Expert Opinion on Pharmacotherapy
ISSN: 1465-6566 (Print) 1744-7666 (Online) Journal homepage: http://www.tandfonline.com/loi/ieop20
Efficacy and safety of canagliflozin in type 2 diabetes mellitus: systematic review of randomized controlled trials Rizwana Parveen, Nidhi Bharal Agarwal, Neelam Kaushal, Ghanshyam Mali & Sheikh Raisuddin To cite this article: Rizwana Parveen, Nidhi Bharal Agarwal, Neelam Kaushal, Ghanshyam Mali & Sheikh Raisuddin (2015): Efficacy and safety of canagliflozin in type 2 diabetes mellitus: systematic review of randomized controlled trials, Expert Opinion on Pharmacotherapy, DOI: 10.1517/14656566.2016.1109629 To link to this article: http://dx.doi.org/10.1517/14656566.2016.1109629
Published online: 09 Dec 2015.
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Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ieop20 Download by: [University of Otago]
Date: 11 December 2015, At: 14:34
Downloaded by [University of Otago] at 14:34 11 December 2015
Review
1.
Introduction
2.
Method
3.
Results
4.
Conclusion
5.
Expert opinion
Efficacy and safety of canagliflozin in type 2 diabetes mellitus: systematic review of randomized controlled trials Rizwana Parveen, Nidhi Bharal Agarwal†, Neelam Kaushal, Ghanshyam Mali & Sheikh Raisuddin †
Centre for Translational and Clinical Research, Jamia Hamdard, New Delhi 110062, India
Background: Currently available antihyperglycemic agents (AHAs), despite being effective, do not provide adequate glycemic control in some cases and are associated with side effects. A sodium glucose co-transporter 2 inhibitor, canagliflozin, is a newer AHA, which acts by decreasing the reabsorption of filtered glucose thereby elevating the urinary glucose excretion in diabetics. Areas covered: This systematic review was completed to assess the clinical effectiveness and safety of canagliflozin in T2DM. A literature search in PubMed, MEDLINE, Cochrane and ClinicalTrials.gov was conducted for randomized clinical trials of canagliflozin as an AHA by applying predetermined inclusion and exclusion criteria. Total 13 studies were included in the systematic review. The main outcomes assessed were change in HbA1c and fasting plasma glucose. Expert opinion: Canagliflozin monotherapy or combination therapy has the potential to decrease inadequately controlled hyperglycemia in T2DM. It acts by a novel insulin independent mechanism which complements the action of the existing AHA and improves glycemic control and decreases the body weight. Safety profile of canagliflozin indicates lower number of hypoglycemic episodes. Some manageable adverse events include genital mycotic infections, urinary tract infections, osmotic diuresis-related events etc. These findings affirm the utility of canagliflozin in T2DM; however, data on longterm safety and efficacy are needed. Keywords: canagliflozin, oral hypoglycemics, SGLT2 inhibitor, type 2 diabetes mellitus Expert Opin. Pharmacother. [Early Online]
1.
Introduction
Hyperglycemia in type 2 diabetes mellitus (T2DM) is associated with the risk of long-term complications.[1] Although there are effective and well-tolerated treatments available, still many patients could not attain recommended glycemic level. [2,3] First-line therapy with metformin has been found to be associated with poor glycemic control and often requires combination therapy with a second- or thirdline glucose-lowering agents [1,4] such as sulfonylureas, incretins, thiazolidinediones and insulin. Although having beneficial effect on glucose levels, many of these drugs are associated with weight gain, fluid retention, increased risk of congestive heart failure and hypoglycemia [5,6] that limit their usage. These effects are further associated with less effectiveness of antihyperglycemic agents (AHAs) due to β-cell dysfunction as initial and combination therapy. Thus, glucose-lowering agents that are independent of β-cell function may prove to be 10.1517/14656566.2016.1109629 © 2015 Taylor & Francis ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted
1
Parveen et al.
Downloaded by [University of Otago] at 14:34 11 December 2015
Article highlights ● Canagliflozin acts by a new insulin-independent mechanism, which complements the action of the available conventional therapies for diabetes. ● It adequately improves glycemic control, as evident from the reduction in HbA1c and fasting plasma glucose. Moreover, it produces weight loss that is an add-on benefit to diabetics with obesity. ● Canagliflozin produces less episodes of hypoglycemia but is associated with increased risk of genital mycotic infections, urinary tract infection and osmotic diuresisrelated adverse events. ● The results of clinical trials on canagliflozin are convincing enough to affirm the utility of canagliflozin as an adjunct therapy with a background therapy of conventional drugs. ● Safety issues about its use need to be studied further in long duration trials. This box summarizes key points contained in the article.
beneficial in combination therapy.[1] There is a strong need for drugs that can improve β-cell function, devoid of adverse effects such as weight gain and hypoglycemia and above all provide adequate glycemic control.[5–7] Sodium glucose co-transporters (SGLTs) belong to the family of sodium glucose co-transporter solute carrier family 5. SGLT1 are present predominantly in proximal tubule of nephrons, myocardium and small intestines, whereas SGLT2 are specifically expressed in the brush border of epithelial cells in S1 and S2 segments of proximal renal tubules. Increase in plasma glucose level raises the expression and activity of SGLT2, which is not related to renal gluconeogenesis and may be increased in diabetics.[8] Most of the filtered glucose is reabsorbed by SGLT2 from the tubular lumen. [7,9–11] Persistent increase in the blood glucose levels in diabetics may be attributed to increased renal glucose reabsorption.[1] SGLT2 inhibitors represent a new class of drugs [12] and are expected to have a substantial influence in the management of diabetes and anticipated to attain a successful status.[13] SGLT2 inhibitors include canagliflozin, ipragliflozin, dapagliflozin, empagliflozin, tofogliflozin and luseogliflozin.[14] Canagliflozin, an orally active SGLT2 inhibitor,[10] decreases the reabsorption of filtered glucose and reduces the renal threshold for glucose, thereby elevating the urinary glucose excretion (UGE) and reducing the raised plasma glucose levels in patients of T2DM [5,7,9–11,15,16] by an insulin-independent mechanism. The elevated urinary glucose excretion converts in an osmotic diuresis, which causes loss of calories resulting in a decrease in body weight.[10] Osmotic diuresis may be one of the causes for reduction in systolic blood pressure (SBP), other proposed mechanisms for antihypertensive action of SGLT2 inhibitors include weight loss and nitric oxide release that is secondary to reduced oxidant stress due to better glycemic control.[17] 2
At present, SGLT2 inhibitors have been highlighted as an alternative approach in addition to the conventional AHAs in T2DM.[5,17] SGLT2 inhibitors have been found to be effective in improving glycemic control, reducing body weight, lowering SBP and decreasing fasting plasma glucose (FPG) level when used in combination therapies.[18] Also, canagliflozin monotherapy has been shown to improve glycemic control and reduce body weight in patients with T2DM inadequately controlled with diet and exercise.[19] In spite of having numerous beneficial effects such as lowering of blood glucose and body weight, canagliflozin is associated with many adverse effects. The general objective of this systematic review is to assess the efficacy and safety profile of canagliflozin in patients with T2DM based on reported randomized controlled trials (RCTs) and the specific objectives were to analyze percentage change in glycated hemoglobin (HbA1c), FPG, body weight and proportion of patients achieving HbA1c
ISSN: 1465-6566 (Print) 1744-7666 (Online) Journal homepage: http://www.tandfonline.com/loi/ieop20
Efficacy and safety of canagliflozin in type 2 diabetes mellitus: systematic review of randomized controlled trials Rizwana Parveen, Nidhi Bharal Agarwal, Neelam Kaushal, Ghanshyam Mali & Sheikh Raisuddin To cite this article: Rizwana Parveen, Nidhi Bharal Agarwal, Neelam Kaushal, Ghanshyam Mali & Sheikh Raisuddin (2015): Efficacy and safety of canagliflozin in type 2 diabetes mellitus: systematic review of randomized controlled trials, Expert Opinion on Pharmacotherapy, DOI: 10.1517/14656566.2016.1109629 To link to this article: http://dx.doi.org/10.1517/14656566.2016.1109629
Published online: 09 Dec 2015.
Submit your article to this journal
Article views: 6
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ieop20 Download by: [University of Otago]
Date: 11 December 2015, At: 14:34
Downloaded by [University of Otago] at 14:34 11 December 2015
Review
1.
Introduction
2.
Method
3.
Results
4.
Conclusion
5.
Expert opinion
Efficacy and safety of canagliflozin in type 2 diabetes mellitus: systematic review of randomized controlled trials Rizwana Parveen, Nidhi Bharal Agarwal†, Neelam Kaushal, Ghanshyam Mali & Sheikh Raisuddin †
Centre for Translational and Clinical Research, Jamia Hamdard, New Delhi 110062, India
Background: Currently available antihyperglycemic agents (AHAs), despite being effective, do not provide adequate glycemic control in some cases and are associated with side effects. A sodium glucose co-transporter 2 inhibitor, canagliflozin, is a newer AHA, which acts by decreasing the reabsorption of filtered glucose thereby elevating the urinary glucose excretion in diabetics. Areas covered: This systematic review was completed to assess the clinical effectiveness and safety of canagliflozin in T2DM. A literature search in PubMed, MEDLINE, Cochrane and ClinicalTrials.gov was conducted for randomized clinical trials of canagliflozin as an AHA by applying predetermined inclusion and exclusion criteria. Total 13 studies were included in the systematic review. The main outcomes assessed were change in HbA1c and fasting plasma glucose. Expert opinion: Canagliflozin monotherapy or combination therapy has the potential to decrease inadequately controlled hyperglycemia in T2DM. It acts by a novel insulin independent mechanism which complements the action of the existing AHA and improves glycemic control and decreases the body weight. Safety profile of canagliflozin indicates lower number of hypoglycemic episodes. Some manageable adverse events include genital mycotic infections, urinary tract infections, osmotic diuresis-related events etc. These findings affirm the utility of canagliflozin in T2DM; however, data on longterm safety and efficacy are needed. Keywords: canagliflozin, oral hypoglycemics, SGLT2 inhibitor, type 2 diabetes mellitus Expert Opin. Pharmacother. [Early Online]
1.
Introduction
Hyperglycemia in type 2 diabetes mellitus (T2DM) is associated with the risk of long-term complications.[1] Although there are effective and well-tolerated treatments available, still many patients could not attain recommended glycemic level. [2,3] First-line therapy with metformin has been found to be associated with poor glycemic control and often requires combination therapy with a second- or thirdline glucose-lowering agents [1,4] such as sulfonylureas, incretins, thiazolidinediones and insulin. Although having beneficial effect on glucose levels, many of these drugs are associated with weight gain, fluid retention, increased risk of congestive heart failure and hypoglycemia [5,6] that limit their usage. These effects are further associated with less effectiveness of antihyperglycemic agents (AHAs) due to β-cell dysfunction as initial and combination therapy. Thus, glucose-lowering agents that are independent of β-cell function may prove to be 10.1517/14656566.2016.1109629 © 2015 Taylor & Francis ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted
1
Parveen et al.
Downloaded by [University of Otago] at 14:34 11 December 2015
Article highlights ● Canagliflozin acts by a new insulin-independent mechanism, which complements the action of the available conventional therapies for diabetes. ● It adequately improves glycemic control, as evident from the reduction in HbA1c and fasting plasma glucose. Moreover, it produces weight loss that is an add-on benefit to diabetics with obesity. ● Canagliflozin produces less episodes of hypoglycemia but is associated with increased risk of genital mycotic infections, urinary tract infection and osmotic diuresisrelated adverse events. ● The results of clinical trials on canagliflozin are convincing enough to affirm the utility of canagliflozin as an adjunct therapy with a background therapy of conventional drugs. ● Safety issues about its use need to be studied further in long duration trials. This box summarizes key points contained in the article.
beneficial in combination therapy.[1] There is a strong need for drugs that can improve β-cell function, devoid of adverse effects such as weight gain and hypoglycemia and above all provide adequate glycemic control.[5–7] Sodium glucose co-transporters (SGLTs) belong to the family of sodium glucose co-transporter solute carrier family 5. SGLT1 are present predominantly in proximal tubule of nephrons, myocardium and small intestines, whereas SGLT2 are specifically expressed in the brush border of epithelial cells in S1 and S2 segments of proximal renal tubules. Increase in plasma glucose level raises the expression and activity of SGLT2, which is not related to renal gluconeogenesis and may be increased in diabetics.[8] Most of the filtered glucose is reabsorbed by SGLT2 from the tubular lumen. [7,9–11] Persistent increase in the blood glucose levels in diabetics may be attributed to increased renal glucose reabsorption.[1] SGLT2 inhibitors represent a new class of drugs [12] and are expected to have a substantial influence in the management of diabetes and anticipated to attain a successful status.[13] SGLT2 inhibitors include canagliflozin, ipragliflozin, dapagliflozin, empagliflozin, tofogliflozin and luseogliflozin.[14] Canagliflozin, an orally active SGLT2 inhibitor,[10] decreases the reabsorption of filtered glucose and reduces the renal threshold for glucose, thereby elevating the urinary glucose excretion (UGE) and reducing the raised plasma glucose levels in patients of T2DM [5,7,9–11,15,16] by an insulin-independent mechanism. The elevated urinary glucose excretion converts in an osmotic diuresis, which causes loss of calories resulting in a decrease in body weight.[10] Osmotic diuresis may be one of the causes for reduction in systolic blood pressure (SBP), other proposed mechanisms for antihypertensive action of SGLT2 inhibitors include weight loss and nitric oxide release that is secondary to reduced oxidant stress due to better glycemic control.[17] 2
At present, SGLT2 inhibitors have been highlighted as an alternative approach in addition to the conventional AHAs in T2DM.[5,17] SGLT2 inhibitors have been found to be effective in improving glycemic control, reducing body weight, lowering SBP and decreasing fasting plasma glucose (FPG) level when used in combination therapies.[18] Also, canagliflozin monotherapy has been shown to improve glycemic control and reduce body weight in patients with T2DM inadequately controlled with diet and exercise.[19] In spite of having numerous beneficial effects such as lowering of blood glucose and body weight, canagliflozin is associated with many adverse effects. The general objective of this systematic review is to assess the efficacy and safety profile of canagliflozin in patients with T2DM based on reported randomized controlled trials (RCTs) and the specific objectives were to analyze percentage change in glycated hemoglobin (HbA1c), FPG, body weight and proportion of patients achieving HbA1c
