Effects of Canagliflozin on Cardiovascular Biomarkers in Older Adults With Type 2 Diabetes Review

Central Analogy

Abstruse

Background

Sodium glucose co-transporter two inhibitors may reduce cardiovascular and heart failure risk in patients with type 2 diabetes mellitus (T2DM).

Objectives

The goal of this study was to examine the effects of canagliflozin on cardiovascular biomarkers in older patients with T2DM.

Methods

In 666 T2DM patients randomized to receive canagliflozin 100 or 300 mg or placebo, the study assessed the median percent change in serum N-terminal pro–B-type natriuretic peptide (NT-proBNP), loftier-sensitivity troponin I (hsTnI), soluble (due south)ST2, and galectin-iii from baseline to 26, 52, and 104 weeks.

Results

Both serum NT-proBNP and serum hsTnI levels increased in placebo recipients, only they remained largely unchanged in those randomized to canagliflozin. Hodges-Lehmann estimates of the divergence in median percent change between pooled canagliflozin and placebo were −fifteen.0%, −16.1%, and −26.8% for NT-proBNP, and −eight.3%, −11.nine%, and −10.0% for hsTnI at weeks 26, 52, and 104, respectively (all p < 0.05). Serum sST2 was unchanged with canagliflozin and placebo over 104 weeks. Serum galectin-3 modestly increased from baseline with canagliflozin versus placebo, with significant differences observed at 26 and 52 weeks merely non at 104 weeks. These results remained unchanged when only patients with complete samples were assessed.

Conclusions

Compared with placebo, handling with canagliflozin delayed the rise in serum NT-proBNP and hsTnI for over ii years in older T2DM patients. These cardiac biomarker information provide back up for the beneficial cardiovascular event of sodium glucose co-transporter 2 inhibitors in T2DM. (A Safety and Efficacy Study of Canagliflozin in Older Patients [55 to lxxx Years of Age] With Blazon 2 Diabetes Mellitus; NCT01106651)

Introduction

Sodium glucose co-transporter 2 (SGLT2) inhibitors are a new form of diabetes drugs that lower claret glucose in patients with type ii diabetes mellitus (T2DM) through increased urinary excretion of glucose (i). SGLT2 inhibitors may have other cardiometabolic benefits; they cause natriuresis, a mild osmotic diuresis, and a net caloric loss that contribute to reductions in body weight and blood force per unit area (BP) (i). Additionally, increased delivery of sodium to the macula densa helps to restore normal glomerular pressure, which, in turn, results in improved renal function over the longer term (two).

SGLT2 inhibitors have recently been studied in large cardiovascular outcomes trials for evaluating the cardiovascular effects of newer T2DM agents (three). In the EMPA-REG OUTCOME (Empagliflozin Cardiovascular Effect Outcome Trial in Type 2 Diabetes Mellitus Patients) study, treatment with empagliflozin resulted in reduction in the risk for major adverse cardiovascular events (three-indicate MACE: cardiovascular decease, nonfatal stroke, and nonfatal myocardial infarction) compared with placebo, driven by a 38% reduction in cardiovascular death; empagliflozin also reduced the risk of hospitalization for heart failure by 35% relative to placebo (4). These effects were credible early afterwards initiating treatment with empagliflozin, suggesting that astute changes may exist at least partially responsible for the observed outcomes (iv). Hypotheses regarding the mechanism of cardiovascular do good for SGLT2 inhibition observed in the EMPA-REG Upshot study accept focused on the multiple effects beyond glucose lowering, such as diuresis and natriuresis, weight loss, BP lowering, metabolic effects on the myocardium, favorable hemodynamic changes, and attenuation of cardiac remodeling (five–12); each may result in improved cardiovascular outcomes (xi).

Biomarkers are useful in prognosis conclusion and informing the mechanism of benefit provided by therapeutic agents (13). N-terminal pro–B-type natriuretic peptide (NT-proBNP) is recommended for the diagnosis and direction of center failure, with potential utility in the prediction of coronary eye disease and stroke outcomes (fourteen). Similarly, biomarkers of cardiomyocyte injury (due east.grand., high-sensitivity troponin I [hsTnI]) and those involved in cardiovascular stress/tissue fibrosis (e.k., soluble [due south]ST2, galectin-3) may aid elucidate prognosis and affliction progression, with recent data, in particular, for hsTnI in T2DM (15).

At that place are very express data on the furnishings of SGLT2 inhibitors on cardiovascular biomarkers (sixteen–18). In this study, we sought to assess the longitudinal changes in the concentrations of NT-proBNP, hsTnI, sST2, and galectin-three in older patients with T2DM randomized to receive canagliflozin or placebo in a 104-week written report (19,20) to proceeds insights into the mechanisms of the potential beneficial cardiovascular effect of SGLT2 inhibitors.

Methods

Patients

This post hoc, exploratory analysis was conducted using stored serum samples from a 104-week, randomized, double-blind, placebo-controlled written report ( NCT01106651) that evaluated the efficacy and rubber of canagliflozin 100 and 300 mg in older patients with T2DM. Full study design and key inclusion/exclusion criteria have previously been reported (nineteen,20). Briefly, eligible patients were adults with T2DM who were 55 to 80 years of age, had glycosylated hemoglobin ≥7.0% and ≤10.0% and estimated glomerular filtration rate (eGFR) ≥l ml/min/i.73 m², and were either not on any antihyperglycemic agent or were on a stable regimen of monotherapy or combination therapy. Patients with a history of myocardial infarction, unstable angina, previous coronary revascularization, cerebrovascular accident within 3 months before screening, history of New York Eye Association functional class Three to IV symptoms, or uncontrolled hypertension were not eligible to participate. This study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki and followed proficient clinical practice and applicable regulatory requirements. Approval was obtained from institutional review boards and independent ethics committees for each participating center. Participants provided informed written consent before enrollment in the written report.

Endpoints/assessments

Serum samples were nerveless at baseline and at weeks 26, 52, and 104, and stored at −eighty°C. NT-proBNP was measured on the cobas e601 immunoanalyzer using the proBNP II electrochemiluminescent immunoassay (Roche Diagnostics, Indianapolis, Indiana), with interassay coefficients of variation (CV) of ii.5% at 137.ii pg/ml (depression-quality command concentration) and 2.3% at four,830 pg/ml (loftier-quality command concentration). High-sensitivity TnI and galectin-3 were measured on the Architect i2000SR immunoanalyzer using chemiluminescent microparticle immunoassays (Abbott Laboratories, Abbott Park, Illinois). CV were 4.0% at xx.4 ng/l and 3.seven% at 15,050 ng/fifty for hsTnI, and 4.0% at 9.3 ng/ml and ii.nine% at 74.4 ng/ml for galectin-3. Soluble ST2 was measured using a sandwich monoclonal enzyme-linked immunosorbent assay (Disquisitional Diagnostics, San Diego, California), and the CV were 7.6% at 28.two ng/ml and 7.5% at sixty.0 ng/ml. For each assay, all samples were run in a blinded mode and in the aforementioned flow, thereby minimizing interassay variations.

To understand secular trends in biomarkers as a function of treatment allocation, absolute and percent modify from baseline in serum levels of NT-proBNP, hsTnI, sST2, galectin-3, eGFR, and hematocrit were analyzed at each time point for patients with data at baseline and at any follow-up fourth dimension signal thereafter. Given the not-normality of these biomarker data including alter and pct modify from visit to visit, the medians of the modify and percentage change were analyzed. Data for the 2 canagliflozin doses were pooled after information technology was determined that there was no dose response observed on any of the biomarkers. A sensitivity analysis was also performed to evaluate absolute and percent change from baseline in biomarkers in the accomplice of patients with complete sets of samples (i.e., data available at all visits, including baseline and weeks 26, 52, and 104).

Statistical analyses

Nonparametric Hodges-Lehmann estimates of the difference between canagliflozin and placebo in median change and median percent change from baseline were calculated for each biomarker at each time point. The distribution-free confidence intervals (CIs) and nominal p values for the differences in the median modify and median percent modify were based on the Wilcoxon rank sum exam (21). SE for the median and median percentage modify at each fourth dimension point were estimated using the bootstrap technique by imitation repeated samples for each biomarker and treatment group. Spearman correlation coefficients between alter from baseline in the specific biomarker and change from baseline in selected clinical parameters (i.east., glycosylated hemoglobin, body weight, systolic BP, hemoglobin, hematocrit, eGFR) were adamant within each treatment group at each fourth dimension point.

Results

Patients

Of 714 patients in the overall study population, 666 patients (93.3%) had serum samples at baseline and ≥i postal service-baseline follow-upwards time betoken, and these patients were included in this analysis. Among patients included in the biomarker assessments, baseline characteristics were counterbalanced between groups and were generally consistent with the overall written report population (Table 1); 77% had a history of hypertension and 30% had a history of microvascular disease (i.e., neuropathy, retinopathy, or nephropathy). The bulk of patients (74%) were taking an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker; 25%, 23%, and 34% of patients were on beta-blockers, calcium-aqueduct blockers, and diuretic agents, respectively (Table one). Of those taking diuretic agents, the majority took thiazides (29.2% in the placebo arm and 28.ix% in the canagliflozin arm), whereas loop diuretic agents (4.6% and iii.vi%) or mineralocorticoid receptor antagonists (0.5% and three.1%) were less normally used. During the course of the study, no changes in electrocardiographic parameters, such as PR interval, QRS interval, QT/QTc, or RR intervals, were noted between treatment groups (data non shown).

Table i Baseline Demographic and Disease Characteristics Amid Patients With Biomarker Assessments

	Placebo (due north = 216)	Canagliflozin (n = 450)
Male person	133 (62)	248 (55)
Age, yrs	63.ii (6.3)	64.0 (vi.3)
55 to <65	136 (63)	269 (60)
≥65	80 (37)	181 (40)
Race
White	170 (79)	349 (78)
Black or African American	xvi (7)	34 (8)
Asian	19 (9)	37 (8)
Other ∗	eleven (5)	30 (7)
HbA1c, %	7.8 ± 0.8	7.7 ± 0.8
BMI, kg/m2	31.ix ± 4.8	31.4 ± 4.v
T2DM elapsing, yrs	10.0 (half-dozen.0–15.0)	10.3 (half-dozen.1–16.0)
eGFR, ml/min/ane.73 ktwo	76.i ± 16.five	78.two ± 16.9
Systolic BP, mm Hg	131.2 ± 12.3	130.eight ± 14.0
History of microvascular illness	55 (25)	145 (32)
History of hypertension	169 (78)	346 (77)
Concomitant medications
ACE inhibitor/ARB	163 (76)	327 (73)
Beta-blockers	threescore (28)	109 (24)
Calcium-channel blockers	48 (22)	103 (23)
Diuretic agents	73 (34)	151 (34)

Biomarker changes

Table 2 summarizes the observed changes in serum NT-proBNP, hsTnI, sST2, galectin-3, eGFR, and hematocrit at all fourth dimension points. From a baseline median of approximately 47 pg/ml, serum NT-proBNP concentrations increased with placebo, just changed simply minimally with canagliflozin over the 2-yr written report menstruum (Effigy 1A). Hodges-Lehmann estimates of the difference in median percent change betwixt canagliflozin and placebo at weeks 26, 52, and 104 were −15.0% (95% CI: −27.4% to −3.iii%), −sixteen.1% (95% CI: −28.eight% to −iii.8%), and −26.8% (95% CI: −42.3% to −x.seven%), respectively. A between-group treatment effect was observed at 26 weeks and persisted over 104 weeks (nominal p < 0.05 at weeks 26 and 52, nominal p < 0.01 at calendar week 104). Because the relationship between baseline and 104-week concentrations of NT-proBNP (Online Effigy 1A), a lower gradient from baseline to final measurement was observed in those treated with canagliflozin.

Figure 1

Median Percent Modify From Baseline in Cardiac Biomarkers Over 104 Weeks

Treatment with canagliflozin prevented a rise of N-terminal pro–B-type natriuretic peptide (NT-proBNP) (A) and high-sensitivity troponin I (hsTnI) (B) over a 104-week period, compared with placebo. Soluble ST2 (sST2) concentrations were unchanged (C), whereas galectin-iii concentrations increased modestly (D). *Nominal p < 0.05 versus placebo. **Nominal p < 0.01 versus placebo.

Table ii Summary of Changes in Serum Concentrations of Cardiovascular Biomarkers, eGFR, and Hematocrit

	Calendar week 26		Calendar week 52		Calendar week 104
	Placebo	Canagliflozin	Placebo	Canagliflozin	Placebo	Canagliflozin
Serum NT-proBNP	187	402	165	389	155	341
Baseline, pg/ml	48.3 (22.0–110.8)	48.6 (24.2–103.3)	43.6 (22.one–98.two)	48.1 (24.5–103.3)	43.4 (20.8–92.ane)	47.four (23.7–98.1)
Change from baseline, pg/ml ∗	3.6 ± iii.6	−0.8 ± 4.0	4.three ± iii.half dozen	−0.3 ± three.0	12.five ± 4.v	2.4 ± iii.2
Difference vs. placebo†		−seven.2 (−13.five to −ane.0)‡		−viii.ix (−16.2 to −2.4)§		−11.8 (−19.9 to −4.3)§
Serum hsTnI	172	344	145	329	140	294
Baseline, pg/ml	3.4 (2.two–v.6)	3.3 (2.2–5.0)	3.3 (2.2–5.1)	3.1 (two.two–5.0)	3.3 (2.2–5.four)	3.2 (ii.2–5.0)
Change from baseline, pg/ml ∗	0.ii ± 0.1	−0.two ± 0.one	0.2 ± 0.1	−0.ii ± 0.one	0.3 ± 0.ane	0.0 ± 0.ane
Difference vs. placebo†		−0.three (−0.5 to −0.ane)§		−0.iv (−0.6 to −0.1)§		−0.4 (−0.vi to −0.1)§
Serum sST2	187	409	165	392	155	343
Baseline, ng/ml	28.8 (25.0–35.8)	29.0 (23.nine–34.3)	28.eight (25.0–35.viii)	29.0 (24.two–34.four)	28.iv (24.7–36.vii)	28.9 (23.8–34.2)
Change from baseline, ng/ml ∗	−0.7 ± 0.5	−1.1 ± 0.four	−0.5 ± 0.5	−0.4 ± 0.5	0.two ± 0.five	0.3 ± 0.4
Difference vs. placebo†		−0.iii (−one.0 to 0.5)		0.1 (−0.8 to 0.9)		−0.one (−1.0 to 0.8)
Serum galectin-3	172	343	145	330	140	294
Baseline, ng/ml	17.3 (14.viii–20.1)	17.1 (xiii.vii–20.eight)	17.4 (15.i–xx.iv)	xvi.9 (13.7–xx.eight)	17.2 (14.6–20.2)	17.0 (13.vii–20.8)
Change from baseline, ng/ml ∗	0.2 ± 0.3	1.1 ± 0.4	−0.ane ± 0.3	0.8 ± 0.3	0.iii ± 0.4	0.eight ± 0.4
Deviation vs. placebo†		1.ii (0.vii to i.7)§		0.9 (0.3 to 1.iv)§		0.6 (−0.0 to 1.two)
eGFR	216	450	216	450	216	450
Baseline, ml/min/1.73 m2	74.0 (64.0–86.0)	77.0 (66.0–89.0)	74.0 (64.0–86.0)	77.0 (66.0–89.0)	74.0 (64.0–86.0)	77.0 (66.0–89.0)
Modify from baseline, ml/min/1.73 m2 ∗	−1.0 ± 0.9	−3.0 ± 1.0	−1.0 ± 1.ane	−3.0 ± 1.0	−3.0 ± 1.4	−three.0 ± ane.1
Divergence vs. placebo†		−2.0 (−3.0 to 0.0)‡		−1.0 (−2.0 to 1.0)		0.0 (−1.0 to 2.0)
Hematocrit	215	450	215	450	215	450
Baseline, fraction	0.41 (0.39–0.43)	0.41 (0.39–0.43)	0.41 (0.39–0.43)	0.41 (0.39–0.43)	0.41 (0.39–0.43)	0.41 (0.39–0.43)
Modify from baseline, fraction ∗	0.000 ± 0.002	0.020 ± 0.005	0.000 ± 0.002	0.020 ± 0.004	−0.010 ± 0.004	0.020 ± 0.004
Departure vs. placebo†		0.02 (0.02 to 0.03)§		0.02 (0.02 to 0.03)§		0.02 (0.02 to 0.03)§

From a baseline median of approximately 3.iii pg/ml, serum hsTnI also gradually increased with placebo at each time signal, but was reduced or unchanged with canagliflozin over 104 weeks (Effigy 1B). Hodges-Lehmann estimates of the difference in median percent change between canagliflozin and placebo at weeks 26, 52, and 104 were −8.3% (95% CI: −14.0% to −ii.five%), −11.ix% (95% CI: −18.0% to −5.six%), and −x.0% (95% CI: −17.iii% to −2.6%), respectively. Differences between canagliflozin and placebo were meaning at each time point (nominal p < 0.01 for each between-grouping difference). Considering the correlation between baseline and 104-week concentrations of hsTnI (Online Figure 1B), a lower gradient from baseline to final measurement was observed in those treated with canagliflozin.

Baseline serum sST2 concentrations were approximately 29 ng/ml. In contrast to NT-proBNP and hsTnI, median sST2 levels were unchanged in both the canagliflozin and placebo groups at each fourth dimension betoken (Hodges-Lehmann estimates of the difference in median percentage change of −0.8% [95% CI: −3.3% to 1.7%], 0.2% [95% CI: −ii.half-dozen% to 3.0%], and −0.4% [95% CI: −3.v% to 2.seven%] at weeks 26, 52, and 104, respectively; nominal p > 0.05 at each fourth dimension bespeak) (Figure 1C).

Baseline serum galectin-3 concentrations were approximately 17 ng/ml. Small increases from baseline in median galectin-3 levels were observed with canagliflozin relative to placebo at 26 weeks (half-dozen.6% [95% CI: three.seven% to nine.6%]; nominal p < 0.01) and 52 weeks (five.1% [95% CI: ii.0% to viii.3%]; nominal p < 0.01); past 104 weeks, the difference in galectin-3 was still numerically higher in the canagliflozin arm only not statistically significant (iii.0% [95% CI: −0.7% to six.6%]; nominal p = 0.11) (Effigy 1D). Information technology is of annotation that similar trends in eGFR were seen every bit in the galectin-3 data; modest decreases in eGFR were seen at 26 and 52 weeks with canagliflozin compared with placebo, simply by 104 weeks, no difference in change in eGFR was observed betwixt treatment groups.

With the exception of a negative correlation betwixt galectin-3 concentrations and eGFR, there were generally no clinically meaningful correlations between change in biomarkers and change in selected physiological parameters at any time point (Online Table 1).

In a sensitivity assay amid patients who had biomarker data at baseline and all 3 time points, changes in cardiovascular biomarkers were consistent with those seen in the principal analysis (Online Figures 2A to 2D).

Word

In this randomized trial of older patients with T2DM with biomarker profiles consistent with a generally higher risk for cardiovascular events, we found that serum concentrations of NT-proBNP and hsTnI, biomarkers with proven prognostic value for cardiovascular risk in T2DM (22), rose over a 2-year flow in patients allocated to placebo, whereas canagliflozin treatment attenuated their rise. In dissimilarity, we found no obvious consequence of handling with canagliflozin on concentrations of sST2, with a modest, nonpersistent rise in galectin-iii. The effects on NT-proBNP and hsTnI seen with canagliflozin versus placebo in this post hoc analysis are compatible with attenuation of cardiovascular take chances in those treated with SGLT2 inhibitors (Key Analogy). To the extent that it is unclear whether benefits seen in the EMPA-REG OUTCOME study could exist expected from treatment with all SGLT2 inhibitors, our results provide novel data regarding possible cardiovascular benefits from canagliflozin treatment.

Fundamental Illustration

Proposed Mechanisms of Do good of Canagliflozin and Outcome on Cardiac Biomarkers

Through its benign effects on the middle, canagliflozin prevented a ascent in N-terminal pro–B-type natriuretic peptide (NT-proBNP) and loftier-sensitivity troponin I (hsTnI). Possibly through transient reduction in estimated glomerular filtration charge per unit (eGFR), galectin-3 increased modestly. Na/H = sodium/proton; SGLT2 = sodium glucose co-transporter 2.

Numerous theories have emerged to explain how SGLT2 inhibitors may reduce cardiovascular risk; however, no consensus exists as to the mechanism of such run a risk reduction. The early difference of survival curves seen in the EMPA-REG Outcome study suggests an astute effect in particular on heart failure outcomes (four). It has been proposed that sodium and fluid loss, reduction in BP and body weight, attenuation of inflammation and oxidative stress, improvement in arterial stiffness, as well equally preservation of renal function may contribute to the observed cardiac benefits (7,10,11,23). Involvement has also focused on metabolic furnishings in the myocardium, including changes in glucagon handling, mitigation of glucotoxicity, and shift to fatty acrid metabolism, also as attenuation of cardiac remodeling (v–ix,eleven). Treatment with SGLT2 inhibitors has been shown to increase levels of ketone bodies, which may be a more than favorable energetic substrate for the heart compared with glucose or fat acids (5,6). Additionally, SGLT2 inhibitors may inhibit the sodium-hydrogen exchanger, leading to reduction of intracellular sodium and calcium in a cariporide-dependent fashion (24), which may foster a cardioprotective event. Finally, in a basic scientific discipline model of heart failure, empagliflozin treatment or knockdown of the SLC5A2 gene (simulating SGLT2 inhibition) created a phenotype with improved cardiac role and reduced BNP expression (25). Our biomarker results help to farther the understanding of how SGLT2 inhibition might exert a favorable touch on cardiovascular events.

We lack data on biomarker concentrations during the first 26 weeks of handling with canagliflozin, making it impossible to determine whether the biomarker changes observed in this analysis are somewhat related to diuretic furnishings from SGLT2 inhibition; studies suggest there is a ten% reduction in plasma volume after ane week of treatment with canagliflozin, but the plasma volume virtually returns to baseline by week 12 (26). An alternative or linked possibility is to consider that our findings betoken prevention of rise in NT-proBNP or hsTnI.

Biomarker measurements may assistance inform the mechanism of benefit in patients treated with novel therapies (13), with change over time frequently imparting greater prognostic information than a single measurement or noesis of absolute concentration. Our results stand for the first larger-scale, placebo-controlled information regarding cardiac biomarkers in patients treated with SGLT2 inhibition. In a recent study of 66 patients treated with empagliflozin, but without placebo control, serum NT-proBNP concentrations were unchanged subsequently iv weeks in patients with or without T2DM (16). In another small study of 75 patients with T2DM randomized to dapagliflozin, hydrochlorothiazide, or placebo, no differences in NT-proBNP were seen over 12 weeks of follow-up (17). Thus, our results, gathered in much larger numbers and for a much longer flow of fourth dimension, substantially extend the understanding of how novel drugs for T2DM may exert favorable cardiovascular effects.

Concentrations of each biomarker measured in this exploratory analysis are consistent with those expected for an older patient study group with at least a moderate risk for cardiovascular events (27). Furthermore, over time, placebo-treated patients demonstrated increases in both NT-proBNP and hsTnI; such changes, though pocket-sized, may be indicative of increasing risk for cardiovascular events and heart failure (14,27). Our findings bespeak that treatment with canagliflozin was associated with a blunting of the ascension in NT-proBNP and hsTnI over fourth dimension. Taken together, these results are compatible with the early and sustained cardiovascular benefits seen in the EMPA-REG Effect study.

Baseline sST2 concentrations in our written report participants indicate a more often than not higher-gamble patient population, with a median value nigh the 90th percentile for a normal healthy population (28). Nosotros did non discover any effect on sST2 concentrations with canagliflozin. In contrast, relatively smaller, but significant increases in galectin-3 concentrations were observed at 26 and 52 weeks in patients treated with canagliflozin; by 104 weeks, galectin-3 concentrations were nevertheless numerically, but not significantly, higher in the canagliflozin arm. Renal function is a known confounder of galectin-iii, and canagliflozin treatment is associated with initial reductions in eGFR that trend back toward baseline with connected treatment (29). Indeed, modest reductions in eGFR paralleled the increase in galectin-iii, and there was a correlation between change in galectin-iii and change in eGFR over time: thus, alter in renal office may business relationship for the declining betwixt-group difference beyond fourth dimension points. Information technology is unknown whether a pocket-size early increase in galectin-3 with canagliflozin is clinically relevant.

Study limitations

Though the electric current results are the first larger-scale, placebo-controlled assessment of multiple cardiovascular biomarkers in patients with T2DM treated with canagliflozin, in that location are a few limitations of this report. Starting time, not all patients had samples at every time point; however, a sensitivity analysis using data from patients with samples at all 3 time points showed consistent results. Likewise, exclusion of patients with eGFR <50 ml/min/1.73 m^two might render our data less generalizable to those with worse renal function; this exclusion criterion was due to utilise of metformin in an older patient population. However, this minimizes confounding effects of worse renal function on biomarker concentrations. Differences in the concentrations of NT-proBNP and hsTnI between placebo- and canagliflozin-treated patients were relatively small. However, small changes in both biomarkers may exist substantially prognostic, and consistency beyond multiple time points suggests that these changes for NT-proBNP and hsTnI are more likely to be robust. Lastly, we lack data on other novel biomarkers with prognostic value such every bit mid-regional pro-adrenomedullin or growth differentiation factor-15. Larger studies should confirm our findings, and, ideally, hereafter outcomes trials should examine links between biomarker changes and long-term cardiovascular affliction outcomes.

Conclusions

Our findings advise that canagliflozin handling was associated with attenuation of biomarkers associated with agin cardiovascular outcomes in this study population of older patients with T2DM. Every bit it is difficult to know for sure whether the benefits seen in the EMPA-REG Issue report related to treatment with empagliflozin can be extrapolated to treatment with canagliflozin, our results are important, and might predict similar risk reduction from canagliflozin handling. Results from the Canvas Program, including CANVAS (CANagliflozin cardioVascular Assessment Study [ NCT01032629]) and CANVAS-R (CANagliflozin cardioVascular Assessment Written report-Renal [ NCT01989754]), provide direct evidence on the effects of canagliflozin on cardiovascular outcomes in patients with a history or high risk of cardiovascular disease (thirty–33).

Perspectives

COMPETENCY IN MEDICAL Knowledge: Elevated levels of NT-proBNP and hsTnI are associated with an increased risk of cardiovascular events, including centre failure and bloodshed, in older patients with T2DM. SGLT2 inhibitors reduce NT-proBNP and hsTnI concentrations and lower cardiovascular risk in these patients.

TRANSLATIONAL OUTLOOK: Farther studies are needed to understand the mechanisms by which SGLT2 inhibitors ameliorate myocardial stress and prevent necrosis in patients with T2DM and to clarify how biomarkers can be optimally utilized to guide therapy.

Abbreviations and Acronyms

BP	blood pressure
CI	confidence interval
CV	coefficients of variation
eGFR	estimated glomerular filtration rate
hsTnI	loftier-sensitivity troponin I
NT-proBNP	N-final pro–B-type natriuretic peptide
SGLT2	sodium glucose co-transporter 2
sST2	soluble ST2
T2DM	type 2 diabetes mellitus

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Footnotes

This report was sponsored by Janssen Scientific Affairs, LLC, and Janssen Global Services, LLC, funded the medical writing support. Dr. Januzzi has received inquiry support from Janssen, Boehringer Ingelheim, Novartis, Roche Diagnostics, Siemens, Prevencio, Singulex, and Amgen; has served as a consultant for Janssen, Abbott, Boehringer Ingelheim, Novartis, Roche Diagnostics, and Philips; and has served on clinical endpoints adjudication committees for AbbVie and Pfizer. Dr. Butler has served every bit a consultant for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, CardioCell, CVRx, Janssen, Merck, Novartis, Relypsa, Vifor Pharma, and ZS Pharma. Dr. Jarolim has received research back up through his institution from Abbott Laboratories, AstraZeneca, Daiichi-Sankyo, GlaxoSmithKline, Janssen, Merck, Roche Diagnostics, Takeda Global Research and Development Center, and Waters Technologies Corporation. Dr. Sattar has served on advisory boards for Janssen, Boehringer Ingelheim, Eli Lilly, Amgen, and Novo Nordisk; and has received enquiry support from AstraZeneca and Boehringer Ingelheim. Drs. Vijapurkar and Desai are full-time employees of Janssen Research & Evolution, LLC; and own stock in Johnson & Johnson. Dr. Davies is a full-time employee of Janssen Scientific Affairs, LLC; and owns stock in Johnson & Johnson. P.K. Shah, Md, served as Guest Editor-in-Principal, and Wolfgang Koenig, Doc, served equally Invitee Editor for this article.

Listen to this manuscript's audio summary by JACC Editor-in-Primary Dr. Valentin Fuster.

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Source: https://www.jacc.org/doi/10.1016/j.jacc.2017.06.016

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