Ronald Goldenberg, MD

Ronald Goldenberg, MD, completed his residency in Internal Medicine in 1987 at the University of Toronto, and his fellowship in Endocrinology & Metabolism in 1989 at the University of Toronto.  Dr. Goldenberg is a past chair of the Ontario Medical Association Section on Endocrinology & Metabolism and a previous President of the Toronto Diabetes Association. Dr. Goldenberg has been an investigator in a wide array of clinical trials in the areas of diabetes, hypertension, obesity, and dyslipidemia. His major areas of interest include clinical care of diabetes, obesity, dyslipidemia and thyroid disorders. He has been actively involved in Continuing Medical Education for the last 3 decades, with a strong focus on translating evidence-based medicine into practical patient care.

As a consultant endocrinologist with an area of interest that includes clinical care of diabetes, can you briefly tell us what the top 5 studies of 2021 were that are most likely to influence diabetes or obesity practice?

Dr. Goldenberg: 2021 was a banner year for clinicians managing diabetes and or obesity. There were many key trials that were published and or presented. In my mind, the most important ones that will really influence practice include the STEP program of semaglutide 2.4 mg once weekly in the management of overweight or obesity. There is the FIGARO-DKD and FIDELITY analysis of finerenone in patients with type 2 diabetes and chronic kidney disease. Other top studies include the SURPASS trials of a novel dual incretin agonist called tirzepatide, the EMPEROR-Preserved trial with empagliflozin and a pooled analysis of empagliflozin in both HFrEF and HFpEF trials, and the AMPLITUDE-O trial, which is a cardiovascular outcome trial with an exendin-based GLP-1 receptor agonist known as efpeglenatide.

2021 was definitely a landmark year in diabetes. Let's start with the STEP program with semaglutide 2.4. What were the important findings in these studies?

Dr. Goldenberg: STEP is the Phase III program for 2.4 milligrams once weekly in the management of overweight or obesity. The STEP program studies that have been published and/or presented in 2021 include four Phase IIIa trials STEP 1 through STEP 4, as well as three Phase IIIb trials, STEP 5, 6, and 8. They're all rather similar, as they each enrolled patients with overweight and/or obesity. Patients were up-titrated to semaglutide 2.4 milligrams once weekly, and the top-line summary across all of these trials is that patients randomized to semaglutide 2.4 mg once weekly lost 15% to 17% of their body weight amongst those that did not have diabetes, which is really a tremendous amount of weight loss for an anti-obesity drug. And even those with type 2 diabetes lost almost 10% of their body weight, which is pretty impressive given that patients with type 2 diabetes are often somewhat refractory to weight loss.

There was a high percentage of body weight loss across these trials, as roughly 86 to 90% of patients without diabetes achieved at least a 5% body weight loss and even in those with diabetes, almost 70% achieved a 5% loss in their body weight. As far as overall safety, the safety profile of semaglutide 2.4 mg once weekly was generally similar to the GLP-1 receptor agonist class. The most common side effects were gastrointestinal. Nausea occurred anywhere from 20% to 58% of patients, but it was generally transient. Very few people withdrew because of gastrointestinal side effects.

 I think the key thing for clinicians to know about the STEP program is that it's the results of these trials that led to the FDA approving semaglutide 2.4 mg once weekly as a new agent for the management of overweight and/or obesity.

You mentioned FIGARO-DKD and FIDELITY with Finerenone. Can you talk more about the relevance of this data and summarize the key findings?

Dr. Goldenberg: Finerenone is a new selective non-steroidal mineralocorticoid receptor antagonist that interacts with the mineralocorticoid receptor in a different way compared to traditional steroidal mineralocorticoid receptor agonists.  We know from pre-clinical data that this agent targets inflammation and fibrosis in both the kidney and the heart. The finerenone Phase III program focused on patients with type 2 diabetes and chronic kidney disease. In 2021, they published the FIGARO-DKD trial. This enrolled almost 7,500 patients with type 2 diabetes and an eGFR of 25 ml/min or more along with albuminuria.

The key result of this trial is the primary outcome of CV death non-fatal MI, non-fatal stroke, or hospitalization for heart failure was reduced by 13%. The number needed to treat after 3 ½ years was 47. The primary outcome was mainly driven by a reduction for hospitalization for heart failure. Key secondary outcomes included composite kidney outcomes, one of which was defined by a sustained eGFR reduction of 40% or more along with end-stage kidney disease or renal death. This did not quite reach statistical significance, but a more stringent outcome that included a reduction in eGFR of at least 57% or more was in fact reduced by 23%.

End-stage kidney disease was reduced by 36% in the FIGARO-DKD trial. Finerenone was well tolerated. Hyperkalemia occurred in 10.8% of patients on finerenone and 5.3% on placebo but it was quite unusual to have to stop finerenone because of hyperkalemia. Building on FIGARO-DKD in 2021 was a prespecified meta-analysis of two large Phase III trials, the FIGARO-DKD trial and also the previously published FIDELIO-DKD trial and in this pooled analysis the composite cardiovascular outcome was reduced by 14%. The benefit on cardiovascular events was independent of the baseline eGFR or urine albumin to creatinine ratio, as well as independent of the use of SGLT2 inhibitors or GLP-1 receptor agonists.

There was also a 23% reduction in a composite kidney outcome that used a sustained 57% reduction in eGFR as part of that outcome and essentially each component of the composite kidney outcome was reduced,  including kidney failure, end-stage kidney disease, eGFR of less than 15 ml/min in addition to a  ≥57% decrease in eGFR. And this kidney outcome showed a benefit irrespective of the use of SGLT2 inhibitor at baseline although the number of patients taking an SGLT2 inhibitor in this analysis was relatively small. So overall, the results of finerenone in 2021 support the use of this agent in patients with type 2 diabetes and chronic kidney disease to improve both cardiovascular and kidney outcomes.

Thank you for this insight. Regarding the SURPASS trials with tirzepatide, what is tirzepatide and what was its impact on glycemia and weight?

Dr. Goldenberg. My pleasure. Tirzepatide is a unique dual GIP/GLP-1 receptor agonist that has been formulated to be given as a once weekly injection. In 2021, we heard the first results from the Phase III program including SURPASS-1 through SURPASS-5. In these trials, patients were randomized to tirzepatide 5 mg, 10 mg, or 15 mg, and often compared to placebo or an active comparator. Across the SURPASS trials, the A1C reduction from baseline was between 1.9% to 2.6%. Up to 97% of patients on tirzepatide achieved a HbA1c of less than 7%, and up to 62% achieve a normal HbA1c of less than 5.7%.

In addition to these rather robust glycemic outcomes, there was excellent weight loss in the SURPASS program with the weight reduction ranging from 6 to 13 kg from baseline. Interestingly, in the SURPASS studies, tirzepatide showed superiority to semaglutide 1 mg and also superiority to titrated basal insulin. As far as safety, the side effect profile was similar to all GLP-1 receptor agonists with transient nausea being the most common side effect. Overall, tirzepatide will definitely add to our ability to treat our patients with type 2 diabetes with an incretin agent, and when this agent gets approved, hopefully, it will provide robust glycemic lowering and weight loss.

The fourth key study you mentioned is the EMPEROR-Preserved along with the EMPEROR-Pooled with the empagliflozin. What did they find in this analysis?

Dr. Goldenberg: The EMPEROR-Preserved was the first completed large randomized clinical trial of an SGLT2 inhibitor in patients with heart failure with preserved ejection fraction. They enrolled almost 6,000 patients with HFpEF with or without type 2 diabetes and they were randomized to empagliflozin 10 mg or placebo. The primary outcome of cardiovascular death or hospitalization for heart failure was reduced by 21% with empagliflozin and the number needed to treat was 31. This primary outcome was largely driven by a reduction in hospitalization for heart failure. The primary outcome showed consistent benefit across 15 prespecified subgroups, including those with or without type 2 diabetes, and including a spectrum of baseline left ventricular ejection fractions from 40% to 50% to greater than 60%.

There were also some key secondary endpoints:  total hospitalization for heart failure was reduced by 27% and empagliflozin also slowed the decline of eGFR over time in the EMPEROR-Preserved trial. The agent was well tolerated. There was a slight signal for more hypotension and genital mycotic infections, but otherwise really no concerning adverse effects.

Building on the EMPEROR-Preserved trial was a prespecified pooled analysis of EMPEROR-Reduced and EMPEROR-Preserved,  the two large outcome trials with empagliflozin in heart failure patients. The prespecified primary outcome of this analysis was a major renal outcome which included a GFR reduction of ≥40%, renal replacement therapy or sustained eGFR <10-15 ml/min. While in EMPEROR-Reduced there was a significant 49% reduction in this composite renal outcome, in EMPEROR-Preserved there was no significant reduction. Because of the heterogeneity across these two trials, it was not statistically valid to pool these two results for the composite renal outcome. However, what they found in EMPEROR-Pooled is that if you use a more robust renal outcome including at least a 50% decline in eGFR, then there seems to be a trend that varies depending on baseline left ventricular ejection fraction, suggesting a benefit on the renal outcome if your baseline left ventricular function ranges from 40% to 60%, but lack of benefit with a baseline left ventricular ejection fraction of over 60%. The top line summary of this data is that for the first time we have robust evidence that an SGLT2 inhibitor, in this case empagliflozin 10 mg, can provide a cardiovascular benefit in patients with HFpEF, in addition to the known benefit in HFrEF patients.

Finally, there's the AMPLITUDE-O with efpeglenatide, an international randomized controlled trial conducted at approximately 344 sites in 28 countries. What are the key learnings and messages for this specific study?

Dr. Goldenberg: Efpeglenatide is an exendin-4-based GLP-1 receptor agonist that is given once weekly and the AMPLITUDE-O trial is the cardiovascular outcome trial with efpeglenatide done in patients with type 2 diabetes and either cardiovascular disease or chronic kidney disease plus at least one cardiovascular risk factor. It was an important trial because prior to this cardiovascular outcome trial studies of exendin-4-based GLP-1 receptor agonist have been neutral. However, the AMPLITUDE-O study showed for the first-time superiority with an exendin-4-based GLP-1 receptor agonist. In this case, efpeglenatide 4 or 6 milligrams versus placebo was associated with a 27% reduction in the primary outcome of CV death, non-fatal MI or non-fatal stroke.

Importantly, there was a consistent benefit with efpeglenatide across a spectrum of prespecified subgroups,  the most important one being those that entered the trial on a background SGLT2 inhibitor, which represented about 15% of the patients. They derived the same overall benefit as those not taking an SGLT2 inhibitor. It is important to appreciate that this is probably the most robust data we have for showing a cardiovascular benefit of adding a GLP-1 receptor agonist to an SGLT2 inhibitor in high risk patients with type 2 diabetes. AMPLITUDE-O also adds to the already appreciated knowledge of the cardiovascular benefit of GLP-1 receptor agonists and builds on this story by showing that you can get a cardiovascular benefit with an exendin-4-based GLP-1 receptor agonist and you can get a benefit as an add on to SGLT2 inhibitors.

Ronald Goldenberg, MD, completed his residency in Internal Medicine in 1987 at the University of Toronto, and his fellowship in Endocrinology & Metabolism in 1989 at the University of Toronto.  Dr. Goldenberg is a past chair of the Ontario Medical Association Section on Endocrinology & Metabolism and a previous President of the Toronto Diabetes Association. Dr. Goldenberg has been an investigator in a wide array of clinical trials in the areas of diabetes, hypertension, obesity, and dyslipidemia. His major areas of interest include clinical care of diabetes, obesity, dyslipidemia and thyroid disorders. He has been actively involved in Continuing Medical Education for the last 3 decades, with a strong focus on translating evidence-based medicine into practical patient care.

As a consultant endocrinologist with an area of interest that includes clinical care of diabetes, can you briefly tell us what the top 5 studies of 2021 were that are most likely to influence diabetes or obesity practice?

Dr. Goldenberg: 2021 was a banner year for clinicians managing diabetes and or obesity. There were many key trials that were published and or presented. In my mind, the most important ones that will really influence practice include the STEP program of semaglutide 2.4 mg once weekly in the management of overweight or obesity. There is the FIGARO-DKD and FIDELITY analysis of finerenone in patients with type 2 diabetes and chronic kidney disease. Other top studies include the SURPASS trials of a novel dual incretin agonist called tirzepatide, the EMPEROR-Preserved trial with empagliflozin and a pooled analysis of empagliflozin in both HFrEF and HFpEF trials, and the AMPLITUDE-O trial, which is a cardiovascular outcome trial with an exendin-based GLP-1 receptor agonist known as efpeglenatide.

2021 was definitely a landmark year in diabetes. Let's start with the STEP program with semaglutide 2.4. What were the important findings in these studies?

Dr. Goldenberg: STEP is the Phase III program for 2.4 milligrams once weekly in the management of overweight or obesity. The STEP program studies that have been published and/or presented in 2021 include four Phase IIIa trials STEP 1 through STEP 4, as well as three Phase IIIb trials, STEP 5, 6, and 8. They're all rather similar, as they each enrolled patients with overweight and/or obesity. Patients were up-titrated to semaglutide 2.4 milligrams once weekly, and the top-line summary across all of these trials is that patients randomized to semaglutide 2.4 mg once weekly lost 15% to 17% of their body weight amongst those that did not have diabetes, which is really a tremendous amount of weight loss for an anti-obesity drug. And even those with type 2 diabetes lost almost 10% of their body weight, which is pretty impressive given that patients with type 2 diabetes are often somewhat refractory to weight loss.

There was a high percentage of body weight loss across these trials, as roughly 86 to 90% of patients without diabetes achieved at least a 5% body weight loss and even in those with diabetes, almost 70% achieved a 5% loss in their body weight. As far as overall safety, the safety profile of semaglutide 2.4 mg once weekly was generally similar to the GLP-1 receptor agonist class. The most common side effects were gastrointestinal. Nausea occurred anywhere from 20% to 58% of patients, but it was generally transient. Very few people withdrew because of gastrointestinal side effects.

 I think the key thing for clinicians to know about the STEP program is that it's the results of these trials that led to the FDA approving semaglutide 2.4 mg once weekly as a new agent for the management of overweight and/or obesity.

You mentioned FIGARO-DKD and FIDELITY with Finerenone. Can you talk more about the relevance of this data and summarize the key findings?

Dr. Goldenberg: Finerenone is a new selective non-steroidal mineralocorticoid receptor antagonist that interacts with the mineralocorticoid receptor in a different way compared to traditional steroidal mineralocorticoid receptor agonists.  We know from pre-clinical data that this agent targets inflammation and fibrosis in both the kidney and the heart. The finerenone Phase III program focused on patients with type 2 diabetes and chronic kidney disease. In 2021, they published the FIGARO-DKD trial. This enrolled almost 7,500 patients with type 2 diabetes and an eGFR of 25 ml/min or more along with albuminuria.

The key result of this trial is the primary outcome of CV death non-fatal MI, non-fatal stroke, or hospitalization for heart failure was reduced by 13%. The number needed to treat after 3 ½ years was 47. The primary outcome was mainly driven by a reduction for hospitalization for heart failure. Key secondary outcomes included composite kidney outcomes, one of which was defined by a sustained eGFR reduction of 40% or more along with end-stage kidney disease or renal death. This did not quite reach statistical significance, but a more stringent outcome that included a reduction in eGFR of at least 57% or more was in fact reduced by 23%.

End-stage kidney disease was reduced by 36% in the FIGARO-DKD trial. Finerenone was well tolerated. Hyperkalemia occurred in 10.8% of patients on finerenone and 5.3% on placebo but it was quite unusual to have to stop finerenone because of hyperkalemia. Building on FIGARO-DKD in 2021 was a prespecified meta-analysis of two large Phase III trials, the FIGARO-DKD trial and also the previously published FIDELIO-DKD trial and in this pooled analysis the composite cardiovascular outcome was reduced by 14%. The benefit on cardiovascular events was independent of the baseline eGFR or urine albumin to creatinine ratio, as well as independent of the use of SGLT2 inhibitors or GLP-1 receptor agonists.

There was also a 23% reduction in a composite kidney outcome that used a sustained 57% reduction in eGFR as part of that outcome and essentially each component of the composite kidney outcome was reduced,  including kidney failure, end-stage kidney disease, eGFR of less than 15 ml/min in addition to a  ≥57% decrease in eGFR. And this kidney outcome showed a benefit irrespective of the use of SGLT2 inhibitor at baseline although the number of patients taking an SGLT2 inhibitor in this analysis was relatively small. So overall, the results of finerenone in 2021 support the use of this agent in patients with type 2 diabetes and chronic kidney disease to improve both cardiovascular and kidney outcomes.

Thank you for this insight. Regarding the SURPASS trials with tirzepatide, what is tirzepatide and what was its impact on glycemia and weight?

Dr. Goldenberg. My pleasure. Tirzepatide is a unique dual GIP/GLP-1 receptor agonist that has been formulated to be given as a once weekly injection. In 2021, we heard the first results from the Phase III program including SURPASS-1 through SURPASS-5. In these trials, patients were randomized to tirzepatide 5 mg, 10 mg, or 15 mg, and often compared to placebo or an active comparator. Across the SURPASS trials, the A1C reduction from baseline was between 1.9% to 2.6%. Up to 97% of patients on tirzepatide achieved a HbA1c of less than 7%, and up to 62% achieve a normal HbA1c of less than 5.7%.

In addition to these rather robust glycemic outcomes, there was excellent weight loss in the SURPASS program with the weight reduction ranging from 6 to 13 kg from baseline. Interestingly, in the SURPASS studies, tirzepatide showed superiority to semaglutide 1 mg and also superiority to titrated basal insulin. As far as safety, the side effect profile was similar to all GLP-1 receptor agonists with transient nausea being the most common side effect. Overall, tirzepatide will definitely add to our ability to treat our patients with type 2 diabetes with an incretin agent, and when this agent gets approved, hopefully, it will provide robust glycemic lowering and weight loss.

The fourth key study you mentioned is the EMPEROR-Preserved along with the EMPEROR-Pooled with the empagliflozin. What did they find in this analysis?

Dr. Goldenberg: The EMPEROR-Preserved was the first completed large randomized clinical trial of an SGLT2 inhibitor in patients with heart failure with preserved ejection fraction. They enrolled almost 6,000 patients with HFpEF with or without type 2 diabetes and they were randomized to empagliflozin 10 mg or placebo. The primary outcome of cardiovascular death or hospitalization for heart failure was reduced by 21% with empagliflozin and the number needed to treat was 31. This primary outcome was largely driven by a reduction in hospitalization for heart failure. The primary outcome showed consistent benefit across 15 prespecified subgroups, including those with or without type 2 diabetes, and including a spectrum of baseline left ventricular ejection fractions from 40% to 50% to greater than 60%.

There were also some key secondary endpoints:  total hospitalization for heart failure was reduced by 27% and empagliflozin also slowed the decline of eGFR over time in the EMPEROR-Preserved trial. The agent was well tolerated. There was a slight signal for more hypotension and genital mycotic infections, but otherwise really no concerning adverse effects.

Building on the EMPEROR-Preserved trial was a prespecified pooled analysis of EMPEROR-Reduced and EMPEROR-Preserved,  the two large outcome trials with empagliflozin in heart failure patients. The prespecified primary outcome of this analysis was a major renal outcome which included a GFR reduction of ≥40%, renal replacement therapy or sustained eGFR <10-15 ml/min. While in EMPEROR-Reduced there was a significant 49% reduction in this composite renal outcome, in EMPEROR-Preserved there was no significant reduction. Because of the heterogeneity across these two trials, it was not statistically valid to pool these two results for the composite renal outcome. However, what they found in EMPEROR-Pooled is that if you use a more robust renal outcome including at least a 50% decline in eGFR, then there seems to be a trend that varies depending on baseline left ventricular ejection fraction, suggesting a benefit on the renal outcome if your baseline left ventricular function ranges from 40% to 60%, but lack of benefit with a baseline left ventricular ejection fraction of over 60%. The top line summary of this data is that for the first time we have robust evidence that an SGLT2 inhibitor, in this case empagliflozin 10 mg, can provide a cardiovascular benefit in patients with HFpEF, in addition to the known benefit in HFrEF patients.

Finally, there's the AMPLITUDE-O with efpeglenatide, an international randomized controlled trial conducted at approximately 344 sites in 28 countries. What are the key learnings and messages for this specific study?

Dr. Goldenberg: Efpeglenatide is an exendin-4-based GLP-1 receptor agonist that is given once weekly and the AMPLITUDE-O trial is the cardiovascular outcome trial with efpeglenatide done in patients with type 2 diabetes and either cardiovascular disease or chronic kidney disease plus at least one cardiovascular risk factor. It was an important trial because prior to this cardiovascular outcome trial studies of exendin-4-based GLP-1 receptor agonist have been neutral. However, the AMPLITUDE-O study showed for the first-time superiority with an exendin-4-based GLP-1 receptor agonist. In this case, efpeglenatide 4 or 6 milligrams versus placebo was associated with a 27% reduction in the primary outcome of CV death, non-fatal MI or non-fatal stroke.

Importantly, there was a consistent benefit with efpeglenatide across a spectrum of prespecified subgroups,  the most important one being those that entered the trial on a background SGLT2 inhibitor, which represented about 15% of the patients. They derived the same overall benefit as those not taking an SGLT2 inhibitor. It is important to appreciate that this is probably the most robust data we have for showing a cardiovascular benefit of adding a GLP-1 receptor agonist to an SGLT2 inhibitor in high risk patients with type 2 diabetes. AMPLITUDE-O also adds to the already appreciated knowledge of the cardiovascular benefit of GLP-1 receptor agonists and builds on this story by showing that you can get a cardiovascular benefit with an exendin-4-based GLP-1 receptor agonist and you can get a benefit as an add on to SGLT2 inhibitors.

Ronald Goldenberg, MD, completed his residency in Internal Medicine in 1987 at the University of Toronto, and his fellowship in Endocrinology & Metabolism in 1989 at the University of Toronto.  Dr. Goldenberg is a past chair of the Ontario Medical Association Section on Endocrinology & Metabolism and a previous President of the Toronto Diabetes Association. Dr. Goldenberg has been an investigator in a wide array of clinical trials in the areas of diabetes, hypertension, obesity, and dyslipidemia. His major areas of interest include clinical care of diabetes, obesity, dyslipidemia and thyroid disorders. He has been actively involved in Continuing Medical Education for the last 3 decades, with a strong focus on translating evidence-based medicine into practical patient care.

As a consultant endocrinologist with an area of interest that includes clinical care of diabetes, can you briefly tell us what the top 5 studies of 2021 were that are most likely to influence diabetes or obesity practice?

Dr. Goldenberg: 2021 was a banner year for clinicians managing diabetes and or obesity. There were many key trials that were published and or presented. In my mind, the most important ones that will really influence practice include the STEP program of semaglutide 2.4 mg once weekly in the management of overweight or obesity. There is the FIGARO-DKD and FIDELITY analysis of finerenone in patients with type 2 diabetes and chronic kidney disease. Other top studies include the SURPASS trials of a novel dual incretin agonist called tirzepatide, the EMPEROR-Preserved trial with empagliflozin and a pooled analysis of empagliflozin in both HFrEF and HFpEF trials, and the AMPLITUDE-O trial, which is a cardiovascular outcome trial with an exendin-based GLP-1 receptor agonist known as efpeglenatide.

2021 was definitely a landmark year in diabetes. Let's start with the STEP program with semaglutide 2.4. What were the important findings in these studies?

Dr. Goldenberg: STEP is the Phase III program for 2.4 milligrams once weekly in the management of overweight or obesity. The STEP program studies that have been published and/or presented in 2021 include four Phase IIIa trials STEP 1 through STEP 4, as well as three Phase IIIb trials, STEP 5, 6, and 8. They're all rather similar, as they each enrolled patients with overweight and/or obesity. Patients were up-titrated to semaglutide 2.4 milligrams once weekly, and the top-line summary across all of these trials is that patients randomized to semaglutide 2.4 mg once weekly lost 15% to 17% of their body weight amongst those that did not have diabetes, which is really a tremendous amount of weight loss for an anti-obesity drug. And even those with type 2 diabetes lost almost 10% of their body weight, which is pretty impressive given that patients with type 2 diabetes are often somewhat refractory to weight loss.

There was a high percentage of body weight loss across these trials, as roughly 86 to 90% of patients without diabetes achieved at least a 5% body weight loss and even in those with diabetes, almost 70% achieved a 5% loss in their body weight. As far as overall safety, the safety profile of semaglutide 2.4 mg once weekly was generally similar to the GLP-1 receptor agonist class. The most common side effects were gastrointestinal. Nausea occurred anywhere from 20% to 58% of patients, but it was generally transient. Very few people withdrew because of gastrointestinal side effects.

 I think the key thing for clinicians to know about the STEP program is that it's the results of these trials that led to the FDA approving semaglutide 2.4 mg once weekly as a new agent for the management of overweight and/or obesity.

You mentioned FIGARO-DKD and FIDELITY with Finerenone. Can you talk more about the relevance of this data and summarize the key findings?

Dr. Goldenberg: Finerenone is a new selective non-steroidal mineralocorticoid receptor antagonist that interacts with the mineralocorticoid receptor in a different way compared to traditional steroidal mineralocorticoid receptor agonists.  We know from pre-clinical data that this agent targets inflammation and fibrosis in both the kidney and the heart. The finerenone Phase III program focused on patients with type 2 diabetes and chronic kidney disease. In 2021, they published the FIGARO-DKD trial. This enrolled almost 7,500 patients with type 2 diabetes and an eGFR of 25 ml/min or more along with albuminuria.

The key result of this trial is the primary outcome of CV death non-fatal MI, non-fatal stroke, or hospitalization for heart failure was reduced by 13%. The number needed to treat after 3 ½ years was 47. The primary outcome was mainly driven by a reduction for hospitalization for heart failure. Key secondary outcomes included composite kidney outcomes, one of which was defined by a sustained eGFR reduction of 40% or more along with end-stage kidney disease or renal death. This did not quite reach statistical significance, but a more stringent outcome that included a reduction in eGFR of at least 57% or more was in fact reduced by 23%.

End-stage kidney disease was reduced by 36% in the FIGARO-DKD trial. Finerenone was well tolerated. Hyperkalemia occurred in 10.8% of patients on finerenone and 5.3% on placebo but it was quite unusual to have to stop finerenone because of hyperkalemia. Building on FIGARO-DKD in 2021 was a prespecified meta-analysis of two large Phase III trials, the FIGARO-DKD trial and also the previously published FIDELIO-DKD trial and in this pooled analysis the composite cardiovascular outcome was reduced by 14%. The benefit on cardiovascular events was independent of the baseline eGFR or urine albumin to creatinine ratio, as well as independent of the use of SGLT2 inhibitors or GLP-1 receptor agonists.

There was also a 23% reduction in a composite kidney outcome that used a sustained 57% reduction in eGFR as part of that outcome and essentially each component of the composite kidney outcome was reduced,  including kidney failure, end-stage kidney disease, eGFR of less than 15 ml/min in addition to a  ≥57% decrease in eGFR. And this kidney outcome showed a benefit irrespective of the use of SGLT2 inhibitor at baseline although the number of patients taking an SGLT2 inhibitor in this analysis was relatively small. So overall, the results of finerenone in 2021 support the use of this agent in patients with type 2 diabetes and chronic kidney disease to improve both cardiovascular and kidney outcomes.

Thank you for this insight. Regarding the SURPASS trials with tirzepatide, what is tirzepatide and what was its impact on glycemia and weight?

Dr. Goldenberg. My pleasure. Tirzepatide is a unique dual GIP/GLP-1 receptor agonist that has been formulated to be given as a once weekly injection. In 2021, we heard the first results from the Phase III program including SURPASS-1 through SURPASS-5. In these trials, patients were randomized to tirzepatide 5 mg, 10 mg, or 15 mg, and often compared to placebo or an active comparator. Across the SURPASS trials, the A1C reduction from baseline was between 1.9% to 2.6%. Up to 97% of patients on tirzepatide achieved a HbA1c of less than 7%, and up to 62% achieve a normal HbA1c of less than 5.7%.

In addition to these rather robust glycemic outcomes, there was excellent weight loss in the SURPASS program with the weight reduction ranging from 6 to 13 kg from baseline. Interestingly, in the SURPASS studies, tirzepatide showed superiority to semaglutide 1 mg and also superiority to titrated basal insulin. As far as safety, the side effect profile was similar to all GLP-1 receptor agonists with transient nausea being the most common side effect. Overall, tirzepatide will definitely add to our ability to treat our patients with type 2 diabetes with an incretin agent, and when this agent gets approved, hopefully, it will provide robust glycemic lowering and weight loss.

The fourth key study you mentioned is the EMPEROR-Preserved along with the EMPEROR-Pooled with the empagliflozin. What did they find in this analysis?

Dr. Goldenberg: The EMPEROR-Preserved was the first completed large randomized clinical trial of an SGLT2 inhibitor in patients with heart failure with preserved ejection fraction. They enrolled almost 6,000 patients with HFpEF with or without type 2 diabetes and they were randomized to empagliflozin 10 mg or placebo. The primary outcome of cardiovascular death or hospitalization for heart failure was reduced by 21% with empagliflozin and the number needed to treat was 31. This primary outcome was largely driven by a reduction in hospitalization for heart failure. The primary outcome showed consistent benefit across 15 prespecified subgroups, including those with or without type 2 diabetes, and including a spectrum of baseline left ventricular ejection fractions from 40% to 50% to greater than 60%.

There were also some key secondary endpoints:  total hospitalization for heart failure was reduced by 27% and empagliflozin also slowed the decline of eGFR over time in the EMPEROR-Preserved trial. The agent was well tolerated. There was a slight signal for more hypotension and genital mycotic infections, but otherwise really no concerning adverse effects.

Building on the EMPEROR-Preserved trial was a prespecified pooled analysis of EMPEROR-Reduced and EMPEROR-Preserved,  the two large outcome trials with empagliflozin in heart failure patients. The prespecified primary outcome of this analysis was a major renal outcome which included a GFR reduction of ≥40%, renal replacement therapy or sustained eGFR <10-15 ml/min. While in EMPEROR-Reduced there was a significant 49% reduction in this composite renal outcome, in EMPEROR-Preserved there was no significant reduction. Because of the heterogeneity across these two trials, it was not statistically valid to pool these two results for the composite renal outcome. However, what they found in EMPEROR-Pooled is that if you use a more robust renal outcome including at least a 50% decline in eGFR, then there seems to be a trend that varies depending on baseline left ventricular ejection fraction, suggesting a benefit on the renal outcome if your baseline left ventricular function ranges from 40% to 60%, but lack of benefit with a baseline left ventricular ejection fraction of over 60%. The top line summary of this data is that for the first time we have robust evidence that an SGLT2 inhibitor, in this case empagliflozin 10 mg, can provide a cardiovascular benefit in patients with HFpEF, in addition to the known benefit in HFrEF patients.

Finally, there's the AMPLITUDE-O with efpeglenatide, an international randomized controlled trial conducted at approximately 344 sites in 28 countries. What are the key learnings and messages for this specific study?

Dr. Goldenberg: Efpeglenatide is an exendin-4-based GLP-1 receptor agonist that is given once weekly and the AMPLITUDE-O trial is the cardiovascular outcome trial with efpeglenatide done in patients with type 2 diabetes and either cardiovascular disease or chronic kidney disease plus at least one cardiovascular risk factor. It was an important trial because prior to this cardiovascular outcome trial studies of exendin-4-based GLP-1 receptor agonist have been neutral. However, the AMPLITUDE-O study showed for the first-time superiority with an exendin-4-based GLP-1 receptor agonist. In this case, efpeglenatide 4 or 6 milligrams versus placebo was associated with a 27% reduction in the primary outcome of CV death, non-fatal MI or non-fatal stroke.

Importantly, there was a consistent benefit with efpeglenatide across a spectrum of prespecified subgroups,  the most important one being those that entered the trial on a background SGLT2 inhibitor, which represented about 15% of the patients. They derived the same overall benefit as those not taking an SGLT2 inhibitor. It is important to appreciate that this is probably the most robust data we have for showing a cardiovascular benefit of adding a GLP-1 receptor agonist to an SGLT2 inhibitor in high risk patients with type 2 diabetes. AMPLITUDE-O also adds to the already appreciated knowledge of the cardiovascular benefit of GLP-1 receptor agonists and builds on this story by showing that you can get a cardiovascular benefit with an exendin-4-based GLP-1 receptor agonist and you can get a benefit as an add on to SGLT2 inhibitors.