Targeting Multiple Domains of Residual Cardiovascular Disease Risk in Patients with Diabetes

Abstract

Purpose of review:

There has been a recent resurgence of diabetes-related cardiovascular complications after years of steady improvement. This review highlights established and emerging contemporary secondary prevention approaches that lower the risk of atherosclerotic and non-atherosclerotic cardiovascular disease events among patients with diabetes.

Recent findings:

Secondary prevention therapies modify residual risk targets, including cardiometabolic pathways, lipoproteins, thrombosis, and inflammation. Large-scale clinical trials of sodium-glucose cotransporter-2 inhibitors have demonstrated significant reductions in hospitalization for heart failure. Glucagon-like peptide-1 receptor agonists have reduced the risk of major adverse cardiovascular events. Recent clinical trials provide evidence supporting the use of non-statin lipid-lowering therapies, novel antiplatelet and anticoagulant strategies, and anti-inflammatory strategies in select cases.

Summary:

Therapeutic approaches targeting multiple distinct pathways have been shown to improve cardiometabolic risk in diabetes. Individual patient characteristics and consideration of residual risk targets may help guide selection of comprehensive secondary prevention approaches.

INTRODUCTION

Cardiovascular disease (CVD) is the leading cause of death among patients with diabetes [1]. The presence of both diabetes and established CVD identifies an especially high-risk patient cohort [2]. While historical management strategies aiming to mitigate CVD risk narrowly focused on glycemic control, recent paradigms have shifted towards more comprehensive risk management approaches [3]. CVD event rates have declined with improved risk factor control over time [1, 4]. However, there has been a resurgence in observed rates of myocardial infarction (MI), stroke, and peripheral artery disease among young and middle-aged adults with diabetes [**5]. Furthermore, residual risk of heart failure (HF) persists despite achieving target levels of traditional risk factors [6]. Recent clinical trial evidence supports the use of several cardioprotective therapies to address residual risk of CVD but prescription of these guideline-recommended medications has been suboptimal [**7].

Given the evolving epidemiology and growing number yet limited use of evidence-based therapies available for secondary prevention, we will discuss contemporary strategies for secondary prevention of CVD in diabetes. Secondary prevention has traditionally focused on reducing the risk of atherosclerotic CVD (ASCVD) events. However, patients with diabetes are at increased risk for systemic CVD and broad organ protection is warranted. Modification of lifestyle risk factors, smoking cessation, statin therapy, blood pressure control, and antiplatelet therapy remain the foundation for secondary prevention and are highlighted in the American Heart Association and American College of Cardiology Foundation guidelines [8]. This review will highlight additional contemporary preventive strategies to reduce the risk of subsequent ASCVD, HF, and other adverse health outcomes among patients with type 2 diabetes.

Target causal pathways:

Most patients with a prior history of ASCVD are eligible for multiple preventive therapies that have demonstrated benefits in cardiovascular (CV) outcomes trials [9]. Findings from recent studies suggest that an individualized approach targeting the underlying biology may prevent future CVD events [10]. Residual risk targets have been proposed to identify potential causal pathways as well as the associated disease modifying strategies [11]. In this review, we will discuss secondary prevention therapies within the context of the following residual risk targets: cardiometabolic pathways, lipoproteins, thrombosis, and inflammation.

CARDIOMETABOLIC PATHWAYS

The close relationship between poor glycemic control and increased risk of CVD led to multiple clinical trials evaluating the effects of intensive glycemic control in diabetes [12]. However, strict glucose control has failed to improve important CV outcomes and even led to increased harm in select settings [13]. Previously, there were no diabetes therapies available that had consistently demonstrated survival benefits or protection against macrovascular complications or HF. In 2008, the US Food and Drug Administration issued an industry-wide guidance that required large-scale clinical trials to evaluate CV outcomes of emerging antihyperglycemic medications, and in turn prompted a wave of high-quality clinical science of the health effects of antihyperglycemic therapies [14]. In recent clinical trials, sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RA) demonstrated CV, kidney, and mortality benefits (Table 1) [15–23].

Table 1.

Summary of selected cardiovascular outcome trials of 2 classes of antihyperglycemic therapies demonstrating cardiovascular benefits

	SGLT-2 inhibitors					GLP-1RAs
Medication	Empagliflozin	Canagliflozin		Dapagliflozin		Liraglutide	Semaglutide	Albiglutide	Dulaglutide
Clinical trial	EMPA-REG OUTCOME [15]	CANVAS Program [16]	CREDENCE [17]	DECLARE-TIMI 58 [18, 26]	DAPA-HF [19] *	LEADER [20]	SUSTAIN-6 [21]	Harmony Outcomes [22]	REWIND [23]
Secondary prevention, %	100%	65.6%	50.4%	40.6%	100%	81.3%	83.0%	100%	31.5%
MACE	↓	↓	↓	↔	-	↓	↓	↓	↓
CV death	↓	↔	↓	↔	↓	↓	↔	↔	↔
MI	↔	↔	-	↔	-	↔	↔	↓	↔
Stroke	↔	↔	-	↔	-	↔	↓	↔	↓
Hospitalization for HF	↓	↓	↓	↓	↓	↔	↔	↓	↔
Atrial fibrillation	-	-	-	↓	-	-	-	-	-
Expanded FDA labels in type 2 diabetes	↓ CV death	↓ MACE; in albuminuric diabetic kidney disease: ↓ renal disease progression, ↓ CV death, ↓ HF hospitalization		↓ HF hospitalization (**)		↓ MACE	↓ MACE	(withdrawn from market)	↓ MACE

^*DAPA-HF: all participants had HF with reduced ejection fraction and thus are considered secondary prevention. At baseline, 42% of trial participants had diabetes.

^**Data from DAPA-HF is currently under review for consideration in patients with HF with reduced ejection fraction.

Green = significant reduction; orange = no significant difference; blue = unknown effect.

CV = cardiovascular; FDA = Food and Drug Administration; GLP-1RAs: glucagon-like peptide-1 receptor agonists; HF = heart failure; MACE = major adverse cardiovascular events; MI = myocardial infarction; SGLT-2 = sodium-glucose cotransporter-2.

Sodium-glucose cotransporter-2 inhibitors:

SGLT-2 is a protein predominantly expressed in the proximal tubule of the nephron responsible for the avid reuptake of glucose from fluid filtered by the kidney. Inhibition of SGLT-2 prevents the reclamation of filtered glucose and subsequently leads to glucosuria and reductions in blood glucose, weight, and blood pressure. In the EMPA-REG OUTCOME trial, among patients with diabetes and a prior history of ASCVD, empagliflozin was not only safe but also was unexpectedly shown to significantly reduce the risk of major adverse CV events (MACE), a composite of MI, stroke, or death from CV causes [15]. Empagliflozin also led to a 38% lower risk of CV death and 35% lower risk of hospitalization for HF. The CV benefits of other SGLT-2 inhibitors, especially with respect to HF risk reduction, were confirmed in separate clinical trials. In the CANVAS program (of patients with type 2 diabetes with and without ASCVD) and the CREDENCE trial (of patients with albuminuric diabetic kidney disease), canagliflozin reduced the risk of hospitalization for HF [16, 17]. Similarly, dapagliflozin lowered the risk of HF events in the DECLARE-TIMI 58 clinical trial [18]. Recent pooled analyses suggest that the CV benefits of SGLT-2 inhibitors may vary according to whether they are used for primary versus secondary prevention of ASCVD [*24, 25]. The beneficial effect of SGLT-2 inhibitors for MACE and CV death appears to be limited to patients with a prior history of ASCVD. In contrast, SGLT-2 inhibitors reduced the risk of hospitalization for HF and kidney outcomes irrespective of prior history of ASCVD.

As it became quickly apparent that SGLT-2 inhibitors prevent HF events in patients with type 2 diabetes, whether they may be effective in treatment of HF in patients with and without diabetes is now being investigated in a number of dedicated clinical trials. In the landmark DAPA-HF trial, patients with HF with reduced ejection fraction with (42%) and without diabetes (58%) who were randomized to receive dapagliflozin had a lower risk of the primary composite outcome of worsening HF or CV death [*19]. The beneficial effects of dapagliflozin were remarkably similar regardless of diabetes status. The CV benefits of SGLT-2 inhibitors may extend to other non-fatal outcomes. In a post-hoc analysis of the DECLARE-TIMI 58 trial, dapagliflozin also reduced the incidence of atrial fibrillation similarly in patients with and without established ASCVD [26]. In addition, the class has consistently been shown to reduce clinically important kidney outcomes and offer nephroprotection against subsequent episodes of acute kidney injury [27]. Beyond their capacity for glycemic control, the Food and Drug Administration (FDA) now has offered additional labels for the use of empagliflozin (to reduce CV death), canagliflozin (to reduce MACE), and dapagliflozin (to reduce HF events) in patient with at-risk diabetes. In addition, canagliflozin is approved to reduce HF events and prevent end-stage kidney disease, doubling of serum creatinine, and CV death in patients with albuminuric diabetic kidney disease.

Glucagon-like peptide-1 receptor agonists:

Intestinal cells release glucagon-like peptide-1 in response to food intake. Glucagon-like peptide-1 binds to its receptor in the pancreas and leads to glucose-appropriate insulin secretion which can lead to lower blood glucose levels. In the LEADER trial, among patients with diabetes and either established ASCVD or multiple risk factors, liraglutide reduced risk of MACE by 13% and CV death by 22% [20]. Multiple other GLP-1RAs demonstrated CV benefits in large-scale clinical trials. Specifically, semaglutide, albiglutide (which has since been removed from the global market), and dulaglutide each significantly reduced the risk of MACE among patients with diabetes who had high risk of CVD [*28]. The FDA has extended the labels of liraglutide, semaglutide, and dulaglutide to reduce MACE. The AMPLITUDE-O trial (NCT03496298) is evaluating the CV effects of a long-acting GLP-1RA, efpeglenatide, and the SOUL trial (NCT03914326) is studying oral semaglutide in at-risk patients with diabetes.

Pioglitazone:

Thiazolidinediones are insulin-sensitizing therapies that have reduced metabolic and inflammatory markers in patients with diabetes [29]. The improvement in subclinical markers of CVD suggested that cardiometabolic and inflammatory pathways may underlie the cardioprotective effects of pioglitazone. In the PROactive study examining patients with diabetes and a history of ASCVD, pioglitazone did not reduce the main secondary composite outcome of all-cause death, non-fatal MI, and stroke [30]. However, a post-hoc analysis examining patients with a history of stroke revealed that pioglitazone reduced the rate of stroke [31]. These findings led to the IRIS trial that enrolled patients with a recent history of an ischemic stroke or transient ischemic attack who had insulin resistance but not diabetes. In the IRIS trial, participants randomized to pioglitazone had a lower risk of a composite of stroke or MI [32].

Metabolic surgery:

Obesity and diabetes are often comorbid conditions and each intersect to increase the risk of CVD [33]. Metabolic surgical procedures can lead to significant weight loss and improvements in biomarkers of cardiometabolic pathways, lipoproteins, thrombosis, and inflammation [34]. Randomized clinical trials of metabolic surgery have examined surrogate endpoints and demonstrated significant improvements in weight and risk factor control [33]. In the STAMPEDE trial, among patients with type 2 diabetes and obesity, bariatric surgery combined with intensive medical therapy led to significant reductions in glycated hemoglobin and durable resolution of cardiometabolic disease over 5-year follow-up [35].

LIPOPROTEINS: focusing on non-statin therapies

Diabetic dyslipidemia is typically characterized by high triglycerides, low high-density lipoprotein cholesterol (HDL-C), and greater concentration of small-dense low-density lipoprotein cholesterol (LDL-C) [36]. LDL-C is a key modifiable risk factor and important target for secondary prevention therapies [8]. Ezetimibe blocks the absorption of cholesterol from the intestine and lowers LDL-C. In the IMPROVE-IT trial, patients with recent acute coronary syndrome were all prescribed simvastatin and randomly assigned to receive either ezetimibe or placebo [37]. The risk of adverse CV events was significantly lower with ezetimibe compared with placebo. Furthermore, the beneficial CV effects of ezetimibe differed according to diabetes status such that patients with diabetes were more likely to benefit [38].

Variations in the proprotein convertase subtilisin-kexin type 9 (PCSK9) gene are associated with significantly lower levels of LDL-C and risk of coronary heart disease [39]. In two large clinical trials (FOURIER, ODYSSEY OUTCOMES) of patients with a prior history of ASCVD, PCSK9 inhibitors (evolocumab, alirocumab) led to dramatic declines in LDL-C and reduced the risk of CV events [40, 41]. PCSK9 inhibitors led to similar relative risk reductions among patients with and without diabetes [42, 43].

Increased concentration of triglycerides is seen in diabetes and has been the target of multiple classes of therapies [36]. Multiple formulations of omega-3 fatty acids did not lead to CV benefits when added to statin therapy in previous clinical trials. In the REDUCE-IT trial, among patients with elevated triglycerides while taking statin therapy who had a prior history of CVD or diabetes with an additional risk factor, high-dose icosapent ethyl (highly purified eicosapentaenoic acid) significantly reduced a broad range of CV events, including CV death, compared with mineral oil placebo [*44]. While enrollment was enriched for patients with elevated triglycerides, relative risk reduction was observed across a broad range of baseline triglyceride levels [45].

Fibrates can lower triglycerides and raise HDL-C. In the PROMINENT study, the CV effects of the highly potent, selective peroxisome proliferator-activated receptor alpha modulator pemafibrate will be examined among patients with diabetes, which has now fully enrolled (NCT03071692) [46].

THROMBOSIS

Primary Prevention:

The “diabetic platelet” is a term used to describe the enhanced platelet aggregation that predisposes patients with diabetes to higher risk for thrombotic events [47]. Aspirin inhibits platelet aggregation and has been evaluated in several historic clinical trials for primary prevention of CVD [48]. However, in the contemporary era with greater use of statins, routine use of aspirin for primary prevention is not recommended and its CV benefits should be considered in the context of bleeding risk [49].

Secondary Prevention in Stable ASCVD:

Secondary prevention strategies to combat the heightened thrombotic state in diabetes include aspirin therapy combined with an additional antiplatelet agent, commonly referred to as dual-antiplatelet therapy (DAPT). Soon after an ASCVD event, patients are recommended DAPT for at least 12 months [8]. However, the role of DAPT is less clear among patients with diabetes and stable CV disease. In the THEMIS trial, the largest clinical trial of patients with diabetes completed to date, over 19,000 patients with diabetes and a history of stable coronary artery disease but no history of an MI or stroke were randomly assigned to ticagrelor or placebo on the background of aspirin [*50]. Patients who were assigned to ticagrelor therapy had a lower rate of MACE but increased rate of bleeding. In a pre-specified subgroup analysis of patients who had a prior history of percutaneous coronary intervention enrolled in the THEMIS trial, patients randomly assigned to ticagrelor had a 15% lower rate of irreversible harm events defined as a composite of all-cause death, MI, stroke, fatal bleeding, or intracranial hemorrhage [51].

In the COMPASS trial, patients with stable ASCVD were randomly assigned to one of the following treatments: 1) aspirin monotherapy; 2) rivaroxaban 5 mg twice daily monotherapy; 3) aspirin plus rivaroxaban 2.5 mg twice daily [52]. Patients randomly assigned to aspirin plus rivaroxaban 2.5 mg twice daily had fewer CV events but more major bleeding events than those assigned to aspirin monotherapy. However, there was no significant difference in fatal bleeding or symptomatic intracranial hemorrhage between these two groups. The combination of aspirin and rivaroxaban 2.5 mg twice daily appeared to have a beneficial profile among patients with and without diabetes.

INFLAMMATION

Diabetes is associated with systemic inflammation, a potential pathophysiologic determinant of both atherosclerotic and non-atherosclerotic CVD events. Observational data suggests that C-reactive protein, a marker of systemic inflammation, is an important predictor of ASCVD and HF events [53, 54]. The interleukin-1-to-interleukin-6 inflammatory pathway may be involved in the pathogenesis of atherothrombotic disease based on findings from the CANTOS trial [10]. Colchicine is a potent anti-inflammatory agent that inhibits microtubule generation and may affect the inflammatory complex. Among patients with a recent MI in the COLCOT trial, colchicine reduced the risk of a composite of ischemic CV events compared with placebo [*55]. Furthermore, subgroup analysis revealed that the benefit of colchicine may be greater in patients with diabetes. A separate clinical trial (COLCOT-T2D) has been proposed to examine the CV effects of colchicine in patients with type 2 diabetes.

SECLECTION OF SECONDARY PREVENTION THERAPIES

Currently, there are several distinct classes of established and recently introduced therapies that target residual risk pathways among patients with diabetes. In considering appropriate treatment candidates, optimal control of traditional risk factors highlighted in the current guideline for secondary prevention remains critically important, including advancing best lifestyle habits [8]. In selecting optimal therapeutic regimens, a framework for addressing residual ASCVD risk has been proposed and broader application of residual risk targets to HF and other CV conditions should be evaluated [11]. Medications that have demonstrated CV efficacy in well-conducted clinical trials should be prioritized ahead of those therapies without proven CV benefits. However, given a growing list of effective therapies, costs and polypharmacy may ultimately pose barriers to long-term treatment adherence, which may in turn limit the effectiveness of these therapies when delivered in practice. Unique adverse events may guide prioritization of therapies in patients who qualify for multiple therapies; for instance, a patient at high ASCVD risk with recurrent coronary events who also faces elevated bleeding risks may benefit from GLP-1RA and additional effective non-statin therapeutic options. That said, while the safety of each of these therapies has been independently evaluated in dedicated CV outcomes trials, specific combinations or sequencing of distinct therapeutic classes has not been rigorously evaluated. Patients with diabetes have multiple comorbid conditions requiring multiple medications, several care teams, and coordination of care. Understanding patients’ goals, priorities, adherence patterns, and therapeutic affordability will be important as we move towards an individualized approach to CV and diabetes care.

CONCLUSION

Paralleling the recent rise in diabetes-related CVD complications, there has been an expansion in evidence regarding secondary prevention therapies available for patients with diabetes. SGLT-2 inhibitors and GLP-1RAs represent first-line antihyperglycemic options to reduce a broad range of cardiovascular, kidney, and mortality outcomes. Several other secondary prevention therapies are available that target unique residual risk pathways. Evidence-based strategies for selection of beneficial therapies amongst the expanding list of available options are greatly needed.

KEY POINTS.

• Among patients with type 2 diabetes with or at-risk for cardiovascular disease, sodium-glucose cotransporter-2 inhibitors significantly prevent heart failure events.

• Glucagon-like peptide-1 receptor agonists lower the risk of major atherosclerotic cardiovascular events in patients with diabetes at high cardiovascular risk.

• Several novel strategies for secondary prevention of cardiovascular disease events in diabetes are emerging, including therapies targeting residual lipoprotein, thrombosis, and inflammation risk.