Cardiovascular and Renal Protection in Diabetes—Emphasis on SGLT2 Inhibitors and GLP-1 Receptor Agonists
Presented by:
Julie A. Lovshin, MD, PhD
University of Toronto, Toronto, Canada Jens J. Holst, MD, DMSc
Panum Institute, Copenhagen, Denmark David C. Wheeler, MD
University College London, London, UK
Since patients with diabetes are at increased risk for CV and renal events, reducing the risk of these events is of primary interest to improve outcomes in the long-term.
SGLT2 inhibitors and GLP-1 RAs have dramatically changed the treatment landscape of type 2 diabetes due to their established CV benefits, and the observed improvements in renal function seen with these classes of agents are currently undergoing intense investigation.
The treatment of patients with diabetes has undergone radical changes in recent years with the development of novel antihyperglycemic agents, namely inhibitors of sodium-glucose cotransporter-2 (SGLT2) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs). It is now apparent that both SGLT2 inhibitors and GLP-1 RAs show consistent reductions in major adverse cardiovascular events for patients with established cardiovascular (CV) disease, and both appear to have renal benefits as well. These speakers summarized the renal effects of GLP-1 RAs and SGLT2 inhibitors as well as the cardiovascular effects of GLP-1 RAs.
GLP-1 RAs are able to reduce fasting and postprandial hyperglycemia by directly stimulating GLP-1 receptors on pancreatic beta cells, thereby regulating islet cell hormone secretion.
These agents typical lower HbA1c by 1.0-1.5% and body weight by 3-5 kg.
Several short- and long-acting GLP-1 RAs have been approved for clinical use, and as a class they are structurally divergent, giving rise to differences in pharmacology, administration, pharmacokinetics, tolerability, risk for immunogenicity, and clearance.
These drugs may exert their beneficial actions on the kidneys through their effects on lowering blood glucose and blood pressure and by reducing the levels of insulin.
Several gut hormones and peptides have been hypothesized to be effectors of the natriuretic axis in the kidney, and GLP-1 RAs may exert at least some of their action by affecting these factors.
Indeed, changes in renal hemodynamics observed with GLP-1 RAs have the potential to facilitate excretion of renal solutes, including sodium, although this possibility still warrants further study.
In addition, GLP-1 RAs are believed to have hemodynamic effects that appear to be independent of their natriuretic effects, possibly through a direct vasodilatory mechanism.
The integrated effect of GLP-1 RA-based therapy on renal hemodynamics thus appears to be the result of both direct vasodilative actions and inhibition of glomerular hyperfiltration pathways.
The renal benefits of GLP-1R agonists were first suggested from data emerging from large randomized phase III CV outcomes trials.
For GLP-1RAs, these include ELIXA with lixisenatide, LEADER with liraglutide, SUSTAIN-6 with semaglutide, EXCSEL with exenatide once-weekly, HARMONY with albiglutide, and REWIND with dulaglutide.
All these studies indicate that albuminuria is reduced during treatment with GLP-1 RAs, and eGFR appears to be stabilized.
These benefits are seen independently of HbA1c, weight, and blood pressure variations.
Notwithstanding, dedicated renal outcomes trials are needed with GLP-1 RAs to more precisely investigate their effects on renal function, and in particular to determine if they can slow progression of chronic kidney disease in individuals with normal renal function.
Impeding progression of diabetic nephropathy before the onset of tubular hypertrophy, glomerular hyperfiltration, and irreversible glomerular injury is obviously an area of substantial clinical interest in patients with diabetes, and GLP-1 RAs have demonstrated considerable promise in this regard.
Large CV outcomes trials with GLP-1 RAs have shown that these agents can reduce the risk of major adverse CV events, CV mortality, and all-cause mortality.
These CV benefits appear to be related to four distinct mechanisms:
Improve myocardial performance in ischemic heart failure
Improve myocardial survival in ischemic heart disease
Ameliorate endothelial dysfunction
Decrease markers of CV risk.
They can improve myocardial performance in ischemic heart failure and improve myocardial survival in ischemic heart disease.
They can also ameliorate endothelial dysfunction and decrease markers of CV risk.
GLP-1 RAs also have effects on lipids and, in particular, a decrease in postprandial hypertriglyceridemia has been observed.
In animal models, GLP-1 RAs improve cardiac function after ischemia/reperfusion injury and reduce infarct size and improve outcomes following myocardial infarction.
Clinically, exenatide has been shown to reduce reperfusion injury in patients with ST-segment elevation myocardial infarction (STEMI).
In terms of reductions in indices of CV risk, in addition to lowering HbA1c, GLP-1 RAs are associated with reductions in weight and blood pressure.
Reduction of body weight may also have beneficial CV effects by decreasing chronic proatherogenic inflammation.
Indeed, semaglutide, for example, is associated with significant reductions in C-reactive protein, substantiating such a hypothesis.
GLP-1 RAs appear to have no effect on the failing heart, but may work in part by increasing heart rate to a small extent.
They have no effects on coronary arteries and there are no GLP-1 receptors on these vessels.
They do, however, appear to reduce the risk of stroke, acute MI, and revascularization.
These effects are in addition to the observed benefits on renal function, which together may help to explain the observed improvements in metabolic health of patients with type 2 diabetes. Such CV action may indeed have a preventive role in these patients.
Inhibition of SGLT2 is associated with reductions in HbA1c and weight, as well as enhanced excretion of sodium that leads to reduction in blood pressure.
However, many potential mechanisms have been linked to the renoprotective effects of SGLT2 inhibitors.
These include reduction of blood pressure, improved metabolic parameters, reduced volume overload, reduction in albuminuria, and glomerular pressure.
For the latter, SGLT2 inhibition appears to reduce hyperfiltration via a tubuloglomerular feedback mechanism.
Clinical data from CV outcomes trials have shown consistent variations in eGFR and reduction in death from renal causes with empagliflozin, canagliflozin, and dapagliflozin.
However, to gain more information about the renal effects of these agents, dedicated renal outcomes trials are needed to study reductions in albuminuria, changes in eGFR, number of patients reaching end-stage renal disease, need for dialysis, and deaths due to kidney failure.
In the CV outcomes trials, the patient population was at low renal risk, and thus more information is needed on their use on other populations of patients.
The CREDENCE trial expanded on this by enrolling patients with chronic kidney disease, demonstrating a renoprotective effect of canagliflozin.
In terms of ongoing studies in chronic kidney disease with SGLT2 inhibitors, both DAPACKD and EMPA-CKD are enrolling patients with eGFR of 25-75 ml/min/1.73 m2 and 20-45 ml/min/1.73 m2, respectively.
The CANVAS program on canagliflozin is including those with eGFR <30 ml/min/1.73 m2 and evaluating renal outcomes of 40% reduction in eGFR, end-stage renal disease, and renal death.
Key Messages/Clinical Perspectives
Large CV outcomes trials have shown that both SGLT2 inhibitors and GLP-1 RAs are associated with significant reductions in CV events in patients with elevated CV risk.
From CV outcomes trials both classes of agents also appear to have renal benefits, although large dedicated studies are needed to establish the magnitude of this potential benefit
The mechanism of action at the basis of CV and renal benefits of SGLT2 inhibitors and GLP-1 RAs is complex, multifactorial, and still not completely understood.
Evert AB, Dennison M, Gardner CD, et al. Nutrition Therapy for Adults With Diabetes or Prediabetes: A Consensus Report. Diabetes Care. 2019 May;42(5):731-54.
Present disclosure: J.A. Lovshin: BI/Lilly Alliance, Novo Nordisk, AstraZeneca, Intarcia, Prometric, Merck Canada, Sanofi Canada. J.J. Holst: Merck Sharpe & Dohme, Novo Nordisk. D.C. Wheeler: none.
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