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Safety evaluation of empagliflozin for patients with type 2 diabetes and chronic kidney disease
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Safety evaluation of empagliflozin for patients with type 2 diabetes and chronic kidney disease
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Duration:
T00H11M52S
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https://cadmoreoriginalmedia.blob.core.windows.net/e5b85185-fbbd-4b8e-9b65-28b803a55ca3/VJBM-2023-0008 V2.mp4?sv=2019-02-02&sr=c&sig=CFP5rU9Q9Pha1vslY02gtufSwHSUtBYDQ5Is4Ws0YyE%3D&st=2024-12-22T19%3A27%3A12Z&se=2024-12-22T21%3A32%3A12Z&sp=r
Upload Date:
2023-10-09T00:00:00.0000000
Transcript:
Language: EN.
Segment:1 Introduction.
[MUSIC PLAYING]
DR KATHERINE TUTTLE: Hello, I'm Dr. Kathy Tuttle, a nephrologist and executive director for research at the Providence Medical Research Center in Spokane, Washington. I'm also a Professor of Medicine in the Division of Nephrology and a Regional Principal Investigator for the Institute of Translational Health Sciences at the University of Washington. I would like to welcome you to this video summarizing our paper entitled safety of empagliflozin in patients with type 2 diabetes and chronic kidney disease, pooled analysis of placebo-controlled clinical trials. Before discussing the trials, I would like to provide a refresher on type 2 diabetes and chronic kidney disease, also called CKD.
Segment:2 Background.
DR KATHERINE TUTTLE: Type 2 diabetes is responsible for nearly half of all CKD worldwide. Also CKD attributed to diabetes is the leading global cause of kidney failure. Patients who have both type 2 diabetes and CKD are at high risk for outcomes such as cardiovascular disease, hospitalization for heart failure, and mortality.
DR KATHERINE TUTTLE: Sodium glucose cotransporter 2 inhibitors also known as SGLT2 inhibitors, demonstrate efficacy in slowing the progression of CKD, and reducing risk of heart failure and kidney failure. Given the strong efficacy data for SGLT2 inhibitors in patients with type 2 diabetes and CKD, a clear understanding of safety data is needed to help reduce barriers to implementation.
DR KATHERINE TUTTLE: For patients with type 2 diabetes and CKD, the KDIGO guidelines recommend glycemic management with lifestyle therapy as well as with metformin and SGLT2 inhibitors. KDIGO guidelines recommend use of an SGLT2 inhibitor in patients with type 2 diabetes and CKD, who have an estimated glomerular filtration rate, also known as eGFR, greater than or equal to 20ml per minute per 1.73 meter squared. Metformin is also recommended as needed for glycemic control for those who have an EGFR greater than or equal to 30. Standard of care also includes a statin for patients with diabetes and CKD, as well as a renin angiotensin system inhibitor also known as a RAS inhibitor.
DR KATHERINE TUTTLE: Empagliflozin is a selective SGLT2 inhibitor that has shown efficacy in reducing onset and progression of CKD in patients with type 2 diabetes.
Segment:3 Methods.
DR KATHERINE TUTTLE: The objective of this pooled analysis was to assess the safety of empagliflozin in patients with type 2 diabetes and moderate to severe CKD, defined by KDIGO categories G3 to G4. This pooled analysis included data from 19 randomized, placebo-controlled phase I to IV clinical trials and one extension study trial. The pooled safety population included 2,367 patients with type 2 diabetes and a baseline eGFR less than 60. Patients received empagliflozin 10 or 25mg daily, including dose escalation or uptitration from the 10 to the 25 milligram dose or placebo.
DR KATHERINE TUTTLE: Safety assessments were based on investigator reported adverse events using standardized preferred terms. The adverse events of special interest were hypoglycemia, urinary tract infections, volume depletion, bone fracture, falls, hypokalemia, acute renal failure, also known as ARF, and lower limb amputation.
DR KATHERINE TUTTLE: Lower limb amputations were not usually captured in adverse event reports. So the frequency of lower limb amputations was evaluated based on medical review of study adverse event narratives. Serious adverse events were defined as any adverse event that resulted in death, was immediately life threatening, required or prolonged hospitalization, caused persistent or marked disability, or resulted in a birth defect.
Segment:4 Results.
DR KATHERINE TUTTLE: Patients in this analysis were grouped into three CKD categories according to eGFR in ml per minute per 1.73 meters squared. G3A, eGFR 45 to less than 60, G3B, eGFR 30 to less than 45, and G4 eGFR less than 30. Across the CKD categories, demographic characteristics were similar between empagliflozin and placebo groups. 58 to 69% of patients were female. The mean age was 64 to 69 years, and the mean body mass index also known as BMI was 29.5 to 31.3 kilos per meter squared.
DR KATHERINE TUTTLE: Race and ethnicity were comparable across G3A and G3B groups with most patients being white and not Hispanic or Latino. In the G4 placebo group, over 50% of patients were Asian. And similarly, to the other groups, the majority were also not Hispanic or Latino.
DR KATHERINE TUTTLE: In this pooled analysis, baseline A1C was 8% in both the empagliflozin and placebo groups across CKD categories. Blood pressure was similar among the groups. Finally, the frequency of heart failure and hypertension were similar between empagliflozin and placebo groups and across CKD categories.
DR KATHERINE TUTTLE: The use of concomitant medications was similar between patients in the empagliflozin and placebo groups. In CKD categories, G3A and 3B, angiotensin converting enzyme inhibitors and angiotensin receptor blockers also known as ACE inhibitors and ARBs, were the most common, concomitant medications used in the placebo and empagliflozin groups. In patients with CKD G4, insulin and statins were the most common concomitant medications used.
DR KATHERINE TUTTLE: Rates of serious, adverse events were similar in the empagliflozin and placebo groups overall, and across CKD categories. While there was a numerically higher rate of serious adverse events for empagliflozin versus placebo in category G4, these results should be interpreted with caution because of the low numbers of patients in each group. The rates of adverse events leading to discontinuation were similar between the empagliflozin and placebo groups overall and across the CKD categories.
DR KATHERINE TUTTLE: The frequency of adverse events of special interests, including hypoglycemia, urinary tract infection, bone fractures, and falls were similar between the empagliflozin and placebo groups overall, and across CKD subgroups.
DR KATHERINE TUTTLE: Of note, no difference in rates of lower limb amputation between placebo and empagliflozin was observed. In contrast, the rate of genital infections was more frequent in those receiving empagliflozin than those receiving placebo. However, genital infections occurred less frequently as CKD progressed, with lower rates across the G3A and G3B categories, compared to the G4 category. However, the opposite was true for the other adverse events of interest. Of note, genital infections are a well recognized adverse event associated with SGLT2 inhibitor therapy, and may be preventable by educating patients on proper hygiene techniques.
DR KATHERINE TUTTLE: The rates of volume depletion and acute renal failure were similar in individuals who received placebo and empagliflozin across CKD categories. Upon initiation of SGLT2 inhibitor therapy, an acute decrease in eGFR is typically observed. This is also known as an EGFR dip. Initially, this dip could be misinterpreted as acute renal failure because physicians were concerned that SGLT2 inhibitors would predispose patients to acute kidney injury.
DR KATHERINE TUTTLE: As demonstrated by the Cox regression analysis, the risks for volume depletion were similar for empagliflozin and placebo in both eGFR groups. Also, the risk for acute renal failure was similar for empagliflozin and placebo in both eGFR groups.
DR KATHERINE TUTTLE: Importantly, rates of hyperkalemia and edema were lower in the empagliflozin group than the placebo group, overall and across CKD categories. In the adjusted Cox regression analysis, empagliflozin lowered the risk of hyperkalemia by about 50% in the G3A group and by about 40% in the combined G3B, G4 group. This lower risk of hyperkalemia is important for patients with advanced CKD receiving RAS inhibitors, such as an ACE inhibitor or an ARB, which places patients at higher risk of hyperkalemia.
DR KATHERINE TUTTLE: Empagliflozin significantly reduced the risk of edema by about 60% in the G3A group versus placebo. Similarly, the risk of edema for empagliflozin was reduced by about 50% in the combined G3B and G4 group.
Segment:5 Conclusions.
DR KATHERINE TUTTLE: The safety findings from this large, pooled analysis of patients with type 2 diabetes and CKD treated with empagliflozin, are consistent with those seen in meta analysis of SGLT2 inhibitors. Risks for hyperkalemia and edema were lower with empagliflozin than placebo. Therefore, empagliflozin could have additional benefits in prevention of hyperkalemia and edema in patients with type 2 diabetes and advanced CKD.
DR KATHERINE TUTTLE: Results from a pooled safety analysis showed that the rates of acute renal failure, which included acute kidney injury and other adverse event terms, were similar between empagliflozin and placebo across all CKD categories. Moreover, results from a meta analysis of SGLT2 inhibitor studies in patients with type 2 diabetes, has demonstrated that SGLT2 inhibitors lower the risk of acute kidney injury by about 25%.
DR KATHERINE TUTTLE: In conclusion, the pooled analysis has not raised any new safety concerns for use of empagliflozin in patients with type 2 diabetes and advanced CKD. These findings paint a positive, overall safety picture for the SGLT2 inhibitor, empagliflozin, across a wide range of patients with type 2 diabetes and advanced CKD.
DR KATHERINE TUTTLE: More recently, the EMPA-KIDNEY trial demonstrated that empagliflozin reduced the risk of kidney disease progression or death from cardiovascular causes compared with placebo in patients with CKD from a broad range of causes, regardless of diabetes status.
DR KATHERINE TUTTLE: We hope you've enjoyed this presentation, and thank you for your attention. [MUSIC PLAYING]
Segment:6 Acknowledgements and Disclosures.
DR KATHERINE TUTTLE:
Segment:1 Introduction.
[MUSIC PLAYING]
DR KATHERINE TUTTLE: Hello, I'm Dr. Kathy Tuttle, a nephrologist and executive director for research at the Providence Medical Research Center in Spokane, Washington. I'm also a Professor of Medicine in the Division of Nephrology and a Regional Principal Investigator for the Institute of Translational Health Sciences at the University of Washington. I would like to welcome you to this video summarizing our paper entitled safety of empagliflozin in patients with type 2 diabetes and chronic kidney disease, pooled analysis of placebo-controlled clinical trials. Before discussing the trials, I would like to provide a refresher on type 2 diabetes and chronic kidney disease, also called CKD.
Segment:2 Background.
DR KATHERINE TUTTLE: Type 2 diabetes is responsible for nearly half of all CKD worldwide. Also CKD attributed to diabetes is the leading global cause of kidney failure. Patients who have both type 2 diabetes and CKD are at high risk for outcomes such as cardiovascular disease, hospitalization for heart failure, and mortality.
DR KATHERINE TUTTLE: Sodium glucose cotransporter 2 inhibitors also known as SGLT2 inhibitors, demonstrate efficacy in slowing the progression of CKD, and reducing risk of heart failure and kidney failure. Given the strong efficacy data for SGLT2 inhibitors in patients with type 2 diabetes and CKD, a clear understanding of safety data is needed to help reduce barriers to implementation.
DR KATHERINE TUTTLE: For patients with type 2 diabetes and CKD, the KDIGO guidelines recommend glycemic management with lifestyle therapy as well as with metformin and SGLT2 inhibitors. KDIGO guidelines recommend use of an SGLT2 inhibitor in patients with type 2 diabetes and CKD, who have an estimated glomerular filtration rate, also known as eGFR, greater than or equal to 20ml per minute per 1.73 meter squared. Metformin is also recommended as needed for glycemic control for those who have an EGFR greater than or equal to 30. Standard of care also includes a statin for patients with diabetes and CKD, as well as a renin angiotensin system inhibitor also known as a RAS inhibitor.
DR KATHERINE TUTTLE: Empagliflozin is a selective SGLT2 inhibitor that has shown efficacy in reducing onset and progression of CKD in patients with type 2 diabetes.
Segment:3 Methods.
DR KATHERINE TUTTLE: The objective of this pooled analysis was to assess the safety of empagliflozin in patients with type 2 diabetes and moderate to severe CKD, defined by KDIGO categories G3 to G4. This pooled analysis included data from 19 randomized, placebo-controlled phase I to IV clinical trials and one extension study trial. The pooled safety population included 2,367 patients with type 2 diabetes and a baseline eGFR less than 60. Patients received empagliflozin 10 or 25mg daily, including dose escalation or uptitration from the 10 to the 25 milligram dose or placebo.
DR KATHERINE TUTTLE: Safety assessments were based on investigator reported adverse events using standardized preferred terms. The adverse events of special interest were hypoglycemia, urinary tract infections, volume depletion, bone fracture, falls, hypokalemia, acute renal failure, also known as ARF, and lower limb amputation.
DR KATHERINE TUTTLE: Lower limb amputations were not usually captured in adverse event reports. So the frequency of lower limb amputations was evaluated based on medical review of study adverse event narratives. Serious adverse events were defined as any adverse event that resulted in death, was immediately life threatening, required or prolonged hospitalization, caused persistent or marked disability, or resulted in a birth defect.
Segment:4 Results.
DR KATHERINE TUTTLE: Patients in this analysis were grouped into three CKD categories according to eGFR in ml per minute per 1.73 meters squared. G3A, eGFR 45 to less than 60, G3B, eGFR 30 to less than 45, and G4 eGFR less than 30. Across the CKD categories, demographic characteristics were similar between empagliflozin and placebo groups. 58 to 69% of patients were female. The mean age was 64 to 69 years, and the mean body mass index also known as BMI was 29.5 to 31.3 kilos per meter squared.
DR KATHERINE TUTTLE: Race and ethnicity were comparable across G3A and G3B groups with most patients being white and not Hispanic or Latino. In the G4 placebo group, over 50% of patients were Asian. And similarly, to the other groups, the majority were also not Hispanic or Latino.
DR KATHERINE TUTTLE: In this pooled analysis, baseline A1C was 8% in both the empagliflozin and placebo groups across CKD categories. Blood pressure was similar among the groups. Finally, the frequency of heart failure and hypertension were similar between empagliflozin and placebo groups and across CKD categories.
DR KATHERINE TUTTLE: The use of concomitant medications was similar between patients in the empagliflozin and placebo groups. In CKD categories, G3A and 3B, angiotensin converting enzyme inhibitors and angiotensin receptor blockers also known as ACE inhibitors and ARBs, were the most common, concomitant medications used in the placebo and empagliflozin groups. In patients with CKD G4, insulin and statins were the most common concomitant medications used.
DR KATHERINE TUTTLE: Rates of serious, adverse events were similar in the empagliflozin and placebo groups overall, and across CKD categories. While there was a numerically higher rate of serious adverse events for empagliflozin versus placebo in category G4, these results should be interpreted with caution because of the low numbers of patients in each group. The rates of adverse events leading to discontinuation were similar between the empagliflozin and placebo groups overall and across the CKD categories.
DR KATHERINE TUTTLE: The frequency of adverse events of special interests, including hypoglycemia, urinary tract infection, bone fractures, and falls were similar between the empagliflozin and placebo groups overall, and across CKD subgroups.
DR KATHERINE TUTTLE: Of note, no difference in rates of lower limb amputation between placebo and empagliflozin was observed. In contrast, the rate of genital infections was more frequent in those receiving empagliflozin than those receiving placebo. However, genital infections occurred less frequently as CKD progressed, with lower rates across the G3A and G3B categories, compared to the G4 category. However, the opposite was true for the other adverse events of interest. Of note, genital infections are a well recognized adverse event associated with SGLT2 inhibitor therapy, and may be preventable by educating patients on proper hygiene techniques.
DR KATHERINE TUTTLE: The rates of volume depletion and acute renal failure were similar in individuals who received placebo and empagliflozin across CKD categories. Upon initiation of SGLT2 inhibitor therapy, an acute decrease in eGFR is typically observed. This is also known as an EGFR dip. Initially, this dip could be misinterpreted as acute renal failure because physicians were concerned that SGLT2 inhibitors would predispose patients to acute kidney injury.
DR KATHERINE TUTTLE: As demonstrated by the Cox regression analysis, the risks for volume depletion were similar for empagliflozin and placebo in both eGFR groups. Also, the risk for acute renal failure was similar for empagliflozin and placebo in both eGFR groups.
DR KATHERINE TUTTLE: Importantly, rates of hyperkalemia and edema were lower in the empagliflozin group than the placebo group, overall and across CKD categories. In the adjusted Cox regression analysis, empagliflozin lowered the risk of hyperkalemia by about 50% in the G3A group and by about 40% in the combined G3B, G4 group. This lower risk of hyperkalemia is important for patients with advanced CKD receiving RAS inhibitors, such as an ACE inhibitor or an ARB, which places patients at higher risk of hyperkalemia.
DR KATHERINE TUTTLE: Empagliflozin significantly reduced the risk of edema by about 60% in the G3A group versus placebo. Similarly, the risk of edema for empagliflozin was reduced by about 50% in the combined G3B and G4 group.
Segment:5 Conclusions.
DR KATHERINE TUTTLE: The safety findings from this large, pooled analysis of patients with type 2 diabetes and CKD treated with empagliflozin, are consistent with those seen in meta analysis of SGLT2 inhibitors. Risks for hyperkalemia and edema were lower with empagliflozin than placebo. Therefore, empagliflozin could have additional benefits in prevention of hyperkalemia and edema in patients with type 2 diabetes and advanced CKD.
DR KATHERINE TUTTLE: Results from a pooled safety analysis showed that the rates of acute renal failure, which included acute kidney injury and other adverse event terms, were similar between empagliflozin and placebo across all CKD categories. Moreover, results from a meta analysis of SGLT2 inhibitor studies in patients with type 2 diabetes, has demonstrated that SGLT2 inhibitors lower the risk of acute kidney injury by about 25%.
DR KATHERINE TUTTLE: In conclusion, the pooled analysis has not raised any new safety concerns for use of empagliflozin in patients with type 2 diabetes and advanced CKD. These findings paint a positive, overall safety picture for the SGLT2 inhibitor, empagliflozin, across a wide range of patients with type 2 diabetes and advanced CKD.
DR KATHERINE TUTTLE: More recently, the EMPA-KIDNEY trial demonstrated that empagliflozin reduced the risk of kidney disease progression or death from cardiovascular causes compared with placebo in patients with CKD from a broad range of causes, regardless of diabetes status.
DR KATHERINE TUTTLE: We hope you've enjoyed this presentation, and thank you for your attention. [MUSIC PLAYING]
Segment:6 Acknowledgements and Disclosures.
DR KATHERINE TUTTLE:
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