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SGLT2 inhibitors - an insulin-independent therapeutic approach for treatment of type 2 diabetes: focus on canagliflozin.

Seufert J - Diabetes Metab Syndr Obes (2015)

Bottom Line: SGLT2 inhibitors provide additional reductions in body weight and blood pressure due to the therapeutically induced excretion of glucose and sodium through the kidneys.These "concomitant effects" are particularly interesting with regard to the increased cardiovascular risk in T2DM.New mechanisms of action like that of SGLT2 inhibitors such as canagliflozin, which can be used both in early and late stages of diabetes, are a welcome addition to expand the treatment options for patients at every stage of T2DM.

View Article: PubMed Central - PubMed

Affiliation: Department of Endocrinology and Diabetology, Clinic for Internal Medicine II, Freiburg University Hospital, Freiburg, Germany.

ABSTRACT
Despite the availability of a great variety of medications, a significant proportion of people with type 2 diabetes mellitus (T2DM) are not able to achieve or maintain adequate glycemic control. Beyond improved glucose control, novel treatments would ideally provide a reduction of cardiovascular risk, with a favorable impact on excess weight, and a low intrinsic hypoglycemia risk, as well as a synergistic mechanism of action for broad combination therapy. With the development of sodium glucose cotransporter 2 (SGLT2) inhibitors, an antidiabetic pharmacologic option has recently become available that comes close to meeting these requirements. For the first time, SGLT2 inhibitors offer a therapeutic approach acting directly on the kidneys without requiring insulin secretion or action. Canagliflozin, dapagliflozin, and empagliflozin are the SGLT2 inhibitors approved to date. Taken once a day, these medications can be combined with all other antidiabetic medications including insulin, due to their insulin-independent mechanism of action, with only a minimal risk of hypoglycemia. SGLT2 inhibitors provide additional reductions in body weight and blood pressure due to the therapeutically induced excretion of glucose and sodium through the kidneys. These "concomitant effects" are particularly interesting with regard to the increased cardiovascular risk in T2DM. In many cases, T2DM treatment requires a multidimensional approach where the treatment goals have to be adapted to the individual patient. While there is a consensus on the use of metformin as a first-line drug therapy, various antidiabetics are used for treatment intensification. New mechanisms of action like that of SGLT2 inhibitors such as canagliflozin, which can be used both in early and late stages of diabetes, are a welcome addition to expand the treatment options for patients at every stage of T2DM. The efficacy and tolerability of canagliflozin have been tested in an extensive clinical trial program described in this review article.

No MeSH data available.


Related in: MedlinePlus

Phase III trial program with canagliflozin.Notes: Data from published studies.14,26,28–32,34Abbreviations: OAD, oral antidiabetic; MET, metformin; PBO, placebo; SITA, sitagliptin; PIO, pioglitazone; CANVAS, CANagliflozin cardioVascular Assessment Study; SU, sulfonylurea; GLIM, glimepiride; T2DM, type 2 diabetes mellitus; CV, cardiovascular; eGFR, estimated glomerular filtration rate.
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f2-dmso-8-543: Phase III trial program with canagliflozin.Notes: Data from published studies.14,26,28–32,34Abbreviations: OAD, oral antidiabetic; MET, metformin; PBO, placebo; SITA, sitagliptin; PIO, pioglitazone; CANVAS, CANagliflozin cardioVascular Assessment Study; SU, sulfonylurea; GLIM, glimepiride; T2DM, type 2 diabetes mellitus; CV, cardiovascular; eGFR, estimated glomerular filtration rate.

Mentions: A total of 10,285 patients with T2DM participated in the prospective, double-blind, controlled studies investigating the efficacy and safety of the SGLT2 inhibitor canagliflozin.14 Specific populations, such as elderly patients, patients with moderate renal impairment, and patients with cardiovascular disease or a high cardiovascular risk, were also included in the trial portfolio. The studies with canagliflozin investigate monotherapy as adjunct to diet and exercise, dual therapy with metformin or a sulfonylurea, triple therapy with metformin and a sulfonylurea or pioglitazone, and combination therapy with insulin (with or without additional oral antidiabetic substances; Figure 2).14 Furthermore, in addition to the pivotal Phase III trials, an extensive long-term clinical outcome study program (including the CANagliflozin cardioVascular Assessment Study [CANVAS]25 and CANVAS-R) was initiated to investigate the impact of canagliflozin on classical macro-vascular and microvascular endpoints in patients with T2DM. One of the emphases is on renal parameters; the CANVAS-R study (ClinicalTrials.gov identifier, NCT01989754), which was initiated after license authorization, will test the effects of canagliflozin on the progression of albuminuria and the progression of diabetic nephropathy, for example. Reporting of the outcomes from these endpoint studies is expected in 2017. A recently initiated renal outcomes trial (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation Trial [CREDENCE]; ClinicalTrials.gov identifier, NCT02065791) will assess the renal protective effect of canagliflozin in patients with T2DM, Stage 2 or 3 chronic kidney disease, and macroalbuminuria receiving standard of care and treatment with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker; this study is expected to be completed in 2019.


SGLT2 inhibitors - an insulin-independent therapeutic approach for treatment of type 2 diabetes: focus on canagliflozin.

Seufert J - Diabetes Metab Syndr Obes (2015)

Phase III trial program with canagliflozin.Notes: Data from published studies.14,26,28–32,34Abbreviations: OAD, oral antidiabetic; MET, metformin; PBO, placebo; SITA, sitagliptin; PIO, pioglitazone; CANVAS, CANagliflozin cardioVascular Assessment Study; SU, sulfonylurea; GLIM, glimepiride; T2DM, type 2 diabetes mellitus; CV, cardiovascular; eGFR, estimated glomerular filtration rate.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4644173&req=5

f2-dmso-8-543: Phase III trial program with canagliflozin.Notes: Data from published studies.14,26,28–32,34Abbreviations: OAD, oral antidiabetic; MET, metformin; PBO, placebo; SITA, sitagliptin; PIO, pioglitazone; CANVAS, CANagliflozin cardioVascular Assessment Study; SU, sulfonylurea; GLIM, glimepiride; T2DM, type 2 diabetes mellitus; CV, cardiovascular; eGFR, estimated glomerular filtration rate.
Mentions: A total of 10,285 patients with T2DM participated in the prospective, double-blind, controlled studies investigating the efficacy and safety of the SGLT2 inhibitor canagliflozin.14 Specific populations, such as elderly patients, patients with moderate renal impairment, and patients with cardiovascular disease or a high cardiovascular risk, were also included in the trial portfolio. The studies with canagliflozin investigate monotherapy as adjunct to diet and exercise, dual therapy with metformin or a sulfonylurea, triple therapy with metformin and a sulfonylurea or pioglitazone, and combination therapy with insulin (with or without additional oral antidiabetic substances; Figure 2).14 Furthermore, in addition to the pivotal Phase III trials, an extensive long-term clinical outcome study program (including the CANagliflozin cardioVascular Assessment Study [CANVAS]25 and CANVAS-R) was initiated to investigate the impact of canagliflozin on classical macro-vascular and microvascular endpoints in patients with T2DM. One of the emphases is on renal parameters; the CANVAS-R study (ClinicalTrials.gov identifier, NCT01989754), which was initiated after license authorization, will test the effects of canagliflozin on the progression of albuminuria and the progression of diabetic nephropathy, for example. Reporting of the outcomes from these endpoint studies is expected in 2017. A recently initiated renal outcomes trial (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation Trial [CREDENCE]; ClinicalTrials.gov identifier, NCT02065791) will assess the renal protective effect of canagliflozin in patients with T2DM, Stage 2 or 3 chronic kidney disease, and macroalbuminuria receiving standard of care and treatment with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker; this study is expected to be completed in 2019.

Bottom Line: SGLT2 inhibitors provide additional reductions in body weight and blood pressure due to the therapeutically induced excretion of glucose and sodium through the kidneys.These "concomitant effects" are particularly interesting with regard to the increased cardiovascular risk in T2DM.New mechanisms of action like that of SGLT2 inhibitors such as canagliflozin, which can be used both in early and late stages of diabetes, are a welcome addition to expand the treatment options for patients at every stage of T2DM.

View Article: PubMed Central - PubMed

Affiliation: Department of Endocrinology and Diabetology, Clinic for Internal Medicine II, Freiburg University Hospital, Freiburg, Germany.

ABSTRACT
Despite the availability of a great variety of medications, a significant proportion of people with type 2 diabetes mellitus (T2DM) are not able to achieve or maintain adequate glycemic control. Beyond improved glucose control, novel treatments would ideally provide a reduction of cardiovascular risk, with a favorable impact on excess weight, and a low intrinsic hypoglycemia risk, as well as a synergistic mechanism of action for broad combination therapy. With the development of sodium glucose cotransporter 2 (SGLT2) inhibitors, an antidiabetic pharmacologic option has recently become available that comes close to meeting these requirements. For the first time, SGLT2 inhibitors offer a therapeutic approach acting directly on the kidneys without requiring insulin secretion or action. Canagliflozin, dapagliflozin, and empagliflozin are the SGLT2 inhibitors approved to date. Taken once a day, these medications can be combined with all other antidiabetic medications including insulin, due to their insulin-independent mechanism of action, with only a minimal risk of hypoglycemia. SGLT2 inhibitors provide additional reductions in body weight and blood pressure due to the therapeutically induced excretion of glucose and sodium through the kidneys. These "concomitant effects" are particularly interesting with regard to the increased cardiovascular risk in T2DM. In many cases, T2DM treatment requires a multidimensional approach where the treatment goals have to be adapted to the individual patient. While there is a consensus on the use of metformin as a first-line drug therapy, various antidiabetics are used for treatment intensification. New mechanisms of action like that of SGLT2 inhibitors such as canagliflozin, which can be used both in early and late stages of diabetes, are a welcome addition to expand the treatment options for patients at every stage of T2DM. The efficacy and tolerability of canagliflozin have been tested in an extensive clinical trial program described in this review article.

No MeSH data available.


Related in: MedlinePlus