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 Table of Contents  
REVIEW ARTICLE
Year : 2017  |  Volume : 2  |  Issue : 2  |  Page : 75-79

EMPA-REG OUTCOME trial and Canagliflozin Cardiovascular Assessment Study: Looking beyond the obvious


1 Department of Medicine, KPC Medical College and Hospital, Kolkata, West Bengal, India
2 Department of Medical Affairs, Boehringer Ingelheim Pvt. Ltd., Mumbai, Maharashtra, India

Date of Submission23-Aug-2017
Date of Acceptance09-Oct-2017
Date of Web Publication15-Dec-2017

Correspondence Address:
Dr. Rishad Ahmed
26 Shamsul Huda Road, 3rd Floor, Kolkata - 700 017, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/bjhs.bjhs_19_17

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  Abstract 


With the addition of sodium–glucose cotransporter-2 inhibitors to the current arsenal of oral antidiabetics (OAD), a lot has changed. From questioning their glucouretic mechanism to understanding their pleiotropic effects, it has been an eventful journey. In 2008, after the rosiglitazone fiasco, the US Food and Drug Administration (FDA) mandate was passed to ensure the safety of the OAD. Up to the gliptins, there was an era of cardiovascular (CV) safety which progressed to CV protection with the EMPA-REG OUTCOME trial. It came with a lot of questions regarding the probable mechanism and the doubts of whether it will translate into a class effect or not. After the Canagliflozin CV Assessment Study results, a lot of things have come into light regarding the overall benefits with these molecules. This review highlights the similarities and dissimilarities in the two trial results.

Keywords: Canagliflozin Cardiovascular Assessment Study, EMPA-REG, sodium–glucose cotransporter inhibitors


How to cite this article:
Ahmed R, Kawatra P. EMPA-REG OUTCOME trial and Canagliflozin Cardiovascular Assessment Study: Looking beyond the obvious. BLDE Univ J Health Sci 2017;2:75-9

How to cite this URL:
Ahmed R, Kawatra P. EMPA-REG OUTCOME trial and Canagliflozin Cardiovascular Assessment Study: Looking beyond the obvious. BLDE Univ J Health Sci [serial online] 2017 [cited 2018 Sep 21];2:75-9. Available from: http://www.bldeujournalhs.in/text.asp?2017/2/2/75/220939



The management of diabetes has taken huge leaps in the past decade in terms of the expansion of the drugs available for the management as well as a change in approach from a glucocentric to a holistic management. By virtue of excreting glucose in urine along with sodium, they cause a whole lot of metabolic and hemodynamic changes, discussing which is beyond the scope of this review. Nevertheless, sodium–glucose cotransporter-2 (SGLT2) inhibitors have been a revelation in terms of changing the pathological aspect of glucose excretion in urine into a treatment of diabetes.

The era of SGLT2 inhibitors dawned with the launch of canagliflozin (cana) followed by dapagliflozin and empagliflozin (empa) in the diabetic market. Canagliflozin was approved by the US Food and Drug Administration (FDA) in March 2013 following the interim analysis of the Canagliflozin Cardiovascular (CV) Assessment Study (CANVAS) trial in 2009. But what gave SGLT2 inhibitors a boost were the results of the EMPA-REG OUTCOME trial published in New England Journal of Medicine in 2015. Since then, there has been a huge proclivity of most specialties to go in for this class which offers more than just glucose control. A lot of theories came up regarding their pleiotropic effects. The unexpected, unprecedented massive reduction in CV mortality provoked more questions than answers in terms of the mechanism of action and whether this will be a class effect or not.[1]

The very much awaited results of CANVAS were released in June 2017 in the American Diabetes Association (ADA). They have definitely thrown more light regarding the overall CV safety and the possibility of renal benefits with SGLT2 inhibitors. The two trials have been different in terms of their designs, statistical analysis, and the inclusion criteria. A head-to-head comparison, therefore, may not be suitable in such a scenario. This review highlights the subtle differences between the Canagliflozin CV Assessment Study (CANVAS) and EMPA-REG OUTCOME trials and why the results although positive may be taken with a pinch of salt.


  Trial Design and Duration Top


The CANVAS program is a pooled analysis of the CANVAS and the CANVAS-Renal (CANVAS-R), which was done following approval of the regulatory authorities.[2] The original CANVAS started in 2009 with the primary end point as 3-point major adverse CV events (3P-MACE) consisting of nonfatal myocardial infarction, nonfatal stroke, and CV deaths. Following the partial unblinding in 2012 due to a signal in increase in low-density lipoprotein, further recruitment was stopped. To accrue adequate number of events, CANVAS-R began in 2014 and continued till 2017 with the primary end point of progression of albuminuria and secondary end point as CV mortality or hospitalization due to heart failure. Although it is a pooled analysis, the number of patients is less than the originally planned CANVAS trial reflecting upon the decision to show mainly CV safety.[2] Even the hierarchical statistical analysis plan as mentioned in the study by Neal et al.[2] states the primary outcome to be a noninferiority of 3P-MACE which proceeds directly to superiority for all-cause mortality to preserve the type 1 error as shown in [Figure 2]. In EMPA-REG OUTCOME trial, the hierarchy was noninferiority for 3P-MACE, noninferiority for 4P-MACE, superiority for 3P-MACE, and superiority for 4P-MACE (consist of added events of hospitalization due to unstable angina) [Figure 1] and [Figure 2].
Figure 1: Statistical hierarchy in EMPA-REG OUTCOME trial

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Figure 2: Statistical hierarchy for Canagliflozin Cardiovascular Assessment Study

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The mean follow-up in the pooled CANVAS analysis was 188.2 weeks (3.62 years) and the median follow-up 126.1 weeks (2.43 years) as compared to EMPA-REG OUTCOME trial where the median observation time was 3.1 years.[3]


  Inclusion and Exclusion Criteria Top


EMPA-REG OUTCOME trial had more than 99% of the patients with an established CV disease (CVD). These patients either had a history of a CV event such as MI, stroke, or coronary artery bypass grafting or an objective evidence of underlying CVD. Unlike the EMPA-REG OUTCOME trial, the inclusion criteria of CANVAS were along the lines of the clinical presentation of CVD where 65% of the patients in CANVAS had an established CV disease and the rest 35% had age >50 years with >2 CV risk factors (diabetes duration ≥10 years, systolic blood pressure >140 mmHg on ≥1 medication, current smoker, micro- or macro-albuminuria, or high-density lipoprotein cholesterol <1 mmol/L).


  Results Top


The 3P-MACE of CANVAS pooled analysis was similar when compared to EMPA-REG OUTCOME trial with a hazard ratio (HR) of 0.86. The P value of superiority for CANVAS was 0.02 as against the P value of 0.04 for the EMPA-REG OUTCOME trial. Furthermore, all the three individual end points of the 3P-MACE were in the same direction suggesting a more consistent result when matched with the EMPA-REG OUTCOME trial where the component of nonfatal stroke was numerically increased. Both these trials suggest a certain benefit on the basis of the results of the 3P-MACE, but the other end point such as reduction in CV deaths which was the driving force of the 3P-MACE in EMPA-REG OUTCOME trial was insignificant in CANVAS. The key CV results of the two trials have been shown in [Table 1].
Table 1: The results of both the trials

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  Looking Beyond Top


Despite the fact that the P value of CANVAS seems more robust for the 3P-MACE, the likelihood of a false-positive result cannot be ruled out since it was not a part of the original statistical hierarchical plan questioning the preservation of alpha error in such a scenario.

The results, when compared between the individual studies CANVAS and CANVAS-R, seem to be better in CANVAS-R even though the P value is not significantly different between the two studies as shown in [Table 2].
Table 2: The hazard ratios of the individual results of CANVAS, CANVAS R and the pooled analysis

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  Primary Prevention or Not? Top


It is known that the plaques of atherosclerosis in diabetes are more diffuse, vulnerable, and asymptomatic for a longer time.[4] As per the Framingham Heart Study, two-thirds of diabetic patients have a subclinical CVD.[5] In a study done on the deceased individuals to see for CAD, it was found that in the asymptomatic diabetic patients, 75% of the patients had high-grade coronary atherosclerosis and 50% or more had multivessel disease.[6] The patients in pooled analysis of CANVAS had an average age of 63 years with duration of diabetes of approximately 14 years, and 90% of the patients had hypertension. Overall, the results for the primary outcome in patients with CVD were 0.82 vis-a-vis 0.98 for patients without CVD although the P value of interaction remains insignificant.


  Renal End Points Top


In EMPA-REG OUTCOME trial and CANVAS, the renal end points were exploratory in nature. In both the trials, there were benefits in the renal end points. However, there are subtle differences in the end points chosen in both trials.

In the EMPA-REG OUTCOME trial, there was a 38% reduction in progression to macroalbuminuria along with 46% reduction in a composite end point of doubling of serum creatinine, need for renal replacement therapy, and death due to renal disease with a P value of < 0.001. In CANVAS, there was an 18% reduction in urinary albumin-creatinine ratio and a 40% reduction in the composite end point of prespecified 40% reduction in estimated glomerular filtration rate (eGFR), renal replacement therapy, or renal death. The Gail–Simon P value for progression of albuminuria for the pooled CANVAS analysis is 0.8750, implying that the magnitude of effect has been variable in both CANVAS and CANVAS-R but in the same direction.


  Safety Aspects Top


The incidence rate ratio, comparing the adverse effects in the two trials, has been shown below has been shown below in [Table 3]:
Table 3: Safety aspects in EMPA-REG OUTCOME trial and Canagliflozin Cardiovascular Assessment Study

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Two main signals that were of concern in this analysis were: fractures and amputations.

In the CANVAS study, there was a signal of an increase in fractures (HR: 1.56) in the patients with the following:

  • Low eGFR
  • Patients with high CV risk
  • On high baseline diuretics.


These findings were not replicated in the CANVAS-R, but the pooled analysis had a HR of 1.23. Following this, in 2015, FDA revised and strengthened the warning against the use of canagliflozin in patients predisposed to fracture risk.[7] However, meta-analysis of all studies (excluding CANVAS) comparing canagliflozin with placebo did not show any increase in fracture risk.[8]

The precise reason for these fractures is yet unknown, although in a study, canagliflozin has been found to cause a reduction in bone mineral density of the hip by 0.9% and 1.2% with 100 mg and 300 mg dose.[9] However, this does not correlate with the fractures in CANVAS since they were mainly upper extremity distal fractures. Another theory put forth by Taylor et al. suggests that an increase in phosphate levels following SGLT2 inhibitors results in an increase in parathyroid hormone and fibroblast growth factor-23.[10] Since both have an inverse effect on Vitamin D3, it may be difficult to predict the overall effect on the bone.

Another concern with CANVAS has been the signals of amputations.

The CANVAS trial showed that over a year's time, the risk of amputation for patients in the trial was equivalent to:[11]

  • 5.9 out of every 1000 patients treated with canagliflozin
  • 2.8 out of every 1000 patients treated with placebo.


The CANVAS-R trial showed that over a year's time, the risk of amputation for patients in the trial was equivalent to:

  • 7.5 out of every 1000 patients treated with canagliflozin
  • 4.2 out of every 1000 patients treated with placebo.


This led to a boxed warning on the safety concerns of canagliflozin by FDA. Meanwhile, the european medical association (EMA) recommended a warning in the prescribing information of all the drugs within the class due to unclear mechanisms. Nevertheless, it endorses amputations to be included as an “uncommon adverse effect” specifically for canagliflozin.[12] With empagliflozin, the pooled analysis of all phase I-III trials with >15,000 patients has shown similar incidence of fractures, amputations, and diabetic ketoacidosis as compared to placebo.[13]

In the recently published US FDA Adverse Event Reporting System, out of the total 66 amputations reported from SGLT2 inhibitors in the database, 57 are from canagliflozin. The possible theory suggested is the occurrence of “calciphylaxis” due to SGLT1 inhibition in the gut resulting in a hyperacidotic environment and increase absorption of calcium.[14]


  Conclusion Top


SGLT2 inhibitors as a class have shown to be beneficial in terms of their pleiotropic effects on the weight, blood pressure reduction, reduction in hospitalization due to heart failure, and delaying the progression of renal disorder. However, some questions remain to be answered. The differences in the results of the two trials suggest a variation in results which may be attributed to the difference in their pharmacological characteristics. So far, empagliflozin is the only oral antidiabetic agent, additionally approved by the US FDA and Drug Controller General of India, for CV mortality reduction in patients of T2D with CVD. The mechanism of all the benefits still remains to be elucidated. Mortality benefits have clearly been noted with empagliflozin and not with canagliflozin. The results of DECLARE-TIMI will probably throw more light on these aspects.

Financial support and sponsorship

Nil.

Conflicts of interest

Dr. Pallavi Kawatra is employed with Boehringer Ingelheim India Pvt., Ltd. However, her contribution to this review represents her own personal scientific view and does not endorse the view of Boehringer Ingelheim directly or indirectly.



 
  References Top

1.
Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-28.  Back to cited text no. 1
    
2.
Neal B, Perkovic V, Mahaffey KW, Fulcher G, Erondu N, Desai M, et al. Optimizing the analysis strategy for the CANVAS program: A prespecified plan for the integrated analyses of the CANVAS and CANVAS-R trials. Diabetes Obes Metab 2017;19:926-35.  Back to cited text no. 2
    
3.
Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:644-57.  Back to cited text no. 3
    
4.
Tavares CA, Wajchjenberg BL, Rochitte C, Lerario AC. Screening for asymptomatic coronary artery disease in patients with type 2 diabetes mellitus. Arch Endocrinol Metab 2016;60:143-51.  Back to cited text no. 4
    
5.
Ingelsson E, Sullivan LM, Murabito JM, Fox CS, Benjamin EJ, Polak JF, et al. Prevalence and prognostic impact of subclinical cardiovascular disease in individuals with the metabolic syndrome and diabetes. Diabetes 2007;56:1718-26.  Back to cited text no. 5
    
6.
Goraya TY, Leibson CL, Palumbo PJ, Weston SA, Killian JM, Pfeifer EA, et al. Coronary atherosclerosis in diabetes mellitus: A population-based autopsy study. J Am Coll Cardiol 2002;40:946-53.  Back to cited text no. 6
    
7.
Research C for DE and Drug Safety and Availability – FDA Drug Safety Communication: FDA Revises Label of Diabetes Drug Canagliflozin (Invokana, Invokamet) to Include Updates on Bone Fracture Risk and New Information on Decreased Bone Mineral Density. Available from: . [Last accessed on 2017 Jun 26].  Back to cited text no. 7
    
8.
Watts NB, Bilezikian JP, Usiskin K, Edwards R, Desai M, Law G, et al. Effects of canagliflozin on fracture risk in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab 2016;101:157-66.  Back to cited text no. 8
    
9.
Bilezikian JP, Watts NB, Usiskin K, Polidori D, Fung A, Sullivan D, et al. Evaluation of bone mineral density and bone biomarkers in patients with type 2 diabetes treated with canagliflozin. J Clin Endocrinol Metab 2016;101:44-51.  Back to cited text no. 9
    
10.
Taylor SI, Blau JE, Rother KI. Possible adverse effects of SGLT2 inhibitors on bone. Lancet Diabetes Endocrinol 2015;3:8-10.  Back to cited text no. 10
    
11.
Research C for DE and Drug Safety and Availability – FDA Drug Safety Communication: FDA Confirms Increased Risk of Leg and Foot Amputations with the Diabetes Medicine Canagliflozin (Invokana, Invokamet, Invokamet XR). Available from: https://www.fda.gov/Drugs/DrugSafety/ucm557507.htm. [Last accessed on 2017 Jun 27].  Back to cited text no. 11
    
12.
EMA: Amputation Warning With SGLT2 Inhibitors Must Be on Label. Medscape. Available from: http://www.medscape.com/viewarticle/875649. [Last accessed on 2017 Jun 27].  Back to cited text no. 12
    
13.
Kohler S, Zeller C, Iliev H, Kaspers S. Safety and tolerability of empagliflozin in patients with type 2 diabetes: Pooled analysis of phase I-III clinical trials. Adv Ther 2017;34:1707-26.  Back to cited text no. 13
    
14.
Fadini GP, Avogaro A. SGTL2 Inhibitors and Amputations in the US FDA Adverse Event Reporting System. Lancet Diabetes Endocrinol; Jul 18 2017. Available from: http://www.thelancet.com/journals/landia/article/PIIS2213-8587 (17) 30257-7/abstract. [Last accessed on 2017 Jul 29].  Back to cited text no. 14
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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Looking Beyond
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