture of the fibrous cap. AGE: advanced glycation end-product. Akt: protein kinase B. EC: endothelial cell. NOS: nitric oxide synthase. ER: endoplasmic reticulum. ER: endoplasmi reticulum. ERK: extracellular signal-regulated kinase. FFA: free fatty acids. GlcNAc: N-Acetylglucosamine. IL: interleukin. JNK: c-Jun N-terminal kinase. LDL: low-density lipoprotein. MAPK: mitogen-activated protein kinase. NF-κβ: nuclear factor-kappa beta. NO: nitric oxide. PKC: protein kinase C. PI3K: phosphoinositide 3-kinase. ROS: reactive oxygen species. RNS: reactive nitrogen species. TNF-α: tumor necrosis factor-alpha. VSMC: vascular smooth muscle cell.

Figure 3. Cardiovascular outcomes in two recent blood pressure lowering trials in patients with and without baseline diabetes

Outcomes data for blood pressure-lowering trials in a high-risk population without diabetes: SPRINT (Systolic Blood Pressure Intervention Trial, n=9,361) and in a high risk population with diabetes: ACCORD (Action to Control Cardiovascular Risk in Diabetes, n=4,733). SPRINT was conducted in patients without Diabetes and ACCORD in patients with diabetes. Although reduction in individual outcomes did not reach statistical significance in ACCORD except for stroke, tendencies for benefits are similar and combining ACCORD with SPRINT demonstrated reduction in primary outcome and individual components with intensive treatment. Reprinted with permission from Perkovic V, Rodgers A. N Engl J Med. 2015;373(22):2175–8.

Figure 4. Comparison of data from contemporary trials for aspirin in primary prevention of ASCVD in diabetes

JPAD (Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes, n=2,539) and POPADAD (Prevention of Progression of Arterial Disease and Diabetes, n=1,276). Although there was a trend toward reduction in ischemic outcomes with aspirin therapy for primary prevention in diabetes in both trials (except for CHD or stroke death in POPADAD), there were very few events, highlighting an area of potential controversy in ASCVD risk reduction.

Figure 5. Randomized, controlled, cardiovascular outcome trials of glucose-lowering drugs or strategies in people with type 2 diabetes

ACS=acute coronary syndrome; ASCVD=atherosclerotic cardiovascular disease including myocardial infarction or ischemic stroke; CV risk=increase risk for cardiovascular disease based on risk factors, but not ischemic ASCVD; HR=hazard ratio; MACE=major adverse cardiovascular event: cardiovascular mortality, myocardial infarction, stroke; RRR=relative risk reduction; SFU=sulfonylurea. T₂DM=type 2 diabetes mellitus; MACE=cardiovascular mortality, myocardial infarction, stroke. Studies: ACCORD, Action to Control Cardiovascular Risk in Diabetes; ACCORDION, ACCORD Follow-on study; ADDITION, Intensive Treatment in People With Screen Detected Diabetes in Primary Care; ADVANCE, Action in Diabetes and Vascular Disease Preterax and Diamicron MR Controlled Evaluation; BARI 2D, Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes; DIGAMI₂, Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction; ELIXA, Evaluation of Cardiovascular Outcomes in Patients With Type 2 Diabetes After Acute Coronary Syndrome During Treatment With Lixisenatide; EMPA-REG OUTCOME, (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; EXAMINE trial, EXamination of cArdiovascular outcoMes with alogliptIN versus standard of care; HEART2D, Hyperglycemia and its Effect After Acute Myocardial Infarction on Cardiovascular Outcomes in patients with Type 2 Diabetes; Look AHEAD, Action for Health in Diabetes; ORIGIN, Outcome Reduction With Initial Glargine Intervention; PROactive, PROspective pioglitAzone Clinical Trial In macroVascular Events; RECORD, Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes; SAVOR-TIMI53, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53; Steno-2, Multifactorial Intervention in Type 2 Diabetes at the Steno Diabetes Center;^, TECOS, Trial Evaluating Cardiovascular Outcomes With Sitagliptin; UKPDS, United Kingdom Prospective Diabetes Study;^,, VADT, Veterans Affairs Diabetes Trial.^, Reference: Data taken from Holman RR, Sourij H, Califf RM. Cardiovascular outcome trials of glucose-lowering drugs or strategies in type 2 diabetes. Lancet. 2014;383:2008–2011.

Figure 6. Pathophysiologic mechanisms of heart failure in diabetes

Hyperglycemia, insulin resistance, and hyperinsulinemia, the main physiologic disturbances in diabetes, contribute to atherosclerotic cardiovascular disease (ASCVD), hypertension, and multiple derangements of cellular metabolism, function, and structure, as well as activation of the renin-angiotensin-aldosterone system (RAAS). The different cardiomyopathies that result from these processes clinically present as heart failure in diabetes. AGE, advanced glycation end-product; FFA, free fatty acids.