Despite the heavy burden of heart disease among patients with diabetes, identification of anti-diabetic agents that have a direct reduction in cardiovascular events and mortality have remained elusive. Previous studies, such as the PROactive (Efficacy of Pioglitazone on Macrovascular Outcome in Patients With Type 2 Diabetes) trial, examining the thiazolidinedione pioglitazone, and the EXAMINE (Cardiovascular Outcomes Study of Alogliptin in Patients With Type 2 Diabetes and Acute Coronary Syndrome) trial, examining the dipeptidyl peptidase-4 inhibitor alogliptin, did not reach superiority endpoints of composite cardiovascular outcomes.^1,2 However, more recently, there has been interest in investigating sodium-glucose cotransporter-2 (SGLT-2) inhibitors for their potential role in modifying the cardiac risk profile of patients, in addition to their established role in reducing hyperglycemia.

This search is motivated by the success of trials like EMPA-REG OUTCOME (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), which showed a beneficial effect on a cardiovascular mortality (3.7% vs. 5.9%; P < 0.001) and all-cause mortality (5.7% vs. 8.3%; P < 0.001) in patients with type 2 diabetes receiving empagliflozin.³ Moreover, other studies have shown that treatment with canagliflozin delayed the rise in serum NT-proBNP and high-sensitivity troponin I.⁴ The mechanism driving these outcomes is not fully understood. Naturesis, weight loss, lowering of blood pressure and inhibition of adverse cardiac remodeling have all been proposed as hypotheses that may promote a favorable cardiac state in patients receiving SGLT-2 inhibitors.

The CANVAS Program (CANagliflozin cardiovascular Assessment Study) is a randomized, multicenter double-blinded study that examines the effect of canagliflozin, a SGLT-2 inhibitor, on major adverse cardiovascular outcomes.⁵ The investigation is comprised of two similarly designed trials called CANVAS and CANVAS-R, the latter of which studied renal endpoints.⁶ Recently, Radholm et. al published findings on the interaction between canagliflozin and heart failure (HF) from the CANVAS Program data.⁷

This analysis is particularly important because it studies a vulnerable subset of patients with cardiac disease, namely those with HF. This should be viewed in the context of the SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus--Thrombolysis in Myocardial Infarction 53) trial, which studied saxagliptin.⁸ This study not only failed to show improvement in cardiovascular mortality, but in fact showed an increased burden of HF among patients receiving saxagliptin. Thus, there has been excitement in studying HF related outcomes in canagliflozin, which induces its hypoglycemic effect through osmotic diuresis.

The study enrolled 10,142 participants with type 2 diabetes and an elevated cardiac risk profile. Participants were randomized to either canagliflozin or placebo and were followed for a mean of 188 weeks. Participants in CANVAS were 1:1:1 randomized to placebo, canagliflozin 300 mg, 100 mg while those in CANVAS-R were 1:1 randomized to placebo or canagliflozin 100 mg optionally up-titrated to 300 mg.

The primary outcome was a composite of cardiovascular death and hospitalization due to HF. The former was defined as death resulting for myocardial infarction, HF, stroke or other causes of cardiovascular death. The latter was defined as an inpatient admission or emergency room visit due to HF necessitating increasing therapy. Annualized incidence rates and Cox regression models were constructed for the statistical analysis. No adjustment was made for multiple comparisons. Data was stratified according to the trial that they originated from.

In this study, 36% of participants were female, the average age was 63 years and the mean duration of diabetes was 13.5 years. 14% of participants had HF at baseline. It is important to note that the baseline characteristics of this subset of patients differed significantly from the whole group. In particular, these participants had higher rates of diuretic, renin-angiotensin-aldosterone system blocker and beta blocker use. The risk of the primary outcome was reduced in canagliflozin as compared to placebo (HR, 0.78; 95% CI, 0.67–0.91). Further, participants with canagliflozin had a lower risk of fatal or hospitalized HF (HR, 0.78; 95% CI, 0.67–0.91). Risk of the primary outcome was lower among participants with baseline HF (HR, 0.61; 95% CI, 0.46–0.80) and compared to those without HF (HR, 0.87; 95% CI, 0.72–1.06), although this interaction was of modest statistical significance (P = 0.021).

Subgroup analyses compared the incidence of the primary outcome stratified according to diuretic use. In participants with any-type diuretics use, canagliflozin was associated with a statistically significant reduction in cardiovascular death or hospitalized HF (HR, 0.71; 95% CI, 0.58–0.86) versus placebo (HR, 0.93; 95% CI, 0.72–1.21), P-interaction 0.03. Among participants with loop diuretics, canagliflozin tended towards statistical significance (HR, 0.72; 95% CI, 0.55–0.93) versus (HR, 0.83; 95% CI, 0.68–1.01), P-interaction 0.18. Similarly, among participants with non-loop diuretics, canagliflozin also tended towards statistical significance (HR, 0.71; 95% CI, 0.53–0.96) versus (HR, 0.81; 95% CI, 0.67–0.97), P-interaction 0.53.

In addition, participants with and without HF had similar outcomes in regard to major adverse cardiovascular events, mortality and decline of renal function. Lastly, the results indicate a beneficial effect of canagliflozin early in the course of the trial, which suggests that the beneficial effect may be mediated primarily through osmotic diuresis rather than through cardiac remodeling.

The results of this study are emboldened by the study design and extensive longitudinal participant follow up. However, one of the limitations was the adjudication of heart failure at baseline in participants. The rate of loop diuretic use in participants classified as having HF was low (26%), which questions the severity of their HF. However, we would speculate that misclassification of these patients as having HF would skew the results towards the null. In this case, re-adjudication of these participants to the non-HF group may actually show a more pronounced effect of canagliflozin and we look forward to a retrospective analysis that examines this possibility. Furthermore, definition of HF was based on physician review and did not include quantitative measures such echocardiographic parameters or laboratory-based biomarkers.

Overall, this study gives strong evidence on the beneficial effects of canagliflozin in participants with HF. Although to our knowledge, no guidelines currently recommend the use of SGLT-2 inhibitors as a diuretic in HF, we are cautiously optimistic that in the future SGLT-2 inhibitors will serve as an adjunct therapy in diabetic patients already receiving diuretics for concurrent HF. We now look towards other investigators such as those of up-coming RECEDE-HF (SGLT2 Inhibition in Combination With Diuretics in Heart Failure) trial to better quantify these heart failure outcomes.⁹

References

1. Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitazone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005;366:1279-89.
2. White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013;369:1327-35.
3. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-28.
4. Januzzi JL, Butler J, Jarolim P, et al. Effects of canagliflozin on cardiovascular biomarkers in older adults with type 2 diabetes. J Am Coll Cardiol 2017;70:704-12.
5. Neal B, Parkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:644-57.
6. Perkovic V, de Zeeuw D, Mahaffey KW, et al. Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trails. Lancet Diabetes Endocrinol 2018;6:691-704.
7. Radholm K, Figtree G, Perkovic V, et al. Canagliflozin and heart failure in type 2 diabetes mellitus: results from the CANVAS Program (Canagliflozin Cardiovascular Assessment Study). Circulation 2018. [Epub ahead of print]
8. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369:1317-26.
9. Mordi NA, Mordi IR, Singh JS, et al. Renal and cardiovascular effects of sodium-glucose cotransporter 2 (SGLT2) inhibition in combination with loop Dieuretics in diabetic patients with Chronic Heart Failure (RECEDE-CHF): protocol for a randomised controlled double-blind cross-over trial. BMJ Open 2017;7:e018097.

Keywords: Thiazolidinediones, Hypoglycemic Agents, Dipeptidyl-Peptidase IV Inhibitors, Diabetes Mellitus, Type 2, Sodium Potassium Chloride Symporter Inhibitors, Troponin I, Diuretics, Weight Loss, Blood Pressure, Retrospective Studies, Acute Coronary Syndrome, Renin-Angiotensin System, Glucosides, Benzhydryl Compounds, Piperidines, Dipeptides, Uracil, Adamantane, Heart Failure, Hyperglycemia, Myocardial Infarction, Stroke, Echocardiography, Biomarkers, Sodium-Glucose Transport Proteins, Emergency Service, Hospital, Diuresis, Metabolic Syndrome

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