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Risk Assessment Tool Identifies Diabetic Patients that Benefit Most from SGLT2 Inhibitor Treatment

Risk Assessment Tool Identifies Diabetic Patients that Benefit Most from SGLT2 Inhibitor Treatment

People with type 2 diabetes are at varied risk for adverse cardiovascular and kidney disease outcomes, with a new study showing that patients at the highest risk may benefit the most from the anti-diabetic drug, canagliflozin.

A new study shows that the diabetic drug canagliflozin reduces the risk of adverse cardiovascular and kidney outcomes in individuals with type 2 diabetes, particularly for those at higher risk of kidney failure.

The Canagliflozin Cardiovascular Assessment Study (CANVAS) Program evaluated patients with type 2 diabetes who are at high cardiovascular risk. The latest results from the study, titled “Relative and Absolute Risk Reductions in Cardiovascular and Kidney Outcomes With Canagliflozin Across KDIGO Risk Categories: Findings from the CANVAS Program,” were released yesterday in the National Kidney Foundation’s American Journal of Kidney Diseases (AJKD).

Canagliflozin is a third-line medication to metformin in the treatment of type 2 diabetes and is typically used in conjunction with diet and exercise. It is an inhibitor of subtype 2 sodium-glucose transport proteins (SGLT2), which functions in glucose reabsorption.

SGLT2 inhibitors can reduce the risk of cardiovascular events, particularly heart failure, as well as slow the progression of kidney disease. The treatment is available to patients with type 2 diabetes, although emerging evidence suggests that the cardiovascular and protective kidney benefits of the drug are similar in people with and without diabetes.


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The study investigators conducted a post-hoc analysis of data from the Phase III CANVAS Clinical Trial Program. The trial assessed the effect of canagliflozin on cardiovascular outcomes in participants with different levels of risk for chronic kidney disease – these levels are defined by the Kidney Disease: Improving Global Outcomes (KDIGO) classification system.

“The KDIGO classification of chronic kidney disease is a useful tool for informing prognosis as it allows us to classify people according to their risk of kidney failure and other adverse outcomes,” said lead author on the study Brendon Neuen, MBBS, MSc, of Royal North Shore Hospital and the George Institute for Global Health, UNSW Sydney, Australia in a news release from the National Kidney Foundation (NKS).

He went on to say, “However, it has not been widely used to estimate potential benefits with new treatments, such as SGLT2 inhibitors. We found that the KDIGO classification of chronic kidney disease is clinically useful for identifying people who might benefit most from treatment with canagliflozin in terms of protection against cardiovascular events and progression of kidney disease.”

SGLT2 accounts for at least 90 percent of renal glucose reabsorption (with the remaining 10 percent attributed to SGLT1). Blocking the transporter leads to 119 grams of blood glucose per day to be eliminated through the urine, which amounts to 476 kilocalories. Blood pressure is lowered in the process due to the elimination of additional water by osmotic diuresis.

Compared to other anti-diabetic drugs, such as sulfonylurea derivatives and insulin, SGLT2 inhibitors are associated with a low risk of hypoglycaemia.

The CANVAS Program consisted of two parallel, randomized, double-blind, placebo-controlled trials in which individuals with type 2 diabetes (and an eGFR ≥ 30 mL/min/1.73 m2) who had, or were at high risk of cardiovascular disease, were randomized to canagliflozin or placebo.

The trial had 10,142 participants of which the proportions of participants in low-, moderate-, high-, and very high-risk categories were 58.6, 25.8, 10.6 and 5.0 percent, respectively. The primary outcome of the trial was a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death, along with a set of other cardiovascular and kidney pre-specified outcomes.

The relative effect of canagliflozin on the primary outcome was consistent across KDIGO risk categories, with similar results for other cardiovascular and kidney outcomes. However, absolute reductions in the primary outcome were greater in the higher KDIGO risk categories with a similar pattern of effect for the composite of cardiovascular death or hospitalization for heart failure and for chronic eGFR slope, according to the study.

“This study provides further evidence that the SGLT2 inhibitors have the potential to dramatically improve outcomes for a significant proportion of people with chronic kidney disease,” said Kerry Willis PhD, National Kidney Foundation chief scientific officer. “It also highlights the importance of using risk prediction tools to identify those most in need of interventions to reduce their cardiovascular and kidney risk.”

Canagliflozin is sold by prescription under the name Invokana (among others) as an oral formulation. It received approval from the FDA in 2013 for the management of diabetes. In 2019, it received another approval for the treatment of kidney disease and reducing the risk of hospitalization for heart failure in type 2 diabetic patients.

The utility of the CANVAS study is that it demonstrates that patients who may benefit most from canagliflozin treatment can be readily identified using the widely used and validated KDIGO risk stratification tool. In this way, the tool can help personalize treatment based on the risk levels of kidney disease outcomes, as well as serious cardiovascular events.