Meeting News

Latest CV outcomes trials suggest safety, benefit for newer diabetes therapies

Jay S. Skyler
Jay S. Skyler

BOSTON — Results from key CV outcomes trials presented and soon to be presented in 2018 continue to demonstrate CV safety for several new antidiabetes therapies, and the results are now influencing clinical guidelines, according to a presenter at the Cardiometabolic Health Congress.

Speaking during a presentation on late-breaking clinical trials for diabetes, Jay S. Skyler, MD, MACP, associate director of the Diabetes Research Institute and professor of medicine in pediatrics and psychology at the University of Miami Miller School of Medicine, said a joint consensus report published in September by the American Diabetes Association and European Association for the Study of Diabetes (EASD) now incorporates what numerous studies have demonstrated.

The updated statement now suggests that new medications shown to reduce CV risk — in particular, sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists —should be introduced earlier for high-risk patients with type 2 diabetes.

“The important things that [the consensus statement authors] said that I want to mention, that relates to us, is that among patients with type 2 diabetes and established CVD, SGLT2 inhibitors or GLP-1 receptor agonists with proven cardiovascular benefit are recommended as part of glycemic management,” Skyler said.

Additionally, Skyler said, if atherosclerotic CVD predominates, the consensus statement recommends the GLP-1 receptor agonists liraglutide (Victoza, Novo Nordisk), semaglutide (Ozempic, Novo Nordisk) or extended-release exenatide (Bydureon, AstraZeneca) or the SGLT2 inhibitors empagliflozin (Jardiance, Boehringer Ingelheim) or canagliflozin (Invokana, Janssen). If HF or chronic kidney disease predominates, Skyler said, the statement recommends the use of an SGLT2 inhibitor with evidence for reducing HF and/or chronic kidney disease progression, if tolerated.

Among patients who need the glucose-lowering effect of an injectable medication, GLP-1 receptor agonists are the preferred choice to insulin in type 2 diabetes, Skyler said.

“Finally, they get it right,” he said.

Skyler said insulin should be considered as the first injectable in type 2 diabetes only when HbA1c is very high (> 11%) or when there are symptoms of catabolism, such as weight loss, polyuria or polydipsia, which suggest insulin deficiency.

Several CV outcomes trials this year offered insight on other antidiabetes therapies.

CARMELINA

Among adults with type 2 diabetes, established CVD and/or chronic kidney disease, the dipeptidyl-peptidase IV (DPP-IV) inhibitor linagliptin (Tradjenta, Boehringer Ingelheim/Eli Lilly) demonstrated CV safety and a neutral effect for hospitalization for HF and kidney outcomes vs. placebo, according to findings from the CARMELINA trial presented in September at the EASD annual meeting.

“As with all of the other DPP-IV inhibitors, there is no increased risk of CV death, nonfatal MI and nonfatal stroke,” Skyler said, who added that, unlike the DPP-IV inhibitor saxagliptin (Onglyza, AstraZeneca), there was no increased risk for hospitalization for HF. Hospitalization for HF occurred in 209 adults (6%) in the linagliptin group and 226 adults (6.5%) in the placebo group.

The trial was noteworthy for its population enriched for kidney disease, Skyler said. In CARMELINA, 62.3% of enrolled participants had an estimated glomerular filtration rate less than 60 mL/min/1.73 m² — more than double the number of participants with renal disease in the EXAMINE trial for alogliptin (Nesina, Takeda), and more than three times greater than the number of participants in the SAVOR-TIMI and TECOS CV outcomes trials.

Renal outcomes in the trial included time to first occurrence of renal death, sustained end-stage renal disease or a sustained decrease in eGFR of at least 50%.

Skyler said renal events reflecting declining kidney function occurred in 327 adults (9.4%) in the linagliptin group and 306 adults (8.8%) in the placebo group, suggesting the therapy can be a safe option for patients with type 2 diabetes and kidney disease.

HARMONY

Adults with type 2 diabetes and atherosclerotic disease randomly assigned to the once-weekly GLP-1 receptor agonist albiglutide (Tanzeum, GlaxoSmithKline) experienced a 22% reduction in risk for major adverse cardiac events over 1.6 years vs. similar adults assigned to placebo, according to findings from the HARMONY-Outcomes trial presented in September at the EASD annual meeting.

The findings, an analysis of more than 9,400 patients across 28 countries, come after GlaxoSmithKline announced in August 2017 that it would discontinue production of albiglutide for commercial reasons, Skyler noted.

HRs for each component of the composite endpoint were 0.93 for CV death (95% CI, 0.73-1.19), 0.75 for MI (95% CI, 0.61-0.9) and 0.86 for stroke (95% CI, 0.66-1.14). Additionally, patients assigned albiglutide experienced a greater mean decrease in HbA1c over 16 months vs. those assigned placebo (difference, –0.52%; 95% CI, –0.58 to –0.45), as well as a greater mean reduction in body weight, whereas fewer patients in the albiglutide group initiated treatment with insulin therapy during the study, according to the researchers.

“It was very noble to continue to support the trial to its end, in spite of it being removed from the market,” Skyler said. “Companies don’t often do that.”

DECLARE - TIMI 58

Results from the phase 3 DECLARE-TIMI 58 CV outcomes trial for the SGLT2 inhibitor dapagliflozin (Farxiga, AstraZeneca) will be reported at the American Heart Association Scientific Sessions in November, Skyler said.

Top-line results announced in September showed the drug met one of its two primary efficacy endpoints of a statistically significant reduction in hospitalization for HF or CV death, Skyler said. However, the results demonstrated noninferiority of dapagliflozin to placebo when added to background diabetes therapies for the primary safety endpoint of major adverse CV events. Although the agent was associated with a reduction in major adverse CV events — the other primary efficacy endpoint — the decrease did not reach statistical significance.

The double-blind, placebo-controlled trial randomly assigned 17,160 patients with type 2 diabetes and a history of or high risk for atherosclerotic CVD to dapagliflozin 10 mg or placebo to assess whether therapy increases CV death, MI or ischemic stroke and the composite of CV death or hospitalization for HF.

“The press release for this says they [reached statistical significance] for a reduction in CV death and hospitalization for heart failure but did not [reach statistical significance] for standard [major adverse CV events],” Skyler said. “Results that will be presented next month at the American Heart Association meeting will give us the full answer.” – by Regina Schaffer

Reference:

Skyler J. Late-breaking clinical trials. Presented at: Cardiometabolic Health Congress; Oct. 24-27, 2018; Boston.

Disclosure: Skyler reports no relevant financial disclosures.

Jay S. Skyler
Jay S. Skyler

BOSTON — Results from key CV outcomes trials presented and soon to be presented in 2018 continue to demonstrate CV safety for several new antidiabetes therapies, and the results are now influencing clinical guidelines, according to a presenter at the Cardiometabolic Health Congress.

Speaking during a presentation on late-breaking clinical trials for diabetes, Jay S. Skyler, MD, MACP, associate director of the Diabetes Research Institute and professor of medicine in pediatrics and psychology at the University of Miami Miller School of Medicine, said a joint consensus report published in September by the American Diabetes Association and European Association for the Study of Diabetes (EASD) now incorporates what numerous studies have demonstrated.

The updated statement now suggests that new medications shown to reduce CV risk — in particular, sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists —should be introduced earlier for high-risk patients with type 2 diabetes.

“The important things that [the consensus statement authors] said that I want to mention, that relates to us, is that among patients with type 2 diabetes and established CVD, SGLT2 inhibitors or GLP-1 receptor agonists with proven cardiovascular benefit are recommended as part of glycemic management,” Skyler said.

Additionally, Skyler said, if atherosclerotic CVD predominates, the consensus statement recommends the GLP-1 receptor agonists liraglutide (Victoza, Novo Nordisk), semaglutide (Ozempic, Novo Nordisk) or extended-release exenatide (Bydureon, AstraZeneca) or the SGLT2 inhibitors empagliflozin (Jardiance, Boehringer Ingelheim) or canagliflozin (Invokana, Janssen). If HF or chronic kidney disease predominates, Skyler said, the statement recommends the use of an SGLT2 inhibitor with evidence for reducing HF and/or chronic kidney disease progression, if tolerated.

Among patients who need the glucose-lowering effect of an injectable medication, GLP-1 receptor agonists are the preferred choice to insulin in type 2 diabetes, Skyler said.

“Finally, they get it right,” he said.

Skyler said insulin should be considered as the first injectable in type 2 diabetes only when HbA1c is very high (> 11%) or when there are symptoms of catabolism, such as weight loss, polyuria or polydipsia, which suggest insulin deficiency.

Several CV outcomes trials this year offered insight on other antidiabetes therapies.

CARMELINA

Among adults with type 2 diabetes, established CVD and/or chronic kidney disease, the dipeptidyl-peptidase IV (DPP-IV) inhibitor linagliptin (Tradjenta, Boehringer Ingelheim/Eli Lilly) demonstrated CV safety and a neutral effect for hospitalization for HF and kidney outcomes vs. placebo, according to findings from the CARMELINA trial presented in September at the EASD annual meeting.

PAGE BREAK

“As with all of the other DPP-IV inhibitors, there is no increased risk of CV death, nonfatal MI and nonfatal stroke,” Skyler said, who added that, unlike the DPP-IV inhibitor saxagliptin (Onglyza, AstraZeneca), there was no increased risk for hospitalization for HF. Hospitalization for HF occurred in 209 adults (6%) in the linagliptin group and 226 adults (6.5%) in the placebo group.

The trial was noteworthy for its population enriched for kidney disease, Skyler said. In CARMELINA, 62.3% of enrolled participants had an estimated glomerular filtration rate less than 60 mL/min/1.73 m² — more than double the number of participants with renal disease in the EXAMINE trial for alogliptin (Nesina, Takeda), and more than three times greater than the number of participants in the SAVOR-TIMI and TECOS CV outcomes trials.

Renal outcomes in the trial included time to first occurrence of renal death, sustained end-stage renal disease or a sustained decrease in eGFR of at least 50%.

Skyler said renal events reflecting declining kidney function occurred in 327 adults (9.4%) in the linagliptin group and 306 adults (8.8%) in the placebo group, suggesting the therapy can be a safe option for patients with type 2 diabetes and kidney disease.

HARMONY

Adults with type 2 diabetes and atherosclerotic disease randomly assigned to the once-weekly GLP-1 receptor agonist albiglutide (Tanzeum, GlaxoSmithKline) experienced a 22% reduction in risk for major adverse cardiac events over 1.6 years vs. similar adults assigned to placebo, according to findings from the HARMONY-Outcomes trial presented in September at the EASD annual meeting.

The findings, an analysis of more than 9,400 patients across 28 countries, come after GlaxoSmithKline announced in August 2017 that it would discontinue production of albiglutide for commercial reasons, Skyler noted.

HRs for each component of the composite endpoint were 0.93 for CV death (95% CI, 0.73-1.19), 0.75 for MI (95% CI, 0.61-0.9) and 0.86 for stroke (95% CI, 0.66-1.14). Additionally, patients assigned albiglutide experienced a greater mean decrease in HbA1c over 16 months vs. those assigned placebo (difference, –0.52%; 95% CI, –0.58 to –0.45), as well as a greater mean reduction in body weight, whereas fewer patients in the albiglutide group initiated treatment with insulin therapy during the study, according to the researchers.

“It was very noble to continue to support the trial to its end, in spite of it being removed from the market,” Skyler said. “Companies don’t often do that.”

PAGE BREAK

DECLARE - TIMI 58

Results from the phase 3 DECLARE-TIMI 58 CV outcomes trial for the SGLT2 inhibitor dapagliflozin (Farxiga, AstraZeneca) will be reported at the American Heart Association Scientific Sessions in November, Skyler said.

Top-line results announced in September showed the drug met one of its two primary efficacy endpoints of a statistically significant reduction in hospitalization for HF or CV death, Skyler said. However, the results demonstrated noninferiority of dapagliflozin to placebo when added to background diabetes therapies for the primary safety endpoint of major adverse CV events. Although the agent was associated with a reduction in major adverse CV events — the other primary efficacy endpoint — the decrease did not reach statistical significance.

The double-blind, placebo-controlled trial randomly assigned 17,160 patients with type 2 diabetes and a history of or high risk for atherosclerotic CVD to dapagliflozin 10 mg or placebo to assess whether therapy increases CV death, MI or ischemic stroke and the composite of CV death or hospitalization for HF.

“The press release for this says they [reached statistical significance] for a reduction in CV death and hospitalization for heart failure but did not [reach statistical significance] for standard [major adverse CV events],” Skyler said. “Results that will be presented next month at the American Heart Association meeting will give us the full answer.” – by Regina Schaffer

Reference:

Skyler J. Late-breaking clinical trials. Presented at: Cardiometabolic Health Congress; Oct. 24-27, 2018; Boston.

Disclosure: Skyler reports no relevant financial disclosures.

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