The emerging role of novel antihyperglycemic agents in the treatment of heart failure and diabetes: A focus on cardiorenal outcomes

Abstract

Heart failure (HF) and type 2 diabetes mellitus (T2DM) are two global pandemics, affecting over 25 and 420 million people, respectively. The prevalence of comorbid HF and T2DM is rising, and the prognosis remains poor. One central area of overlap of these two disease processes is renal dysfunction, which contributes to poor cardiovascular outcomes and mortality. As such, there is a growing need for antihyperglycemic agents with cardio‐ and renoprotective effects. Three classes of novel antihyperglycemic agents, sodium‐glucose cotransporter‐2 (SGLT2) inhibitors, glucagon‐like peptide‐1 receptor agonists (GLP‐1RA), and dipeptidyl peptidase‐4 (DPP4) inhibitors have demonstrated varied cardiorenal outcomes in recent cardiovascular outcomes trials. Understanding the differential effects of these agents, together with their proposed mechanisms, is crucial for the development of safe and effective treatment regimens and future pharmacologic targets for HF and T2DM. In this review, we discuss the overlapping pathophysiology of HF and T2DM, summarize outcomes data for the novel antihyperglycemic agents and proposed mechanisms of action, and review how the current evidence informs future management of comorbid HF and T2DM.

1. INTRODUCTION

Heart failure (HF) and type 2 diabetes mellitus (T2DM) are two increasing pandemics with worldwide prevalence estimates of more than 25 and 420 million people, respectively.1, 2 In addition, the prevalence of T2DM among patients with HF is disproportionately high, with estimates of approximately 40% in patients hospitalized with HF compared with 9% in the general population.1, 3 Reasons for this observed dual diagnosis include overlapping risk factors, pathophysiology, and comorbid conditions.4

Both HF and T2DM are associated with the development and exacerbation of chronic kidney disease (CKD), which is associated with poor prognosis. Patients with HF and T2DM have worse renal function and are more likely to develop worsening renal function during hospitalization, compared with those without T2DM.5, 6 Underlying renal dysfunction often limits guideline‐directed HF therapy and is related to worse cardiovascular outcomes.7 As the prevalence of HF and T2DM continues to rise, the need for antihyperglycemic agents with cardio‐ and renoprotective benefits is imperative.3

Recent trials exploring cardiovascular outcomes of three classes of novel antihyperglycemic drugs have shown mixed cardiorenal outcomes, and class effects have yet to be determined. Sodium‐glucose cotransporter‐2 (SGLT2) inhibitors have gained attention due to observed improvements in cardiovascular, HF, and renal outcomes.8, 9, 10 Several glucagon‐like peptide‐1 receptor agonists (GLP‐1 RA) have also been shown to improve cardiovascular outcomes and prevent renal dysfunction.11, 12, 13 The cardio‐ and renoprotective effects of dipeptidyl peptidase‐4 (DPP4) inhibitors are less clear, and studies of some agents suggest increased HF risk.14 Although studies designed to assess primary HF and renal outcomes are needed, results of these trials provide insight into potential treatment and areas of future study for comorbid HF and T2DM.

SGLT2 inhibitors, GLP‐1 RA, and DPP4 inhibitors exhibit multiple pleotropic effects, independent of glucose lowering actions.15, 16 The nature of these effects, some overlapping and others which may be unique to medication classes or individual agents, may help explain their differential cardiorenal outcomes. In this review, we discuss the overlapping pathophysiology of the cardiorenal axis in T2DM and HF. We review the major cardiorenal outcomes of SGLT2 inhibitors, GLP‐1 RA, and DPP4 inhibitors, proposed mechanisms, and future directions based on lessons learned from these agents.

2. CARDIORENAL INTERACTIONS IN HEART FAILURE AND T2DM

The interplay between T2DM and HF is complex and involves multiple metabolic, structural, autonomic, microvascular, and neurohumoral derangements.4 Complete explanation of these pathways is beyond the scope of this review and has been summarized previously.4 However, central to understanding the relationship between HF and T2DM is neurohumoral activation, altered glomerular hemodynamics, and resulting kidney injury (Figure 1).

Figure 1.

The figure exhibits how both a decrease in cardiac output in the setting of HF, as well as metabolic abnormalities in T2DM, such as increased adiposity and hyperinsulinemia, contribute to neurohumoral activation, alterations in sodium handling and renal hemodynamics, and ultimately congestion and renal dysfunction. RAAS activation causes increased systemic vascular resistance and intrarenal vascular resistance, predominately at the efferent arteriole, as well as increased sodium reabsorption in the proximal convoluted tubule by the sodium‐glucose cotransporter 2 (SGLT2) and the sodium‐hydrogen exchanger 3 (NHE3). Decreased solute delivery to the distal tubule is sensed by the macula densa, and through tubuloglomerular feedback, causes afferent arteriole dilation and further RAAS activation. SGLT2 is upregulated in T2DM, so this effect is magnified. Afferent arteriole dilation and efferent constriction lead to a maladaptive state of renal hyperfiltration, the hallmark of diabetic nephropathy. In HF, GFR further falls due to venous hypertension, intravascular under filling, and sympathetic activation. Other consequences of increased proximal absorption include decreased delivery of natriuretic peptides to the distal tubule, and the inability to escape aldosterone's effect of increased sodium reabsorption in the distal tubule, leading to significant edema formation. Finally, hyperglycemia induced production of intrarenal AngII and aldosterone contributes to podocyte injury and fibrosis and subsequent proteinuria. Abbreviations: Aldo, aldosterone; CO, cardiac output; GFR, glomerular filtration rate; Glu, glucose; H, hydrogen; K+, potassium; Na, sodium; NKCC2, Na‐K‐2Cl cotransporter; SNS, sympathetic nervous system; RBF, renal blood flow

In brief, decreased cardiac output in HF leads to activation of the sympathetic and renin‐angiotensin‐aldosterone systems (RAAS). Subsequent vasoconstriction, decreased renal perfusion, and increased proximal sodium reabsorption contribute to congestion and kidney injury. Venous congestion can lead to renal congestion, which further impairs blood flow to the kidney and glomerular filtration.17 In T2DM, SGLT2 expression is increased, further augmenting sodium reabsorption and worsening congestion.18 Evidence supports a positive correlation between metabolic syndrome and excess sympathetic and RAAS activation.19, 20 By preferentially constricting the efferent arteriole, AngII leads to intraglomerular hypertension, which contributes to nephropathy. Due to these overlapping processes, HF patients with T2DM are primed to develop renal dysfunction.

3. SODIUM‐GLUCOSE COTRANSPORTER‐2 INHIBITORS

SGLT2 inhibitors target the sodium‐glucose cotransporter, which normally mediates 97% of glucose reabsorption in the proximal convoluted tubule.18 SGLT2 inhibitors improve glycemic control by promoting glycosuria. Recent results of two landmark studies showed cardio‐ and renoprotective effects of SGLT2 inhibitors compared with placebo in patients with T2DM with or at risk for cardiovascular disease.

4. CARDIOVASCULAR AND HEART FAILURE OUTCOMES OF SGLT2 INHIBITORS

In the Empagliflozin, Cardiovascular Outcomes and Mortality in Type 2 Diabetes (EMPA‐REG OUTCOMES) trial, empagliflozin was associated with a reduction in major adverse cardiovascular events (MACE), a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. This was primarily driven by reduction in cardiovascular death.8 HF hospitalizations were also significantly reduced, irrespective of HF history (Table 1).10 In the Canagliflozin Cardiovascular Assessment Study (CANVAS), MACE was lower in the canagliflozin group, although individual components of MACE were not significant. There were fewer HF hospitalizations in the treatment group, but as death from any cause was not significantly different, due to prespecified conditional hypothesis testing, this was not considered significant (Table 1).21 In both studies, SGLT2 inhibitors were associated with modest decreases in glycated hemoglobin (HbA1c), weight, and systolic blood pressure without change in heart rate. Notably, canagliflozin was associated with greater number of amputations and fractures compared with placebo.21

Table 1.

Selected cardiovascular outcomes from clinical trials of SGLT2 inhibitors, GLP‐1RA, and DPP4 inhibitors

	Cardiovascular outcomesa
	MACEb	CV death	HF hospitalization
SGLT2 inhibitors
EMPA‐REG OUTCOME	0.86 (0.74‐0.99)	0.62 (0.49‐0.77)	0.65 (0.50‐0.85)
CANVAS	0.86 (0.75‐0.97)	0.87 (0.72‐1.06)	0.67 (0.52‐0.87)
GLP‐1RA
ELIXA	1.02 (0.89‐1.17)c	0.98 (0.78‐1.22)	0.96 (0.75‐1.23)
LEADER	0.87 (0.78‐0.97)	0.78 (0.66‐0.93)	0.87 (0.73‐1.05)
SUSTAIN‐6	0.74 (0.58‐0.95)	0.98 (0.65‐1.48)	1.11 (0.77‐1.61)
EXSCEL	0.91 (0.83‐1.0)	0.88 (0.76‐1.02)	0.94 (0.78‐1.13)
DPP4 inhibitors
SAVOR‐TIMI 53	1.00 (0.89‐1.12)	1.03 (0.87‐1.22)	1.27 (1.07‐1.51)
EXAMINE	0.96 (≤1.16)d	0.79 (0.60‐1.04)	1.19 (0.89‐1.58)
TECOS	0.98 (0.88‐1.09)c	1.03 (0.89‐1.19)	1.00 (0.83‐1.20)

Abbreviations: CV, cardiovascular; DPP4, dipeptidyl peptidase‐4; GLP‐1RA, glucagon‐like peptide‐1 receptor agonist; HF, heart failure; MACE, major adverse cardiac endpoints; SGLT2, sodium‐glucose contransporter‐2.

^aHazard ratios with 95% confidence intervals are reported.

^bAll trials except ELIXA and TECOS used three‐point MACE: composite outcome of CV death, nonfatal myocardial infarction, and nonfatal stroke.

^cELIXA and TECOS used a four‐point MACE: CV death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for unstable angina.

^dOne‐tailed test.

The effects of empagliflozin and canagliflozin on cardiovascular and HF outcomes were largely consistent. MACE, cardiovascular death, and HF hospitalizations were lower in both studies, although only the primary outcome, MACE, reached significance in CANVAS. Further studies, many of which are ongoing, will confirm whether these findings represent a class effect (NCT01730534, NCT0198688).

5. RENAL OUTCOMES OF SGLT2 INHIBITORS

In EMPA‐REG OUTCOMES, empagliflozin was associated with a lower incidence of worsening nephropathy, defined as progression to macroalbuminuria, doubling of the serum creatinine accompanied by estimated glomerular filtration rate (eGFR) ≤45 mL/min/1.73 m², initiation of renal replacement therapy or death from renal disease, with all components reaching significance except for death from renal disease (Tables 2 and 3).9 In the empagliflozin group, eGFR decreased modestly over the first 4 weeks, but then stabilized and returned to baseline following cessation of therapy, whereas eGFR gradually declined in the placebo group throughout the study. In CANVAS, progression of albuminuria, defined as more than 30% increase in albuminuria and a change from normo‐ to microalbuminuria or micro‐ to macroalbuminuria, was lower in the canagliflozin group. The composite outcome, sustained 40% reduction in eGFR, need for renal replacement therapy, or death from renal causes, also occurred less frequently with canagliflozin (Table 2).

Table 2.

Renal outcomes of interest defined

Outcome	Outcome definition
Composite outcomes
Incident or worsening nephropathya
EMPA‐REG OUTCOME	Progression to macroalbuminuria; doubling of the serum creatinine level and eGFR ≤45 mL/min/1.73 m2; initiation of renal‐replacement therapy; or death from renal disease
SUSTAIN‐6	Macroalbuminuria; persistent doubling of the serum creatinine level and eGFR ≤45 mL/min/1.73 m2; or the need for continuous renal‐replacement therapy
New‐onset persistent macroalbuminuria; persistent doubling of the serum creatinine level and eGFR ≤45 mL/min/1.73 m2; end stage renal disease (continuous renal replacement therapy); or death due to renal disease
Doubling of serum creatinine, initiation of dialysis, renal transplantation, or creatinine >6.0 mg/dL
40% reduction in eGFR, renal replacement therapy, or death from renal cause
Albuminuria
Progression to macroalbuminuria	Urinary ACR ratio, >300 mg of albumin per gram of creatinine
New‐onset persistent macroalbuminuria	Required two measurements to confirm persistence
Progression of albuminuria	>30% increase in albuminuria and a change from either normoalbuminuria to microalbuminuria/macroalbuminuria or from microalbuminuria to macroalbuminuria
Incident albuminuria in those with normal baseline albumin levels	Normal baseline: urinary ACR <30
Percent change in urine ACR
Mean change in urine ACR
Median urine ACR
Creatinine levels
Doubling of serum creatinine + eGFR ≤45 mL/min/1.73 m2
Persistent doubling of serum creatinine level	Required two measurements to confirm persistence
Other
Initiation of renal replacement therapy
Death due to renal disease
Mean difference in eGFR

Abbreviations: ACR, albumin‐to‐creatinine ratio; eGFR, estimated glomerular filtration rate.

^aNephropathy was defined differently in EMPA‐REG OUTCOMES and SUSTAIN‐6.

Table 3.

Selected renal outcomes from clinical trials of SGLT2 inhibitors, GLP‐1RA, and DPP4 inhibitors

	Renal outcome measure	Resulta	P‐value
SGLT2 inhibitors
EMPA‐REG OUTCOME	Incident or worsening nephropathy	0.61 (0.53‐0.70)	<0.001
	Progression to macroalbuminuria	0.62 (0.54‐0.72)	<0.001
	Doubling of serum creatinine + eGFR ≤45 mL/min/1.73 m2	0.56 (0.39‐0.79)	<0.001
	Initiation of renal replacement therapy	0.45 (0.21‐0.97)	0.04
	Incident albuminuria in those with normal baseline	0.95 (0.87‐1.04)	0.25
CANVAS	Progression of albuminuria	0.73 (0.67‐0.79)	n.a.
	40% reduction in eGFR, renal replacement therapy, or death from renal cause	0.60 (0.47‐0.77)	n.a.
GLP‐1RA
ELIXA	Percent change in urine ACRb (placebo vs lixisenatide)	+32% vs + 26%	0.07
LEADER	New‐onset persistent macroalbuminuria; persistent doubling of the serum creatinine level and eGFR ≤45 mL/min/1.73 m2; end stage renal disease (continuous renal replacement therapy); or death due to renal disease	0.78 (0.67‐0.92)	0.003
	New‐onset persistent macroalbuminuria	0.74 (0.60‐0.91)	0.004
	Persistent doubling of serum creatinine	0.89 (0.67‐1.19)	0.43
	Renal replacement therapy	0.87 (0.61‐1.24)	0.44
	Death due to renal disease	1.59 (0.52‐4.87)	0.41
SUSTAIN‐6	New or worsening nephropathy	0.64 (0.46‐0.88)	0.005
EXSCEL	Data to come	—	—
DPP4 inhibitors
SAVOR‐TIMI 53	Doubling of serum creatinine, initiation of dialysis, renal transplantation, or creatinine >6.0 mg/dL	1.08 (0.88‐1.32)	0.46
	Mean change in urine ACR (mg/g)	−34.3	<0.004
EXAMINE	Initiation of dialysis (placebo vs alogliptin)	22 vs 24c	0.88
TECOS	Median urine ACR	−0.18 (−0.35 to −0.02)d	0.031
	Mean difference in eGFR	−1.34 (−1.76 to −0.91)e	<0.0001

Abbreviations: ACR, albumin‐to‐creatinine ratio; CI, confidence interval; DPP4, dipeptidyl peptidase‐4; eGFR, estimated glomerular filtration rate; GLP‐1RA, glucagon‐like peptide‐1 receptor agonist; HR, hazard ratio; n.a., not available; SGLT2, sodium‐glucose contransporter‐2.

^aOutcomes are reported as HR with 95% CI, unless otherwise specified.

^bPercent change was estimated from baseline to 24 months, with post‐hoc adjustment for baseline and 3 month HbA1c levels.

^cAbsolute numbers of persons initiating dialysis.

^dEstimated overall mean difference in urine ACR in mg/g with 95% CI.

^eOverall estimated least squares mean difference in eGFR in mL/min/1.73 m² with 95% CI.

Although a direct comparison of renal outcomes of empagliflozin and canagliflozin is difficult, given differing composite renal outcomes and worsening albuminuria definitions, both offer significant renoprotection. Renal outcomes of canagliflozin will be further explored in patients with baseline renal dysfunction in the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study.22

6. PROPOSED CARDIORENAL MECHANISMS OF SGLT2 INHIBITORS

Multiple mechanisms have been proposed to explain the cardiorenal benefits of SGLT2 inhibitors including decreased plasma volume, uric acid levels and inflammation, increased natriuresis, and alteration in myocardial fuel.8, 15 Importantly, the cardiovascular benefits of empagliflozin occurred early in the study, suggesting that the observed benefits are independent of atherosclerosis or glycemic control.

SGLT2 inhibitors restore distal sodium delivery to the macula densa, counteracting the maladaptive tubuloglomerular feedback that contributes to hyperfiltration and volume expansion.8, 15 Increased sodium delivery to the loop of Henle and distal nephron promotes diuresis and likely augments the effects of other diuretics that inhibit sodium reabsorption distally. Decreased activity of the sodium‐hydrogen exchanger 3 (NHE3) may increase the diuretic effect.23 Increased distal sodium delivery may also enhance the effectiveness of natriuretic peptides and promote mechanisms of aldosterone escape. As congestion is the primary reason for HF hospitalization, these effects could explain in part the significant reduction in HF hospitalizations observed in clinical trials. Hemodynamic mechanisms may also explain results of a recent observational study that found that patients with HF and signs of fluid overload had improved exercise capacity and lower markers of congestion after 1 month of empagliflozin. To further support the importance of the diuretic and natriuretic effects of SGLT2 inhibitors, a recent exploratory analysis of the EMPA‐REG OUTCOME trial found markers of plasma volume, mainly hemoglobin and hematocrit, to be the most important mediators of reduction of CV death with empagliflozin.24

Nonhemodynamic mechanisms may also contribute to cardiorenal outcomes. In vivo mice studies suggest that attenuation of intrarenal RAAS by SGLT2 inhibition prevents diabetic nephropathy.25 SGLT2 inhibitors may also improve tubulointerstitial function by reducing renal cortical hypoxia. This may explain the observed rise in hematocrit not attributed to hemoconcentration alone.26 Multiple concurrent actions of SGLT2 inhibitors likely contribute to cardio‐ and renoprotective effects. Alteration of sodium handling and subsequent intrarenal and systemic hemodynamic changes may set this drug class apart from others.

7. GLUCAGON‐LIKE PEPTIDE‐1 RECEPTOR AGONISTS

GLP‐1 is an incretin hormone produced by intestinal enteroendocrine cells, which enhances insulin and suppresses glucagon secretion in a glucose‐dependent manner. Results of four major trials of GLP‐1RA compared with placebo in patients with T2DM and established or at risk for cardiovascular disease suggest variable cardiorenal protective effects.11, 12, 13, 27, 28

8. CARDIOVASCULAR AND HEART FAILURE OUTCOMES OF GLP‐1 RECEPTOR AGONISTS

In the Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial of postacute coronary syndrome patients there were no significant differences in MACE or HF hospitalizations between lixisenatide and placebo.27 In the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial, liraglutide was associated with significant reductions in MACE and cardiovascular death but no difference in HF hospitalizations.13 In the semaglutide and cardiovascular outcomes in patients with type 2 diabetes (SUSTAIN‐6) trial, semaglutide was associated with a significant reduction in MACE but no difference in HF hospitalizations or cardiovascular death.12 In the effects of once weekly exenatide on cardiovascular outcomes in type 2 diabetes (EXSCEL) trial, exenatide was not associated with a significant reduction in MACE (Table 1). A recent meta‐analysis of cardiovascular outcomes of GLP‐1RA in three trials found a 10% relative risk reduction (RRR) in MACE, 13% RRR in cardiovascular mortality, but no significant difference in hospitalization for HF.29 In all three trials, GLP‐1 RA were associated with a modest decrease in systolic blood pressure, weight and HbA1c, and a small but significant increase in heart rate.12, 13, 27 Of note, both liraglutide and semaglutide were associated with worsening retinopathy, although the effect was significant only in semaglutide.

HF outcomes of liraglutide were further analyzed in a smaller study of patients with chronic HF with reduced ejection fraction (HFrEF) with and without T2DM. Liraglutide had no effect on left ventricular systolic function after 24 weeks, but was associated with more adverse cardiac events, including worsening HF and ventricular tachycardia.30 In another trial of HFrEF patients recently hospitalized for acute HF, liraglutide had no effect on posthospitalization clinical stability.31

9. RENAL OUTCOMES OF GLP‐1 RECEPTOR AGONISTS

In the LEADER trial, patients in the liraglutide group had significantly lower risk of the composite renal outcome: new‐onset persistent macroalbuminuria, persistent doubling of the serum creatinine level, end‐stage renal disease, or death due to renal disease with benefits driven by lower incidence of macroalbuminuria.11, 13 Despite an overall decrease, eGFR in the liraglutide group was modestly better than placebo at 36 months (eGFR ratio 1.02; 95% confidence interval [CI] 1.00‐1.03). In SUSTAIN‐6, patients receiving semaglutide had lower risk of new or worsening nephropathy, defined as macroalbuminuria, persistent doubling of the serum creatinine level and eGFR ≤45 mL/min/1.73 m² or the need for continuous renal‐replacement therapy. In ELIXA, the change in urine albumin‐to‐creatinine ratio from baseline to 108 weeks was not significantly different between lixisenatide and control after accounting for HbA1c (Tables 2 and 3).27

10. PROPOSED CARDIORENAL MECHANISMS OF GLP‐1 RECEPTOR AGONISTS

Multiple potential mechanisms for cardio‐ and renoprotective effects of GLP‐1RA, beyond glucose control, exist. GLP‐1 receptors are expressed on cardiac endothelial cells and data suggest that GLP‐1 protects against myocardial ischemia. Consistent with the insulin‐like effect of inducing myocardial glucose uptake, short‐term infusion of GLP‐1 has been shown to improve left ventricular function in humans after coronary reperfusion.32 A reduction in atherosclerotic burden has also been suggested in humans.33 GLP‐1 is also expressed on renal endothelium, and GLP‐1 knockout mice develop worse nephropathy compared with wild‐type mice when exposed to hyperglycemia.34 In addition, GLP‐1 has a natriuretic effect, likely due to downregulation of NHE3 activity.35

Despite the cardiovascular and renal benefits observed in LEADER and SUSTAIN‐6, a reduction in HF hospitalizations similar to that of SGLT2 inhibitors was not observed. This may be because HF outcomes of SGLT2 inhibitors are driven primarily by hemodynamic effects and natriuresis achieved by GLP‐1 RA is less than SGLT2 inhibitors. That liraglutide had no beneficial effect and actually increased adverse events in HFrEF challenges a theoretical benefit of improved myocardial glucose metabolism. An increase in heart rate due to direct action of GLP‐1 on the sinoatrial node may prove detrimental in the HF population.36

11. DIPEPTIDYL PEPTIDASE‐4 INHIBITORS

DPP4 inhibitors block the degradation of incretins GLP‐1 and gastric inhibitory peptide (GIP), which promote insulin and inhibit glucagon release. Three trials evaluating the long‐term cardiovascular effects of DPP4 inhibitors have shown mixed results with respect to cardiorenal outcomes in patients with T2DM and established cardiovascular disease.37, 38, 39

12. CARDIOVASCULAR AND HEART FAILURE OUTCOMES OF DPP4 INHIBITORS

In the saxagliptin assessment of vascular outcomes recorded in patients with diabetes mellitus‐thrombolysis in myocardial infarction (SAVOR‐TIMI 53) trial, there was no significant difference in MACE between saxagliptin and placebo. Notably, there was an unexpected 27% increase in HF hospitalization among patients in the treatment group.37 Those with a history of HF, CKD, or elevated NT‐proBNP at baseline were at greatest risk, although no clear detrimental mechanism could be identified.40 In the alogliptin verses standard of care in patients with type 2 diabetes and acute coronary syndrome (EXAMINE) study, there was no significant difference in MACE between alogliptin and placebo. Alogliptin was associated with a nonsignificant increase in HF hospitalization. Post‐hoc analysis of patients at high cardiovascular risk showed increased incidence of HF hospitalization among patients without baseline HF (HR 1.76, 95% CI 1.07‐2.90). In the trial evaluating cardiovascular outcomes with sitagliptin (TECOS), there were no significant differences in MACE or HF hospitalization between sitagliptin and placebo (Table 1). Meta‐analysis of these three trials showed numerically increased but nonsignificant risk of HF hospitalization (HR 1.14, 95% CI 0.97‐1.34), with moderate heterogeneity between studies (P = 0.16, I ² = 44.9).41

13. RENAL OUTCOMES OF DPP4 INHIBITORS

In TECOS, sitagliptin was associated with a slight but sustained decrease in urine albumin‐to‐creatinine ratio over the 3‐year follow‐up period.42 Decreased albuminuria was also seen with saxagliptin.37 However, in TECOS, eGFR in the sitagliptin group was marginally but consistently lower than placebo throughout the study (Tables 2 and 3). This was not observed in SAVOR‐TIMI 53 or EXAMINE. The persistent decrease differs from the initial decline and subsequent stabilization of eGFR seen with empagliflozin.

14. PROPOSED CARDIORENAL MECHANISMS OF DPP4 INHIBITORS

The antihyperglycemic effect of DPP4 inhibitors is largely due to the delayed inactivation of intact GLP‐1. However, the DPP4 enzyme has multiple other targets. Increased levels of certain substrates (ie, natriuretic peptides) may favor cardioprotection, while others (ie, inflammatory chemokines) may favor detrimental ventricular remodeling.43 In fact, in vivo studies of acute and chronic DPP4 inhibition have shown preservation of myocardial function and cardiac fibrosis, respectively.16 In a recent review of HF and DPP4 inhibitors, Packer describes how increased stromal cell‐derived factor‐1 (SDF‐1) in the setting of DPP4 inhibition may contribute to cardiac fibrosis.43 These mechanisms may explain the potential increased HF risk associated with DPP4 inhibitors, but whether HF risk is due to medication‐specific or class effects continues to be debated.40, 43

DPP4 is also expressed on proximal tubular epithelial cells and may play a role in attenuating renal fibrosis and progression of diabetic nephropathy.44 Antifibrotic effects may explain the decrease in albuminuria in SAVOR‐TIMI and TECOS, but the renal effects of DPP4 inhibition deserve additional study. The natriuretic effect of DPP4 inhibitors is primarily a result of action at the distal tubule and is modest compared to GLP‐1RAs and SGLT2 inhibitors, which may contribute to HF outcomes observed.43

15. CLINICAL APPLICATIONS

Clinicians must be aware of the expanding evidence base for the role of antihyperglycemic agents in the treatment of patients with comorbid HF and T2DM. As demonstrated, study results are often inconsistent among drugs in a given class, potentially reflecting differences in study populations or within‐class variability. How then should clinicians make treatment decisions? Safety is paramount. The Food and Drug Administration (FDA) has added warnings of increased HF risk to saxagliptin and alogliptin; sitagliptin labeling also references these findings. Until more evidence is available, saxagliptin and alogliptin should not be preferred agents for patients with HF and T2DM. GLP‐1RAs may be a reasonable treatment choice due to the reduction in adverse cardiovascular outcomes. However, the adverse event profiles in smaller trials of HF patients raise concerns and more evidence is needed to determine class safety.30 SGLT2 inhibitors have the added benefit of improved HF outcomes. Empagliflozin has been FDA approved for the prevention of cardiovascular death and may be the preferred option for patients with HF and T2DM. In all patients, close monitoring of renal function, weight, vital signs, HbA1c, and screening for complications of T2DM are essential for monitoring disease progression and drug effects.

16. CONCLUSIONS AND FUTURE DIRECTIONS

Given the overlapping pathology of the cardiorenal axis in T2DM and HF, inhibition of proximal sodium reabsorption may benefit HF patients without T2DM. Of note, the proposed hyperfiltration mechanism of diabetic nephropathy stands in contrast to the maladaptive afferent arteriolar constriction in chronic HF. Current studies of empagliflozin and dapagliflozin in patients with chronic HF with and without T2DM will investigate whether the cardiorenal benefits of these agents can be extrapolated to the HF population (NCT03057951, NCT03057977, NCT03036124). Renal dysfunction in the setting of acute decompensated HF presents particular challenges for treatment and prognosis. The potential benefits of SGLT2 inhibitors in the acute setting, owing to distinct hemodynamic mechanisms, deserve further study.

While no HF benefits have been observed for GLP‐1RA, dedicated studies of GLP‐1RAs in HF with preserved ejection fraction (HFpEF) have yet to be conducted. HFpEF patients have a pro‐inflammatory phenotype, and given the proposed anti‐inflammatory mechanism of GLP‐1RA, there is potential for distinct benefits in HFpEF. While this may also be true of DPP4 inhibitors, more uncertainty exists surrounding cardiorenal safety. Ongoing studies may help elucidate the clinical impact of DPP4 inhibitors on HF and renal outcomes (NCT01897532). In addition, future trials to assess the comparative or combined effects of these antihyperglycemic agents, as well as those focusing on primary HF and renal outcomes are needed.

In conclusion, as the prevalence of comorbid HF and T2DM continues to rise, the safety and cardiorenal outcomes of antihyperglycemic agents must continue to be investigated in this high‐risk group. Outcomes of novel antihyperglycemic drugs have provided insight into potential pharmacologic targets and the interrelatedness of these disease entities. SGLT2 inhibitors, GLP‐1RA, and DPP4 inhibitors have shown varied cardiorenal effects, with SGLT2 inhibitors offering the most promising outcomes. Given the frequency and negative prognostic effect of renal dysfunction in both HF and T2DM, renal protection should be a major treatment goal and may have significant impact on cardiovascular and HF outcomes.

McHugh KR, DeVore AD, Mentz RJ, Edmonston D, Green JB, Hernandez AF. The emerging role of novel antihyperglycemic agents in the treatment of heart failure and diabetes: A focus on cardiorenal outcomes. Clin Cardiol. 2018;41:1259–1267. 10.1002/clc.23054