New Developments in Cardiorenal Protection in Type 2 Diabetes Mellitus

Cardiorenal complications represent advanced stages of progression for type 2 diabetes mellitus (T2DM).

These complications are two major drivers of DM-related mortality and morbidity. Results of Cardiovascular Outcome Trials (CVOTs) on some recently developed agents suggest that possible ways now exist to mitigate these destructive cardiorenal vasculopathies.

This review focuses on currently available CVOT findings for two classes of agents in particular: sodium glucose cotransporter 2 (SGLT-2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1 RAs).

DM and the Deadly Impact of Comorbid Cardiovascular and Renal Diseases

Diabetes mellitus (DM) has come to be viewed as having reached pandemic status worldwide. According to the International Diabetes Federation (IDF) Diabetes Atlas, 9th Edition, one of every 11 adults around the world currently lives with this disease, and even more alarmingly, one of every two adults who now has DM is undiagnosed.¹

This population requires relevant and appropriate risk cover and support from the insurance industry. However, as DM is highly heterogeneous in phenotype, clinical presentation, metabolic profile, progression, and control, insurers must be vigilant in monitoring its ever-changing epidemiology as well as mortality trends driven by clinical advances.

Cardiovascular Diseases

Over the past several decades, cardiovascular disease (CVD) mortality has been decreasing among general populations in high-income countries. A reduction in CVD risk has also been observed among people living with DM in these countries, but as prevalence of DM has risen, so will the number of people with CVD.

CVD is the chief cause of death in DM. Observational studies in the U.S., Canada, Australia, and Iceland report an approximate 50% reduction in the relative risk of CVD mortality in the general population, but excess risk of death due to CVD in DM populations is approximately two to four times that of non-DM populations. It is also estimated that about 50% of individuals with type 2 diabetes (T2DM) will die of it, with the majority of deaths due to coronary artery disease, followed by stroke.^{1, 2} The IDF estimates that in high-income countries, prevalence of CVD among those with DM may be as high as 16% in the younger (28-44) age band, and jumps to 41% for those in the 56-66 age band. In study groups where the mean age was 53-67, prevalence of stroke ranged from 3.5% to 10%.³

Insufficient data exists about CVD prevalence among DM populations in low-income countries, but approximately 75% of those with DM are known to live in low- and middle-income countries, and DM prevalence in those countries is known to be accelerating.³ 

In terms of heart failure (HF) specifically, T2DM confers a two- to five-fold excess risk of its development. For those living with both existing HF and T2DM, the latter confers a 60% to 80% higher risk of death. In addition, the association between DM and HF is bidirectional; among individuals with HF, DM prevalence is four times higher.⁵

DM also worsens prognoses for individuals who experienced HF with reduced ejection fraction (HFrEF) and those who experienced preserved ejection fraction (HFpEF).⁴ For people living with DM who are 65 or older with existing HF, risk of death leaps tenfold.⁵

Diabetic Nephropathy

The coexistence of chronic kidney disease (CKD) and DM fuels an additive effect on mortality and morbidity: higher risk for arrhythmia, acute coronary syndrome, and congestive heart failure; and earlier and higher mortality rates during and after hospitalization.^{4, 7}

Globally, diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD). This microangiopathic condition is found in approximately 30% of those with type 1 diabetes mellitus (T1DM) and 40% of those with T2DM. As the worldwide prevalence of DM increases, so does that of DN, and its prevalence is further exacerbated by longer survivals of affected individuals due to improved DM management.² In addition, DN-associated mortality, which rose a dramatic 94% from 1990 to 2012, is now considered responsible for most of the excess mortality risk in DM as well as a significant driver of cardiac mortality.⁶

ESRD is expected to cause a significant worldwide future disease burden. Although incidence has been declining in Scandinavian countries and Australia, increases have been detected in several other countries, including the U.S., the Republic of Korea, and Singapore.² As global prevalence of DM is projected to reach a staggering 700 million by the year 2045, the correlating increase in ESRD is expected to be devastatingly high as well.¹

Pathophysiological Mechanisms in DM-Related Kidney Disease

Although vascular dysfunction due to ongoing hyperglycemia may be the precipitating event for DN, DN results from a multidimensional and multicellular process. Its progression is driven by hyperglycemia and hypertension, two key risk factors which are exacerbated by oxidative stress, inflammation, and fibrosis.⁸

The pathophysiological development of DN begins with a thickening of the glomerular basement membrane (BM), coupled with tubular and capillary BM thickening. Next comes loss of endothelial fenestration, with mesangial enlargement, glomerular hypertrophy, and loss of podocytes. Subsequent mesangiolysis, associated with exudative obstructions of small arterioles, glomerular capillaries, and microaneurysms, further compromises the integrity of the glomerulus. Late stages in the development of DN are characterized by interstitial inflammation and glomerulosclerosis.^{6, 8}

These processes are accompanied by hemodynamic alterations, including rising intra-glomerular pressures, hyperfiltration, and changes in permeability, leading to progressive albuminuria.^{8, 9}

The renin-angiotensin-aldosterone system (RAAS) is also implicated in altered kidney function in DM. In early DM, a rise in arterial pressure and renal vascular resistance can be observed, accompanied by increased renin activity.⁹

The two main characteristics of DN are progressive albuminuria and declining estimated glomerular filtration rate (eGFR). Renal damage correlates to the duration and magnitude of hyperglycemia, with incidence beginning to rise after 10 years of DM. DN generally manifests as some degree of proteinuria, which may progress to ESRD. Subsequent renal replacement therapy or transplant are both associated with high morbidity and mortality.^{8, 9, 10} 

It should be noted that in DM, proteinuria does not correlate absolutely to deteriorating glomerular filtration. Microalbuminuria (albumin loss of between 30 and 300 mg/day) may regress, as seen in the Diabetes Control and Complications Trial (DCCT) and Epidemiology of Diabetes Interventions and Complications (EDIC) follow-up study of T1DM cohorts after six to 10 years of optimal DM management. Also, in some, DN develops without any preceding albuminuria, as seen in the United Kingdom Prospective Diabetes Study (UKPDS), which looked at clinical and therapeutic implications for people with T2DM.¹⁰ In addition, and more importantly, approximately 40% of the T2DM cohort in the UKPDS study did not develop renal dysfunction.

A small long-term U.S. study also showed that in the absence of renal disease, 20-year mortality risk for individuals with T1DM did not increase compared with the general population.¹¹

Pathophysiological Mechanisms in DM-Related Cardiovascular Disease

In CVD, DM is an independent risk factor. The two conditions share many metabolic dysfunctions, including obesity, hypertension, and hyperlipidemia.

Multiple health factors can increase CVD risk for those with DM, including:¹²

• hyperglycemia
• hyperinsulinemia (and insulin resistance)
• inflammation
• oxidative stress
• endothelial dysfunction
• hypercoagulability
• dyslipidemia

These factors are known, collectively and synergistically, to promote atherosclerosis, which leads to macrovascular and microvascular damage throughout the body. Macrovascular disease complications include: ischemic heart disease, which can lead to myocardial infarction (MI) and cardiomyopathy; cerebrovascular disease, which can lead to stroke and paralysis; and peripheral vascular disease, which sometimes requires amputation of affected extremities. Microvascular complications can include retinopathy, nephropathy, and neuropathy.

Ischemic heart disease may result in cardiomyopathy, but DM can directly alter myocardial function and structure via metabolic mechanisms that are independent of hypertension, valvular disease, or coronary artery disease.

A wide range of metabolic dysfunctions are implicated in DM-associated cardiomyopathy: aberrant insulin signaling; mitochondrial dysfunction and calcium mishandling aggravating the energy mismatch; rise in oxidative stress and advanced glycation products; inflammation; activation of the RAAS; autonomic neuropathy; and microangiopathy.

The characteristic features of DM-associated cardiomyopathy are an initial subclinical phase of myocardial fibrosis and cardiac remodeling, leading to left ventricular hypertrophy, myocyte stiffness, and cell signal alteration. There is then progression to diastolic dysfunction with preserved ejection fraction and later to systolic dysfunction, leading eventually to HFrEF. This process typically results from long-standing and poorly controlled DM.^{5, 14}

Can Cardiorenal Diseases be Treated Effectively in DM?

For many decades, DM management focused primarily on glycemic control. However, the tight glycemic control arm of the UKPDS did not yield significant CVD improvement. Indeed, a meta-analysis of several large prospective randomized controlled trials showed a rise in adverse events as glycemic control was tightened.^{15, 16} Anti-hyperglycemic agents can cause several adverse effects, such as weight gain, hypoglycemia, and even HF.⁷ Furthermore, the efficacy of oral agents tends to taper off over time, resulting in an increasing medication burden.

For the past two decades, DN treatment has focused on blood pressure and glycemic control with renin-angiotensin system (RAS) blockade, but prevalence of CKD among people living with DM has remained at around 30% to 40%.¹⁷

Cardiovascular Outcome Trials (CVOTs)

CVOTs, which were first mandated by the U.S. Food and Drug Administration (FDA) in 2008, were put in place to ensure that newly approved anti-DM agents demonstrated no CV harm compared to standard care treatments. Results of these trials have shown not only cardiac safety with most of these agents, but also, in some cases, a reduction in CVD and nephropathy progression. The strength of the CVOT evidence has resulted in adjustments in international treatment guidelines for T2DM with existing CVD and CKD.¹⁸

Sodium Glucose Cotransporter 2 (SGLT-2) Inhibitors

The first CVOT that focused on an SGLT-2 inhibitor was completed in 2016 for empagliflozin, a drug first approved for use in 2014 by the European Medicines Agency (EMA) and the FDA. This CVOT, EMPA-REG OUTCOME, conclusively demonstrated that among the T2DM population with established CVD and moderate-to-severe renal dysfunction at baseline, empagliflozin could lower glucose levels safely within the context of standard care, improve CVD mortality, and improve renal outcomes. (Treatments for this population included treatment for hypertension and hyperlipidemia.) The trial also showed the relative risk reduction for cardiovascular death vs. placebo was 38%, and for HF, 35%. In addition, reduction in composite renal outcomes, which included renal function decline, ESRD, and renal death, was 46%.⁴

CVOTs conducted more recently for two newer SGLT-2 inhibitors, CANVAS Program (for canagliflozin) and DECLARE TIMI 58 (for dapagliflozin), supported the findings for empagliflozin. Relative risk reductions for HF with the two agents were 33% and 27%, respectively, and for renal composite outcomes, 40% and 47%, respectively.⁴

A meta-analysis of several observational studies that drew from national registries of 12 countries with wide geographic and diverse population representations provided real-world evidence to back the results of these CVOTs. This study supported the conclusions about the beneficial effect of these medications for HF reduction in those with baseline HF and as primary prevention in those with no baseline HF.^{4, 19}

In addition, the results of the recent CREDENCE CVOT demonstrated the additional renal benefits of adding canagliflozin to a baseline RAS blockade in a DM population with moderate to advanced renal impairment. The eGFR of the recruited cohort was 30 to < 90ml/min/1.73m². (An eGFR of 60 or above is considered normal.) CV death or hospitalization for HF for the cohort taking canagliflozin was reduced by 30%. Concerns of limb amputation risk from the earlier CVOTs have been eased by the comparable adverse effect rates between the active and placebo arms.²⁰

A meta-analysis of three SGLT-2 inhibitor studies published September 2019 by Neuen et al. concluded that these medications prevent major kidney damage in T2DM by decreasing dialysis requirement and transplantation, and reduce the likelihood of death due to CKD.²¹

Hypothesized Mechanisms of Action of SGLT-2 Inhibitors:^{4, 5, 9, 13}

• Renal reabsorption of filtered glucose in the proximal tubules of the kidneys is mostly attributed to the action of sodium glucose cotransporter 2 (SGLT-2), while SGLT-1 is responsible for the remaining 10%. Inactivation of SGLT-2 by inhibitors has pleiotropic effects.⁴ It causes glucose wasting, which effectively lowers glucose toxicity and reduces the caloric burden, thus contributing to weight loss.

• The correlating diuretic effect also lowers blood pressure, which reduces load on the left ventricle along with myocardial oxygen consumption.

• Increased ketone production shifts the myocardial fuel demand away from fatty acids to ketones, which are a more efficient fuel substrate for the myocardium.

• The concomitant natriuresis reactivates the renal tubule-glomerular feedback loop, which causes vasoconstriction of the afferent glomerular arteriole, thus lowering intra-glomerular pressure, resulting in reduced albuminuria.

• Lowering sodium in the myocyte seems to preserve mitochondrial calcium and reverses an energy mismatch, mitigating oxidative stress buildup.

• Reduction in arterial stiffness, inflammation, and oxidative stress have also been observed.

• The impact on glucose lowering, however, is only moderate, averaging 0.6% to 1.2%.

Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RAs)

CVOTs for members of this class of medications offered reassurance of glucose lowering efficacy, favorable safety profiles, and absence of cardiac harm when compared with standard care.⁷ Two specific agents, liraglutide and semaglutide, demonstrated in the LEADER and SUSTAIN-6 CVOTs (respectively) added CV benefits such as reduction of CV death, MI, and stroke in T2DM individuals with high baseline risk, including multiple risk factors or existing CVD.⁷

The primary composite reduction of major adverse cardiovascular events (MACE) due to these medications ranged from 13% to 26%. Some generated higher reductions in stroke, which was the main driver for overall MACE reduction. These benefits do not correlate strictly to the magnitude of body mass reduction nor of glycemic lowering.⁷ The findings of the recently published REWIND study, which investigated dulaglutide, have shown favorable stroke reduction but no significant difference in all-cause mortality or HF when compared to placebo.²³

The actions of GLP-1 RAs are pleotropic. Receptors for GLP-1 are found in multiple sites throughout the human body. Significant glycemic lowering is seen as resulting from members of this class of agents, but weight loss and blood pressure lowering are variable. ⁷

The occurrence of renal function deterioration was a secondary outcome of the GLP-1 RA LEADER and SUSTAIN-6 CVOTs. There was a general trend of improvement seen in the progression of nephropathy, driven mainly by reduction in macroalbuminuria. There is, however, no definitive evidence of any impact on the hard outcomes of renal disease such as the need for renal replacement therapy for ESRD.^{17, 19}

The initial exenatide CVOT, EXSCEL, did not show better cardiac outcome in candidates receiving exenatide compared with those receiving standard care, but the composite renal outcomes were meaningfully reduced in the exenatide group.²²

Current FDA approved GLP-1 RAs include exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide and semaglutide. The CVOTs for these agents did not uniformly show CV and renal benefits. Where there were benefits, the degree was variable. They did, however, all show effective and safe lowering of hyperglycemia, body mass, cholesterol levels, and blood pressure to varying degrees. These benefits may indirectly contribute toward CV and renal improvements over and above the direct mechanisms.^{7, 17, 19, 22}

Hypothesized Mechanisms of the Action of GLP-1 RAs.^{5, 9, 17, 22}

• GLP-1 is released from intestinal cells in response to food ingestion, with a consequent paracrine function that potentiates insulin release commensurate to the rise in the blood glucose level.

• Receptors for GLP-1 are distributed throughout the body. GLP-1 RAs display discernable pleotropic influences.

• Effects of GLP-1 RAs on the pancreas include increased insulin sensitivity and less beta cell apoptosis. GLP-1 RAs also reduce post-prandial glucagon secretion and hyperlipidemia, slow gastric emptying, and contribute to weight loss.

• Other hypothesized cardiorenal protective mechanisms of GLP-1 RAs include:

  • Reduction of inflammation and the infarct size in the ischemic heart

  • Restoration of left ventricular function

  • Improved endothelial function (via reactivation of endothelial nitrous oxide synthase)

  • Stimulation of tubular natriuresis (which may reactivate tubule-glomerular feedback)

  • Modulation of cAMP/PKA signaling

  • Possible minimization of oxidative and inflammatory injuries

  • Reduction of RAS activity, glomerular atherosclerosis, and renal hypoxia

Conclusion

Cardiovascular outcomes trials have resulted in updates to international guidelines for treating individuals with T2DM where there is also established atherosclerotic CVD, CKD, and HF. The updates recommend, depending on baseline pathology, treatment with GLP-1 RAs and/or SGLT-2 inhibitors after standard first-line treatments.¹⁸

Interestingly, cardiorenal benefits observed after administering these agents did not correlate to the magnitude nor the temporal trend of the glycemia lowering effect, thus strongly suggesting that other mechanisms might be at play. Still, other benefits were seen, including weight loss, blood pressure reductions and, in some instances, lipid profile improvements.

It is groundbreaking that, even in individuals with established DM-related CVD, DN and HF, there are now

treatment options that may bring about cardiac and renal improvements. At this time, the effect is known to be mild to moderate. Results of longer therapeutic durations will become available over time. Current investigations are looking into the value of these treatments as primary prevention, with the potential to prevent or postpone cardiorenal complications in T2DM. Indeed, some studies in this area on the T1DM population have also been completed, and more are underway.

These new-generation agents enable profile-specific and individualized treatment methodologies that are approaching those of personalized medicine. For every individual along the multiple points of DM’s treatment path, potential opportunities exist to arrest disease progression and prevent major complications, which may lead to significant improvements in quality of life and survival for people living with DM.