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Heritability of colorectal cancer estimated at 40%
Thus, CRC “has a substantial heritable component, and may be more heritable in women than men,” Rebecca E. Graff, ScD, of the Harvard T.H. Chan School of Public Health, Boston, and the University of California, San Francisco, and her colleagues wrote. “Siblings, and particularly monozygotic cotwins, of individuals with colon or rectal cancer should consider personalized screening,” they added.
The model that best fits the data accounted for additive genetic and environmental effects, the researchers said. Based on this model, genetic factors explained about 40% (95% CI, 33%-48%) of variation in the risk of CRC. Thus, the heritability of CRC was about 40%. The estimated heritability of colon cancer was 16% and that of rectal cancer was 15%, but confidence intervals were wide, ranging from 0% to 47% or 50%, respectively. Individual environmental factors accounted for most of the remaining risk of colon and rectal cancers.
“Heritability was greater among women than men and greatest when colorectal cancer combining all subsites together was analyzed,” the researchers noted. Monozygotic twins of CRC patients were at greater risk of both colon and rectal cancers than were same-sex dizygotic twins, indicating that both types of cancer might share inherited genetic risk factors, they added. Variants identified by genomewide association studies “do not come close to accounting for the disease’s heritability,” but, in the meantime, twins of affected cotwins “might benefit particularly from diligent screening, given their excess risk relative to the general population.”
Funders included the Ellison Foundation, the Odense University Hospital AgeCare program, the Academy of Finland, and US BioSHaRE-EU, and the European Union’s Seventh Framework Programme, BioSHaRE-EU, the Swedish Ministry for Higher Education, and the Karolinska Institutet, and the National Cancer Institute. Dr. Graff had no conflicts of interest.
Thus, CRC “has a substantial heritable component, and may be more heritable in women than men,” Rebecca E. Graff, ScD, of the Harvard T.H. Chan School of Public Health, Boston, and the University of California, San Francisco, and her colleagues wrote. “Siblings, and particularly monozygotic cotwins, of individuals with colon or rectal cancer should consider personalized screening,” they added.
The model that best fits the data accounted for additive genetic and environmental effects, the researchers said. Based on this model, genetic factors explained about 40% (95% CI, 33%-48%) of variation in the risk of CRC. Thus, the heritability of CRC was about 40%. The estimated heritability of colon cancer was 16% and that of rectal cancer was 15%, but confidence intervals were wide, ranging from 0% to 47% or 50%, respectively. Individual environmental factors accounted for most of the remaining risk of colon and rectal cancers.
“Heritability was greater among women than men and greatest when colorectal cancer combining all subsites together was analyzed,” the researchers noted. Monozygotic twins of CRC patients were at greater risk of both colon and rectal cancers than were same-sex dizygotic twins, indicating that both types of cancer might share inherited genetic risk factors, they added. Variants identified by genomewide association studies “do not come close to accounting for the disease’s heritability,” but, in the meantime, twins of affected cotwins “might benefit particularly from diligent screening, given their excess risk relative to the general population.”
Funders included the Ellison Foundation, the Odense University Hospital AgeCare program, the Academy of Finland, and US BioSHaRE-EU, and the European Union’s Seventh Framework Programme, BioSHaRE-EU, the Swedish Ministry for Higher Education, and the Karolinska Institutet, and the National Cancer Institute. Dr. Graff had no conflicts of interest.
Thus, CRC “has a substantial heritable component, and may be more heritable in women than men,” Rebecca E. Graff, ScD, of the Harvard T.H. Chan School of Public Health, Boston, and the University of California, San Francisco, and her colleagues wrote. “Siblings, and particularly monozygotic cotwins, of individuals with colon or rectal cancer should consider personalized screening,” they added.
The model that best fits the data accounted for additive genetic and environmental effects, the researchers said. Based on this model, genetic factors explained about 40% (95% CI, 33%-48%) of variation in the risk of CRC. Thus, the heritability of CRC was about 40%. The estimated heritability of colon cancer was 16% and that of rectal cancer was 15%, but confidence intervals were wide, ranging from 0% to 47% or 50%, respectively. Individual environmental factors accounted for most of the remaining risk of colon and rectal cancers.
“Heritability was greater among women than men and greatest when colorectal cancer combining all subsites together was analyzed,” the researchers noted. Monozygotic twins of CRC patients were at greater risk of both colon and rectal cancers than were same-sex dizygotic twins, indicating that both types of cancer might share inherited genetic risk factors, they added. Variants identified by genomewide association studies “do not come close to accounting for the disease’s heritability,” but, in the meantime, twins of affected cotwins “might benefit particularly from diligent screening, given their excess risk relative to the general population.”
Funders included the Ellison Foundation, the Odense University Hospital AgeCare program, the Academy of Finland, and US BioSHaRE-EU, and the European Union’s Seventh Framework Programme, BioSHaRE-EU, the Swedish Ministry for Higher Education, and the Karolinska Institutet, and the National Cancer Institute. Dr. Graff had no conflicts of interest.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point: If a monozygotic twin developed colorectal cancer, his or her twin had about a threefold higher risk of CRC than did the overall cohort (familial risk ratio, 3.1; 95% CI, 2.4-3.8).
Major finding: Genetic factors explained about 40% (95% CI, 33%-48%) of variation in the risk of colorectal cancer.
Data source: An analysis of 39,990 monozygotic and 61,443 same-sex dizygotic twins from the Nordic Twin Study of Cancer.
Disclosures: Funders included the Ellison Foundation, the Odense University Hospital AgeCare program, the Academy of Finland, US BioSHaRE-EU, and the European Union’s Seventh Framework Programme, BioSHaRE-EU, the Swedish Ministry for Higher Education, and the Karolinska Institutet, and the National Cancer Institute. Dr. Graff had no conflicts of interest.
Endoscopists who took 1 minute longer detected significantly more upper GI neoplasms
Endoscopists who took about a minute longer during screening esophagogastroduodenoscopy (EGD) detected significantly more upper gastrointestinal neoplasms than their quicker colleagues, in a retrospective study reported in the August issue of Gastroenterology (doi: 10.1053/j.gastro.2017.05.009).
Detection rates were 0.28% and 0.20%, respectively (P = .005), and this difference remained statistically significant after the investigators controlled for numerous factors that also can affect the chances of detecting gastric neoplasms during upper endoscopy, reported Jae Myung Park, MD, and his colleagues at Seoul (Korea) St. Mary’s Hospital.
Gastric cancer is the second leading cause of cancer mortality worldwide, they noted. Although EGD has been practiced globally for decades, there is no consensus on which performance metrics optimize diagnostic yield. Both Korea and Japan have adopted screening EGD to help diagnose gastric cancer, but interval cancers and false-positive results remain concerns, and the field lacks rigorous analyses comparing EGD time with gastric cancer detection rates. Therefore, the researchers studied 111,962 consecutive patients who underwent EGD at one hospital in Seoul from 2009 through 2015. Fourteen board-certified endoscopists performed these procedures at a single endoscopy unit.A total of 262 patients (0.23%) were diagnosed with gastric neoplasia or dysplasia, duodenal neoplasia, or esophageal carcinoma. This finding closely resembled a prior report from Korea, the investigators noted. Detection rates among individual endoscopists ranged from 0.14% to 0.32%, and longer EGD time was associated with a higher detection rate with an R value of 0.54 (P = .046). During the first year of the study, EGDs without biopsies averaged 2 minutes, 53 seconds. Based on this finding, the researchers set a cutoff time of 3 minutes and classified eight endoscopists as fast (mean EGD duration, 2 minutes and 38 seconds; standard deviation, 21 seconds) and six endoscopists as slow (mean duration, 3 minutes and 25 seconds; SD, 19 seconds). Slower endoscopists were significantly more likely to detect gastric adenomas or carcinomas, even after the investigators controlled for the biopsy rates and experience level of these endoscopists and patients’ age, sex, smoking status, alcohol use, and family history of cancer (odds ratio, 1.52; 95% confidence interval, 1.17-1.97; P = .0018).
Older age, male sex, and smoking also were significant correlates of cancer detection in the multivariable model. Biopsy rates among endoscopists ranged from 7% to 28%, and taking a biopsy was an even stronger predictor of detecting an upper GI neoplasm than was EGD duration, with an R value of 0.76 (P = .002). Although this study was observational and retrospective and lacked data on prior EGD examinations, surveillance intervals, and rates of false-negative results, it “supports the hypothesis that examination duration affects the diagnostic accuracy of EGD,” Dr. Park and his coinvestigators reported. “Prolonging the examination time will allow more careful examination by the endoscopist, which will enable the detection of more subtle lesions. Based on our data, we believe that these indicators can improve the quality of EGD.”
Funders included the Ministry of Education, Science, and Technology; the Ministry of Science, ICT, and Future Planning; and the Ministry of Health & Welfare, Republic of Korea. The investigators reported having no conflicts of interest.
Screening and surveillance practices remain one of the major indications for performing upper endoscopy in patients to detect esophageal (adenocarcinoma in the West; squamous cell in the East) and gastric cancer (in the East). The goal of the initial endoscopy is to detect precancerous lesions (such as Barrett's esophagus and gastric intestinal metaplasia) and, if detected, to grade them properly and evaluate for the presence of dysplasia and cancer in subsequent surveillance examinations.
Prateek Sharma, MD, is a professor of medicine in the division of gastroenterology and hepatology, Veterans Affairs Medical Center, University of Kansas, Kansas City, Mo. He has no conflicts of interest.
Screening and surveillance practices remain one of the major indications for performing upper endoscopy in patients to detect esophageal (adenocarcinoma in the West; squamous cell in the East) and gastric cancer (in the East). The goal of the initial endoscopy is to detect precancerous lesions (such as Barrett's esophagus and gastric intestinal metaplasia) and, if detected, to grade them properly and evaluate for the presence of dysplasia and cancer in subsequent surveillance examinations.
Prateek Sharma, MD, is a professor of medicine in the division of gastroenterology and hepatology, Veterans Affairs Medical Center, University of Kansas, Kansas City, Mo. He has no conflicts of interest.
Screening and surveillance practices remain one of the major indications for performing upper endoscopy in patients to detect esophageal (adenocarcinoma in the West; squamous cell in the East) and gastric cancer (in the East). The goal of the initial endoscopy is to detect precancerous lesions (such as Barrett's esophagus and gastric intestinal metaplasia) and, if detected, to grade them properly and evaluate for the presence of dysplasia and cancer in subsequent surveillance examinations.
Prateek Sharma, MD, is a professor of medicine in the division of gastroenterology and hepatology, Veterans Affairs Medical Center, University of Kansas, Kansas City, Mo. He has no conflicts of interest.
Endoscopists who took about a minute longer during screening esophagogastroduodenoscopy (EGD) detected significantly more upper gastrointestinal neoplasms than their quicker colleagues, in a retrospective study reported in the August issue of Gastroenterology (doi: 10.1053/j.gastro.2017.05.009).
Detection rates were 0.28% and 0.20%, respectively (P = .005), and this difference remained statistically significant after the investigators controlled for numerous factors that also can affect the chances of detecting gastric neoplasms during upper endoscopy, reported Jae Myung Park, MD, and his colleagues at Seoul (Korea) St. Mary’s Hospital.
Gastric cancer is the second leading cause of cancer mortality worldwide, they noted. Although EGD has been practiced globally for decades, there is no consensus on which performance metrics optimize diagnostic yield. Both Korea and Japan have adopted screening EGD to help diagnose gastric cancer, but interval cancers and false-positive results remain concerns, and the field lacks rigorous analyses comparing EGD time with gastric cancer detection rates. Therefore, the researchers studied 111,962 consecutive patients who underwent EGD at one hospital in Seoul from 2009 through 2015. Fourteen board-certified endoscopists performed these procedures at a single endoscopy unit.A total of 262 patients (0.23%) were diagnosed with gastric neoplasia or dysplasia, duodenal neoplasia, or esophageal carcinoma. This finding closely resembled a prior report from Korea, the investigators noted. Detection rates among individual endoscopists ranged from 0.14% to 0.32%, and longer EGD time was associated with a higher detection rate with an R value of 0.54 (P = .046). During the first year of the study, EGDs without biopsies averaged 2 minutes, 53 seconds. Based on this finding, the researchers set a cutoff time of 3 minutes and classified eight endoscopists as fast (mean EGD duration, 2 minutes and 38 seconds; standard deviation, 21 seconds) and six endoscopists as slow (mean duration, 3 minutes and 25 seconds; SD, 19 seconds). Slower endoscopists were significantly more likely to detect gastric adenomas or carcinomas, even after the investigators controlled for the biopsy rates and experience level of these endoscopists and patients’ age, sex, smoking status, alcohol use, and family history of cancer (odds ratio, 1.52; 95% confidence interval, 1.17-1.97; P = .0018).
Older age, male sex, and smoking also were significant correlates of cancer detection in the multivariable model. Biopsy rates among endoscopists ranged from 7% to 28%, and taking a biopsy was an even stronger predictor of detecting an upper GI neoplasm than was EGD duration, with an R value of 0.76 (P = .002). Although this study was observational and retrospective and lacked data on prior EGD examinations, surveillance intervals, and rates of false-negative results, it “supports the hypothesis that examination duration affects the diagnostic accuracy of EGD,” Dr. Park and his coinvestigators reported. “Prolonging the examination time will allow more careful examination by the endoscopist, which will enable the detection of more subtle lesions. Based on our data, we believe that these indicators can improve the quality of EGD.”
Funders included the Ministry of Education, Science, and Technology; the Ministry of Science, ICT, and Future Planning; and the Ministry of Health & Welfare, Republic of Korea. The investigators reported having no conflicts of interest.
Endoscopists who took about a minute longer during screening esophagogastroduodenoscopy (EGD) detected significantly more upper gastrointestinal neoplasms than their quicker colleagues, in a retrospective study reported in the August issue of Gastroenterology (doi: 10.1053/j.gastro.2017.05.009).
Detection rates were 0.28% and 0.20%, respectively (P = .005), and this difference remained statistically significant after the investigators controlled for numerous factors that also can affect the chances of detecting gastric neoplasms during upper endoscopy, reported Jae Myung Park, MD, and his colleagues at Seoul (Korea) St. Mary’s Hospital.
Gastric cancer is the second leading cause of cancer mortality worldwide, they noted. Although EGD has been practiced globally for decades, there is no consensus on which performance metrics optimize diagnostic yield. Both Korea and Japan have adopted screening EGD to help diagnose gastric cancer, but interval cancers and false-positive results remain concerns, and the field lacks rigorous analyses comparing EGD time with gastric cancer detection rates. Therefore, the researchers studied 111,962 consecutive patients who underwent EGD at one hospital in Seoul from 2009 through 2015. Fourteen board-certified endoscopists performed these procedures at a single endoscopy unit.A total of 262 patients (0.23%) were diagnosed with gastric neoplasia or dysplasia, duodenal neoplasia, or esophageal carcinoma. This finding closely resembled a prior report from Korea, the investigators noted. Detection rates among individual endoscopists ranged from 0.14% to 0.32%, and longer EGD time was associated with a higher detection rate with an R value of 0.54 (P = .046). During the first year of the study, EGDs without biopsies averaged 2 minutes, 53 seconds. Based on this finding, the researchers set a cutoff time of 3 minutes and classified eight endoscopists as fast (mean EGD duration, 2 minutes and 38 seconds; standard deviation, 21 seconds) and six endoscopists as slow (mean duration, 3 minutes and 25 seconds; SD, 19 seconds). Slower endoscopists were significantly more likely to detect gastric adenomas or carcinomas, even after the investigators controlled for the biopsy rates and experience level of these endoscopists and patients’ age, sex, smoking status, alcohol use, and family history of cancer (odds ratio, 1.52; 95% confidence interval, 1.17-1.97; P = .0018).
Older age, male sex, and smoking also were significant correlates of cancer detection in the multivariable model. Biopsy rates among endoscopists ranged from 7% to 28%, and taking a biopsy was an even stronger predictor of detecting an upper GI neoplasm than was EGD duration, with an R value of 0.76 (P = .002). Although this study was observational and retrospective and lacked data on prior EGD examinations, surveillance intervals, and rates of false-negative results, it “supports the hypothesis that examination duration affects the diagnostic accuracy of EGD,” Dr. Park and his coinvestigators reported. “Prolonging the examination time will allow more careful examination by the endoscopist, which will enable the detection of more subtle lesions. Based on our data, we believe that these indicators can improve the quality of EGD.”
Funders included the Ministry of Education, Science, and Technology; the Ministry of Science, ICT, and Future Planning; and the Ministry of Health & Welfare, Republic of Korea. The investigators reported having no conflicts of interest.
FROM GASTROENTEROLOGY
Key clinical point: Adding about 1 minute to an upper endoscopy might significantly increase the detection of upper gastrointestinal neoplasms.
Major finding: Slow endoscopists (with a mean duration for the procedure of 3 minutes and 25 seconds) had a detection rate of 0.28%, while fast endoscopists (2 minutes and 38 seconds) had a detection rate of 0.20% (P = .005).
Data source: A single-center retrospective study of 111,962 individuals who underwent esophagogastroduodenoscopy in Korea between 2009 and 2015.
Disclosures: Funders included the Ministry of Education, Science, and Technology; the Ministry of Science, ICT, and Future Planning; and the Ministry of Health & Welfare, Republic of Korea. The investigators reported having no conflicts of interest.
LEADER post hoc analysis: Mechanism behind liraglutide’s cardioprotective effects unclear
SAN DIEGO – The glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide significantly reduced the risk of initial and recurrent major cardiovascular events in high-risk patients with type 2 diabetes, according to new posthoc analyses from the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial.
Liraglutide’s cardioprotective effect did not depend on baseline use of insulin or cardiovascular medications, nor whether patients started insulin, sulfonylureas, or thiazolidinediones, or developed severe hypoglycemia during the trial, Richard Pratley, MD, told a packed auditorium at the annual scientific sessions of the American Diabetes Association. “It appears unlikely that the cardiovascular risk reduction with liraglutide can be fully explained by the observed differences in hemoglobin A1c, body weight, systolic blood pressure, and lipids,” he said. Experts have proposed several pathways, “but the bottom line is, in humans, we don’t know the mechanism for liraglutide’s benefit.”
In LEADER, 9,340 older patients with suboptimally controlled type 2 diabetes and additional cardiovascular risk factors were randomly assigned to liraglutide or placebo once daily. Patients were typically male, obese, and hypertensive, and about 18% had prior heart failure. Topline results reported last year at ADA included a 13% reduction in the rate of initial cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke in the liraglutide group, compared with the placebo group (hazard ratio, 0.87; 95% confidence interval, 0.78 to 0.97).
The new posthoc analyses indicate that liraglutide also prevents both initial and recurrent cardiovascular events (HR, 0.86; 95% CI, 0.78 to 0.95) and that its cardioprotective effect spans subgroups of patients stratified according to whether they were on insulin, beta-blockers, ACE inhibitors, statins, and platelet aggregation inhibitors at baseline, said Dr. Pratley, senior investigator at the Translational Research Institute for Metabolism and Diabetes, and medical director of the Florida Hospital Diabetes Institute, Orlando. 
Liraglutide also reduced cardiovascular events to about the same extent regardless of whether patients later started insulin, sulfonylureas, or thiazolidinediones or developed severe hypoglycemia.
Such findings signal a fundamental shift in diabetes care, commented Steven Nissen, MD, chair of the department of cardiovascular medicine, at the Cleveland Clinic, Cleveland, Ohio. For decades, patients and clinicians lacked diabetes outcomes trials, and “it took three successive shockwaves to awaken the medical community from its 50-year slumber.”
The wake-up call started when Dr. Nissen and his associates linked muraglitazar (JAMA. 2005 Nov 23;294[20]:2581-6) and rosiglitazone (N Engl J Med 2007; 356:2457-71) to an increased risk of major adverse cardiovascular events. This continued when researchers found that targeting glycated hemoglobin levels below 6.0% increased the risk of death in patients with type 2 diabetes, in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial (N Engl J Med 2008; 358:2545-59).
In response, the Food and Drug Administration began requiring cardiovascular outcomes trials before and after approving new diabetes drugs. “The result has been a new era of research” that has revealed uneven outcomes and a lack of uniform class effects, Dr. Nissen said.
For example, lixisenatide and long-acting exenatide are GLP-1 receptor agonists like liraglutide, but neither of these two drugs were found to prevent cardiovascular outcomes compared with placebo. In addition, the DPP-4 inhibitors “provide no meaningful outcome benefits, minimal glucose lowering, and potential harm at a high cost of about $400 per month,” he said.
This class has suffered “three disappointments,” he added. He referred to findings that alogliptin and sitagliptin did not reduce cardiovascular events compared with placebo in the EXAMINE trial (N Engl J Med 2013; 369:1327-35) and TECOS trial (N Engl J Med 2015; 373:232-42), respectively, while the SAVOR-TIMI 53 trial linked saxagliptin to an increased risk of hospitalization for heart failure (HR, 1.27; 95% CI, 1.07 to 1.51).
In contrast, the sodium-glucose cotransporter-2 (SGLT-2) inhibitor empagliflozin reduced the rate of cardiovascular death, stroke, and MI by about 14% in the EMPA-REG trial (N Engl J Med 2015;373:2117-28).
Based on the LEADER results, the Food and Drug Administration’s Endocrinologic and Metabolic Drugs Advisory Committee voted 17-2 supporting a new cardiovascular indication for liraglutide in type 2 diabetes, at a meeting in June 2017.
“After 60 years of stagnation, we are now witnessing a new era in the pharmacological management of type 2 diabetes, which is allowing a choice of therapies based on actual clinical outcomes – risks and benefits – rather than a surrogate biochemical marker like glucose levels,” Dr. Nissen said.
But current ADA recommendations “only weakly reflect contemporary knowledge,” he added. Although these guidelines do recommend considering empagliflozin or liraglutide for patients with atherosclerotic cardiovascular disease and “long-standing, suboptimally controlled type 2 diabetes,” their guidance on dual therapy does not reflect diverse cardiovascular outcomes data within and between classes, he said. “Just as we observed with statins, adoption of pivotal results is often just too slow.”
Integrating knowledge into practice will require close collaboration between cardiovascular and diabetes practitioners and “leadership from ADA to overcome residual inertia from decades of complacency,” he commented.
Dr. Pratley disclosed ties to AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, and several other pharmaceutical companies. Dr. Nissen disclosed research support from Novo Nordisk, Abbvie, Eli Lilly, and several other pharmaceutical companies, and travel support from Novo Nordisk.
SAN DIEGO – The glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide significantly reduced the risk of initial and recurrent major cardiovascular events in high-risk patients with type 2 diabetes, according to new posthoc analyses from the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial.
Liraglutide’s cardioprotective effect did not depend on baseline use of insulin or cardiovascular medications, nor whether patients started insulin, sulfonylureas, or thiazolidinediones, or developed severe hypoglycemia during the trial, Richard Pratley, MD, told a packed auditorium at the annual scientific sessions of the American Diabetes Association. “It appears unlikely that the cardiovascular risk reduction with liraglutide can be fully explained by the observed differences in hemoglobin A1c, body weight, systolic blood pressure, and lipids,” he said. Experts have proposed several pathways, “but the bottom line is, in humans, we don’t know the mechanism for liraglutide’s benefit.”
In LEADER, 9,340 older patients with suboptimally controlled type 2 diabetes and additional cardiovascular risk factors were randomly assigned to liraglutide or placebo once daily. Patients were typically male, obese, and hypertensive, and about 18% had prior heart failure. Topline results reported last year at ADA included a 13% reduction in the rate of initial cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke in the liraglutide group, compared with the placebo group (hazard ratio, 0.87; 95% confidence interval, 0.78 to 0.97).
The new posthoc analyses indicate that liraglutide also prevents both initial and recurrent cardiovascular events (HR, 0.86; 95% CI, 0.78 to 0.95) and that its cardioprotective effect spans subgroups of patients stratified according to whether they were on insulin, beta-blockers, ACE inhibitors, statins, and platelet aggregation inhibitors at baseline, said Dr. Pratley, senior investigator at the Translational Research Institute for Metabolism and Diabetes, and medical director of the Florida Hospital Diabetes Institute, Orlando.
Liraglutide also reduced cardiovascular events to about the same extent regardless of whether patients later started insulin, sulfonylureas, or thiazolidinediones or developed severe hypoglycemia.
Such findings signal a fundamental shift in diabetes care, commented Steven Nissen, MD, chair of the department of cardiovascular medicine, at the Cleveland Clinic, Cleveland, Ohio. For decades, patients and clinicians lacked diabetes outcomes trials, and “it took three successive shockwaves to awaken the medical community from its 50-year slumber.”
The wake-up call started when Dr. Nissen and his associates linked muraglitazar (JAMA. 2005 Nov 23;294[20]:2581-6) and rosiglitazone (N Engl J Med 2007; 356:2457-71) to an increased risk of major adverse cardiovascular events. This continued when researchers found that targeting glycated hemoglobin levels below 6.0% increased the risk of death in patients with type 2 diabetes, in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial (N Engl J Med 2008; 358:2545-59).
In response, the Food and Drug Administration began requiring cardiovascular outcomes trials before and after approving new diabetes drugs. “The result has been a new era of research” that has revealed uneven outcomes and a lack of uniform class effects, Dr. Nissen said.
For example, lixisenatide and long-acting exenatide are GLP-1 receptor agonists like liraglutide, but neither of these two drugs were found to prevent cardiovascular outcomes compared with placebo. In addition, the DPP-4 inhibitors “provide no meaningful outcome benefits, minimal glucose lowering, and potential harm at a high cost of about $400 per month,” he said.
This class has suffered “three disappointments,” he added. He referred to findings that alogliptin and sitagliptin did not reduce cardiovascular events compared with placebo in the EXAMINE trial (N Engl J Med 2013; 369:1327-35) and TECOS trial (N Engl J Med 2015; 373:232-42), respectively, while the SAVOR-TIMI 53 trial linked saxagliptin to an increased risk of hospitalization for heart failure (HR, 1.27; 95% CI, 1.07 to 1.51).
In contrast, the sodium-glucose cotransporter-2 (SGLT-2) inhibitor empagliflozin reduced the rate of cardiovascular death, stroke, and MI by about 14% in the EMPA-REG trial (N Engl J Med 2015;373:2117-28).
Based on the LEADER results, the Food and Drug Administration’s Endocrinologic and Metabolic Drugs Advisory Committee voted 17-2 supporting a new cardiovascular indication for liraglutide in type 2 diabetes, at a meeting in June 2017.
“After 60 years of stagnation, we are now witnessing a new era in the pharmacological management of type 2 diabetes, which is allowing a choice of therapies based on actual clinical outcomes – risks and benefits – rather than a surrogate biochemical marker like glucose levels,” Dr. Nissen said.
But current ADA recommendations “only weakly reflect contemporary knowledge,” he added. Although these guidelines do recommend considering empagliflozin or liraglutide for patients with atherosclerotic cardiovascular disease and “long-standing, suboptimally controlled type 2 diabetes,” their guidance on dual therapy does not reflect diverse cardiovascular outcomes data within and between classes, he said. “Just as we observed with statins, adoption of pivotal results is often just too slow.”
Integrating knowledge into practice will require close collaboration between cardiovascular and diabetes practitioners and “leadership from ADA to overcome residual inertia from decades of complacency,” he commented.
Dr. Pratley disclosed ties to AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, and several other pharmaceutical companies. Dr. Nissen disclosed research support from Novo Nordisk, Abbvie, Eli Lilly, and several other pharmaceutical companies, and travel support from Novo Nordisk.
SAN DIEGO – The glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide significantly reduced the risk of initial and recurrent major cardiovascular events in high-risk patients with type 2 diabetes, according to new posthoc analyses from the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial.
Liraglutide’s cardioprotective effect did not depend on baseline use of insulin or cardiovascular medications, nor whether patients started insulin, sulfonylureas, or thiazolidinediones, or developed severe hypoglycemia during the trial, Richard Pratley, MD, told a packed auditorium at the annual scientific sessions of the American Diabetes Association. “It appears unlikely that the cardiovascular risk reduction with liraglutide can be fully explained by the observed differences in hemoglobin A1c, body weight, systolic blood pressure, and lipids,” he said. Experts have proposed several pathways, “but the bottom line is, in humans, we don’t know the mechanism for liraglutide’s benefit.”
In LEADER, 9,340 older patients with suboptimally controlled type 2 diabetes and additional cardiovascular risk factors were randomly assigned to liraglutide or placebo once daily. Patients were typically male, obese, and hypertensive, and about 18% had prior heart failure. Topline results reported last year at ADA included a 13% reduction in the rate of initial cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke in the liraglutide group, compared with the placebo group (hazard ratio, 0.87; 95% confidence interval, 0.78 to 0.97).
The new posthoc analyses indicate that liraglutide also prevents both initial and recurrent cardiovascular events (HR, 0.86; 95% CI, 0.78 to 0.95) and that its cardioprotective effect spans subgroups of patients stratified according to whether they were on insulin, beta-blockers, ACE inhibitors, statins, and platelet aggregation inhibitors at baseline, said Dr. Pratley, senior investigator at the Translational Research Institute for Metabolism and Diabetes, and medical director of the Florida Hospital Diabetes Institute, Orlando.
Liraglutide also reduced cardiovascular events to about the same extent regardless of whether patients later started insulin, sulfonylureas, or thiazolidinediones or developed severe hypoglycemia.
Such findings signal a fundamental shift in diabetes care, commented Steven Nissen, MD, chair of the department of cardiovascular medicine, at the Cleveland Clinic, Cleveland, Ohio. For decades, patients and clinicians lacked diabetes outcomes trials, and “it took three successive shockwaves to awaken the medical community from its 50-year slumber.”
The wake-up call started when Dr. Nissen and his associates linked muraglitazar (JAMA. 2005 Nov 23;294[20]:2581-6) and rosiglitazone (N Engl J Med 2007; 356:2457-71) to an increased risk of major adverse cardiovascular events. This continued when researchers found that targeting glycated hemoglobin levels below 6.0% increased the risk of death in patients with type 2 diabetes, in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial (N Engl J Med 2008; 358:2545-59).
In response, the Food and Drug Administration began requiring cardiovascular outcomes trials before and after approving new diabetes drugs. “The result has been a new era of research” that has revealed uneven outcomes and a lack of uniform class effects, Dr. Nissen said.
For example, lixisenatide and long-acting exenatide are GLP-1 receptor agonists like liraglutide, but neither of these two drugs were found to prevent cardiovascular outcomes compared with placebo. In addition, the DPP-4 inhibitors “provide no meaningful outcome benefits, minimal glucose lowering, and potential harm at a high cost of about $400 per month,” he said.
This class has suffered “three disappointments,” he added. He referred to findings that alogliptin and sitagliptin did not reduce cardiovascular events compared with placebo in the EXAMINE trial (N Engl J Med 2013; 369:1327-35) and TECOS trial (N Engl J Med 2015; 373:232-42), respectively, while the SAVOR-TIMI 53 trial linked saxagliptin to an increased risk of hospitalization for heart failure (HR, 1.27; 95% CI, 1.07 to 1.51).
In contrast, the sodium-glucose cotransporter-2 (SGLT-2) inhibitor empagliflozin reduced the rate of cardiovascular death, stroke, and MI by about 14% in the EMPA-REG trial (N Engl J Med 2015;373:2117-28).
Based on the LEADER results, the Food and Drug Administration’s Endocrinologic and Metabolic Drugs Advisory Committee voted 17-2 supporting a new cardiovascular indication for liraglutide in type 2 diabetes, at a meeting in June 2017.
“After 60 years of stagnation, we are now witnessing a new era in the pharmacological management of type 2 diabetes, which is allowing a choice of therapies based on actual clinical outcomes – risks and benefits – rather than a surrogate biochemical marker like glucose levels,” Dr. Nissen said.
But current ADA recommendations “only weakly reflect contemporary knowledge,” he added. Although these guidelines do recommend considering empagliflozin or liraglutide for patients with atherosclerotic cardiovascular disease and “long-standing, suboptimally controlled type 2 diabetes,” their guidance on dual therapy does not reflect diverse cardiovascular outcomes data within and between classes, he said. “Just as we observed with statins, adoption of pivotal results is often just too slow.”
Integrating knowledge into practice will require close collaboration between cardiovascular and diabetes practitioners and “leadership from ADA to overcome residual inertia from decades of complacency,” he commented.
Dr. Pratley disclosed ties to AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, and several other pharmaceutical companies. Dr. Nissen disclosed research support from Novo Nordisk, Abbvie, Eli Lilly, and several other pharmaceutical companies, and travel support from Novo Nordisk.
AT THE ADA ANNUAL SCIENTIFIC SESSIONS
SPRINT: Intensive BP control cut cardiovascular risk in patients with prediabetes
SAN DIEGO – Treating systolic hypertension to a target of 120 mm Hg instead of 140 mm Hg significantly reduced the rate of cardiovascular events in high-risk patients with prediabetes, according to a post-hoc analysis of the multicenter, randomized, controlled, open-label Systolic Blood Pressure Intervention Trial (SPRINT).
Thus, prediabetes did not undercut the cardiovascular benefits of intensive systolic blood pressure (SBP) control in older, high-risk, hypertensive patients, Adam P. Bress, PharmD, MS, and his associates concluded in a late-breaking poster presented at the annual scientific sessions of the American Diabetes Association.
In contrast, intensive SBP control did not prevent cardiovascular events, compared with standard control among diabetic patients in the randomized, nonblinded ACCORD BP trial (N Engl J Med. 2010; 362:1575-85).
To help clarify SBP targets for prediabetic individuals, Dr. Bress and his associates parsed cardiovascular outcomes in SPRINT based on baseline fasting serum glucose (FSG) levels. More than 5,400 normoglycemic (average FSG, 91 mg per dL) patients and more than 3,800 prediabetic (average FSG, 110 mg per dL) patients were followed for a median of 3.3 years, after which 101 (1.6%) prediabetic intensive control patients and 144 (2.3%) prediabetic standard control patients experienced the combined primary endpoint (HR, 0.7; 95% confidence interval, 0.5-0.9). The hazard ratio for normoglycemic patients was similar (0.9) and approached statistical significance.
Intensive SBP control also was associated with lower rates of individual cardiovascular outcomes and all-cause mortality, compared with standard control in both normoglycemic and prediabetic patients, Dr. Bress and his associates reported. Wide confidence intervals precluded statistical significance for most individual outcomes, but intensive control was associated with a significantly lower risk of all-cause mortality in normoglycemic patients (0.7% vs. 1.4% with standard control; HR, 0.7; 95% CI, 0.5-0.9).
Serious adverse events affected about 37% of patients in all subgroups. Hypotension, syncope, bradycardia, and electrolyte abnormalities were slightly more common in the intensive control groups than the standard control groups, regardless of baseline FPG levels.
SPRINT was sponsored by the National Heart, Lung, and Blood Institute. The National Institute on Aging, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke, and Wake Forest University Health Sciences provided additional support. Dr. Bress disclosed research support from Novartis and the National Institutes of Health.
SAN DIEGO – Treating systolic hypertension to a target of 120 mm Hg instead of 140 mm Hg significantly reduced the rate of cardiovascular events in high-risk patients with prediabetes, according to a post-hoc analysis of the multicenter, randomized, controlled, open-label Systolic Blood Pressure Intervention Trial (SPRINT).
Thus, prediabetes did not undercut the cardiovascular benefits of intensive systolic blood pressure (SBP) control in older, high-risk, hypertensive patients, Adam P. Bress, PharmD, MS, and his associates concluded in a late-breaking poster presented at the annual scientific sessions of the American Diabetes Association.
In contrast, intensive SBP control did not prevent cardiovascular events, compared with standard control among diabetic patients in the randomized, nonblinded ACCORD BP trial (N Engl J Med. 2010; 362:1575-85).
To help clarify SBP targets for prediabetic individuals, Dr. Bress and his associates parsed cardiovascular outcomes in SPRINT based on baseline fasting serum glucose (FSG) levels. More than 5,400 normoglycemic (average FSG, 91 mg per dL) patients and more than 3,800 prediabetic (average FSG, 110 mg per dL) patients were followed for a median of 3.3 years, after which 101 (1.6%) prediabetic intensive control patients and 144 (2.3%) prediabetic standard control patients experienced the combined primary endpoint (HR, 0.7; 95% confidence interval, 0.5-0.9). The hazard ratio for normoglycemic patients was similar (0.9) and approached statistical significance.
Intensive SBP control also was associated with lower rates of individual cardiovascular outcomes and all-cause mortality, compared with standard control in both normoglycemic and prediabetic patients, Dr. Bress and his associates reported. Wide confidence intervals precluded statistical significance for most individual outcomes, but intensive control was associated with a significantly lower risk of all-cause mortality in normoglycemic patients (0.7% vs. 1.4% with standard control; HR, 0.7; 95% CI, 0.5-0.9).
Serious adverse events affected about 37% of patients in all subgroups. Hypotension, syncope, bradycardia, and electrolyte abnormalities were slightly more common in the intensive control groups than the standard control groups, regardless of baseline FPG levels.
SPRINT was sponsored by the National Heart, Lung, and Blood Institute. The National Institute on Aging, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke, and Wake Forest University Health Sciences provided additional support. Dr. Bress disclosed research support from Novartis and the National Institutes of Health.
SAN DIEGO – Treating systolic hypertension to a target of 120 mm Hg instead of 140 mm Hg significantly reduced the rate of cardiovascular events in high-risk patients with prediabetes, according to a post-hoc analysis of the multicenter, randomized, controlled, open-label Systolic Blood Pressure Intervention Trial (SPRINT).
Thus, prediabetes did not undercut the cardiovascular benefits of intensive systolic blood pressure (SBP) control in older, high-risk, hypertensive patients, Adam P. Bress, PharmD, MS, and his associates concluded in a late-breaking poster presented at the annual scientific sessions of the American Diabetes Association.
In contrast, intensive SBP control did not prevent cardiovascular events, compared with standard control among diabetic patients in the randomized, nonblinded ACCORD BP trial (N Engl J Med. 2010; 362:1575-85).
To help clarify SBP targets for prediabetic individuals, Dr. Bress and his associates parsed cardiovascular outcomes in SPRINT based on baseline fasting serum glucose (FSG) levels. More than 5,400 normoglycemic (average FSG, 91 mg per dL) patients and more than 3,800 prediabetic (average FSG, 110 mg per dL) patients were followed for a median of 3.3 years, after which 101 (1.6%) prediabetic intensive control patients and 144 (2.3%) prediabetic standard control patients experienced the combined primary endpoint (HR, 0.7; 95% confidence interval, 0.5-0.9). The hazard ratio for normoglycemic patients was similar (0.9) and approached statistical significance.
Intensive SBP control also was associated with lower rates of individual cardiovascular outcomes and all-cause mortality, compared with standard control in both normoglycemic and prediabetic patients, Dr. Bress and his associates reported. Wide confidence intervals precluded statistical significance for most individual outcomes, but intensive control was associated with a significantly lower risk of all-cause mortality in normoglycemic patients (0.7% vs. 1.4% with standard control; HR, 0.7; 95% CI, 0.5-0.9).
Serious adverse events affected about 37% of patients in all subgroups. Hypotension, syncope, bradycardia, and electrolyte abnormalities were slightly more common in the intensive control groups than the standard control groups, regardless of baseline FPG levels.
SPRINT was sponsored by the National Heart, Lung, and Blood Institute. The National Institute on Aging, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke, and Wake Forest University Health Sciences provided additional support. Dr. Bress disclosed research support from Novartis and the National Institutes of Health.
AT THE ADA ANNUAL SCIENTIFIC SESSIONS
Key clinical point: Treating systolic hypertension to a target of 120 mm Hg instead of 140 mm Hg significantly reduced the rate of cardiovascular events in high-risk patients with prediabetes.
Major finding: After a median of 3.3 years, 1.6% of patients with prediabetes in the intensive control group and 2.2% of patients with prediabetes in the standard control group experienced myocardial infarction, acute coronary syndrome without myocardial infarction, stroke, acute decompensated heart failure, or cardiovascular death.
Data source: SPRINT, a randomized, controlled, open-label trial comparing systolic blood pressure targets of less than 140 mm Hg (standard control) and less than 120 mm Hg (intensive control) in hypertensive patients without clinical diabetes who were older than 50 years and at high risk for cardiovascular disease.
Disclosures: SPRINT was sponsored by the National Heart, Lung, and Blood Institute. The National Institute on Aging, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke, and Wake Forest University Health Sciences provided additional support. Dr. Bress disclosed research support from Novartis and the National Institutes of Health.
DURATION-8: Exenatide/dapagliflozin efficacy holds up at 1 year
SAN DIEGO – A year of treatment with once-weekly exenatide and once-daily dapagliflozin significantly outperformed either therapy alone for patients whose type 2 diabetes was uncontrolled on metformin, investigators reported at the annual scientific sessions of the American Diabetes Association.
At week 52, hemoglobin A1c, fasting and 2-hour postprandial glucose levels, body weight, and systolic blood pressure improved significantly more in the exenatide/dapagliflozin arm than in the dapagliflozin/placebo arm in the multicenter randomized, double-blind, phase III DURATION-8 trial, Cristian Guja, MD, said in a late-breaking poster. Exenatide/dapagliflozin also topped dapagliflozin/placebo on glycemic outcomes but not on measures of body weight or blood pressure.
Exenatide (Byetta, AstraZeneca) is a glucagon-like peptide–1 (GLP-1) receptor agonist, while dapagliflozin (Farxiga, AstraZeneca) is a sodium-glucose cotransporter–2 (SGLT-2) inhibitor. For the study, Dr. Guja and coinvestigators randomly assigned patients with type 2 diabetes and HbA1c levels of 8%-12% despite metformin therapy to receive one of three regimens: exenatide once weekly (2-mg subcutaneous injection) plus dapagliflozin (10-mg oral tablet), exenatide with daily placebo tablets, or dapagliflozin with weekly injected placebo. Between weeks 8 and 28, patients received rescue therapy with basal insulin according to progressively stricter fasting plasma glucose criteria that culminated at 200 mg/dL. From weeks 36 to 52, patients received rescue therapy if their HbA1c level exceeded 8%.
A total of 695 patients were randomized to one of the three study arms, and 564 (81%) patients completed 1 year of treatment. Improvements at 1 year resembled those at week 28. Between baseline and week 52, HbA1c levels fell by an average of 1.75% in the exenatide/dapagliflozin arm, 0.37% more than with exenatide/placebo (P less than .01) and 0.52% more than with dapagliflozin/placebo (P less than .01). Combination therapy also cut mean fasting plasma glucose levels by 63 mg/dL, which was 18 mg/dL more than with exenatide/placebo (P less than .001) and 23 mg/dL more than with dapagliflozin/placebo (P less than .001). Two-hour postprandial glucose levels dropped by 82 mg/dL with dual therapy, 18.4 mg/dL more than with exenatide/placebo (P less than .01), and 23 mg/dL more than with dapagliflozin/placebo (P less than .001). Recipients of dual therapy also lost an average of 3.3 kg over a period of 1 year and cut their systolic blood pressure by a mean of 4.5 mm, reductions that significantly exceeded those with exenatide/placebo but not with dapagliflozin/placebo.
Proportionally fewer patients needed rescue therapy in the dual-treatment arm (27%), compared with the exenatide/placebo arm (32%) or the dapagliflozin/placebo arm (38%). Most patients needed rescue therapy because their HbA1c levels exceeded 8%, not because their fasting glucose level exceeded 200 mg/dL, Dr. Guja said.
Combination therapy was “well tolerated, with no unexpected adverse events,” Dr. Guja reported. At 52 weeks, the groups had similar rates of serious adverse events, gastrointestinal adverse events, and adverse events leading to treatment discontinuation. In each arm, about 4% of patients stopped treatment because of adverse events. Dual therapy was associated with slightly higher rates of injection-site nodules (9%) and headaches (6%), compared with exenatide or dapagliflozin alone. There were no cases of severe hypoglycemia or acute renal failure. Glomerular filtration rates dropped by an average of 2 mL/ min per 1.73 m2 after 1 year of exenatide/dapagliflozin, by 1.2 mL/min per 1.73 m2 with exenatide/placebo, and by 0.8 mL/min per 1.73 m2 with dapagliflozin/placebo.
Baseline characteristics were similar between groups in DURATION-8. Glycated hemoglobin levels averaged 9.3% in each arm, fasting plasma glucose averaged 195-198 mg/dL, body mass index averaged 32-33 kg/m2, and systolic blood pressure averaged 130 mm Hg.
AstraZeneca markets Byetta and Farxiga and sponsored the trial. Dr. Guja reported having been on a speakers bureau for AstraZeneca, and she disclosed ties to several other pharmaceutical companies.
SAN DIEGO – A year of treatment with once-weekly exenatide and once-daily dapagliflozin significantly outperformed either therapy alone for patients whose type 2 diabetes was uncontrolled on metformin, investigators reported at the annual scientific sessions of the American Diabetes Association.
At week 52, hemoglobin A1c, fasting and 2-hour postprandial glucose levels, body weight, and systolic blood pressure improved significantly more in the exenatide/dapagliflozin arm than in the dapagliflozin/placebo arm in the multicenter randomized, double-blind, phase III DURATION-8 trial, Cristian Guja, MD, said in a late-breaking poster. Exenatide/dapagliflozin also topped dapagliflozin/placebo on glycemic outcomes but not on measures of body weight or blood pressure.
Exenatide (Byetta, AstraZeneca) is a glucagon-like peptide–1 (GLP-1) receptor agonist, while dapagliflozin (Farxiga, AstraZeneca) is a sodium-glucose cotransporter–2 (SGLT-2) inhibitor. For the study, Dr. Guja and coinvestigators randomly assigned patients with type 2 diabetes and HbA1c levels of 8%-12% despite metformin therapy to receive one of three regimens: exenatide once weekly (2-mg subcutaneous injection) plus dapagliflozin (10-mg oral tablet), exenatide with daily placebo tablets, or dapagliflozin with weekly injected placebo. Between weeks 8 and 28, patients received rescue therapy with basal insulin according to progressively stricter fasting plasma glucose criteria that culminated at 200 mg/dL. From weeks 36 to 52, patients received rescue therapy if their HbA1c level exceeded 8%.
A total of 695 patients were randomized to one of the three study arms, and 564 (81%) patients completed 1 year of treatment. Improvements at 1 year resembled those at week 28. Between baseline and week 52, HbA1c levels fell by an average of 1.75% in the exenatide/dapagliflozin arm, 0.37% more than with exenatide/placebo (P less than .01) and 0.52% more than with dapagliflozin/placebo (P less than .01). Combination therapy also cut mean fasting plasma glucose levels by 63 mg/dL, which was 18 mg/dL more than with exenatide/placebo (P less than .001) and 23 mg/dL more than with dapagliflozin/placebo (P less than .001). Two-hour postprandial glucose levels dropped by 82 mg/dL with dual therapy, 18.4 mg/dL more than with exenatide/placebo (P less than .01), and 23 mg/dL more than with dapagliflozin/placebo (P less than .001). Recipients of dual therapy also lost an average of 3.3 kg over a period of 1 year and cut their systolic blood pressure by a mean of 4.5 mm, reductions that significantly exceeded those with exenatide/placebo but not with dapagliflozin/placebo.
Proportionally fewer patients needed rescue therapy in the dual-treatment arm (27%), compared with the exenatide/placebo arm (32%) or the dapagliflozin/placebo arm (38%). Most patients needed rescue therapy because their HbA1c levels exceeded 8%, not because their fasting glucose level exceeded 200 mg/dL, Dr. Guja said.
Combination therapy was “well tolerated, with no unexpected adverse events,” Dr. Guja reported. At 52 weeks, the groups had similar rates of serious adverse events, gastrointestinal adverse events, and adverse events leading to treatment discontinuation. In each arm, about 4% of patients stopped treatment because of adverse events. Dual therapy was associated with slightly higher rates of injection-site nodules (9%) and headaches (6%), compared with exenatide or dapagliflozin alone. There were no cases of severe hypoglycemia or acute renal failure. Glomerular filtration rates dropped by an average of 2 mL/ min per 1.73 m2 after 1 year of exenatide/dapagliflozin, by 1.2 mL/min per 1.73 m2 with exenatide/placebo, and by 0.8 mL/min per 1.73 m2 with dapagliflozin/placebo.
Baseline characteristics were similar between groups in DURATION-8. Glycated hemoglobin levels averaged 9.3% in each arm, fasting plasma glucose averaged 195-198 mg/dL, body mass index averaged 32-33 kg/m2, and systolic blood pressure averaged 130 mm Hg.
AstraZeneca markets Byetta and Farxiga and sponsored the trial. Dr. Guja reported having been on a speakers bureau for AstraZeneca, and she disclosed ties to several other pharmaceutical companies.
SAN DIEGO – A year of treatment with once-weekly exenatide and once-daily dapagliflozin significantly outperformed either therapy alone for patients whose type 2 diabetes was uncontrolled on metformin, investigators reported at the annual scientific sessions of the American Diabetes Association.
At week 52, hemoglobin A1c, fasting and 2-hour postprandial glucose levels, body weight, and systolic blood pressure improved significantly more in the exenatide/dapagliflozin arm than in the dapagliflozin/placebo arm in the multicenter randomized, double-blind, phase III DURATION-8 trial, Cristian Guja, MD, said in a late-breaking poster. Exenatide/dapagliflozin also topped dapagliflozin/placebo on glycemic outcomes but not on measures of body weight or blood pressure.
Exenatide (Byetta, AstraZeneca) is a glucagon-like peptide–1 (GLP-1) receptor agonist, while dapagliflozin (Farxiga, AstraZeneca) is a sodium-glucose cotransporter–2 (SGLT-2) inhibitor. For the study, Dr. Guja and coinvestigators randomly assigned patients with type 2 diabetes and HbA1c levels of 8%-12% despite metformin therapy to receive one of three regimens: exenatide once weekly (2-mg subcutaneous injection) plus dapagliflozin (10-mg oral tablet), exenatide with daily placebo tablets, or dapagliflozin with weekly injected placebo. Between weeks 8 and 28, patients received rescue therapy with basal insulin according to progressively stricter fasting plasma glucose criteria that culminated at 200 mg/dL. From weeks 36 to 52, patients received rescue therapy if their HbA1c level exceeded 8%.
A total of 695 patients were randomized to one of the three study arms, and 564 (81%) patients completed 1 year of treatment. Improvements at 1 year resembled those at week 28. Between baseline and week 52, HbA1c levels fell by an average of 1.75% in the exenatide/dapagliflozin arm, 0.37% more than with exenatide/placebo (P less than .01) and 0.52% more than with dapagliflozin/placebo (P less than .01). Combination therapy also cut mean fasting plasma glucose levels by 63 mg/dL, which was 18 mg/dL more than with exenatide/placebo (P less than .001) and 23 mg/dL more than with dapagliflozin/placebo (P less than .001). Two-hour postprandial glucose levels dropped by 82 mg/dL with dual therapy, 18.4 mg/dL more than with exenatide/placebo (P less than .01), and 23 mg/dL more than with dapagliflozin/placebo (P less than .001). Recipients of dual therapy also lost an average of 3.3 kg over a period of 1 year and cut their systolic blood pressure by a mean of 4.5 mm, reductions that significantly exceeded those with exenatide/placebo but not with dapagliflozin/placebo.
Proportionally fewer patients needed rescue therapy in the dual-treatment arm (27%), compared with the exenatide/placebo arm (32%) or the dapagliflozin/placebo arm (38%). Most patients needed rescue therapy because their HbA1c levels exceeded 8%, not because their fasting glucose level exceeded 200 mg/dL, Dr. Guja said.
Combination therapy was “well tolerated, with no unexpected adverse events,” Dr. Guja reported. At 52 weeks, the groups had similar rates of serious adverse events, gastrointestinal adverse events, and adverse events leading to treatment discontinuation. In each arm, about 4% of patients stopped treatment because of adverse events. Dual therapy was associated with slightly higher rates of injection-site nodules (9%) and headaches (6%), compared with exenatide or dapagliflozin alone. There were no cases of severe hypoglycemia or acute renal failure. Glomerular filtration rates dropped by an average of 2 mL/ min per 1.73 m2 after 1 year of exenatide/dapagliflozin, by 1.2 mL/min per 1.73 m2 with exenatide/placebo, and by 0.8 mL/min per 1.73 m2 with dapagliflozin/placebo.
Baseline characteristics were similar between groups in DURATION-8. Glycated hemoglobin levels averaged 9.3% in each arm, fasting plasma glucose averaged 195-198 mg/dL, body mass index averaged 32-33 kg/m2, and systolic blood pressure averaged 130 mm Hg.
AstraZeneca markets Byetta and Farxiga and sponsored the trial. Dr. Guja reported having been on a speakers bureau for AstraZeneca, and she disclosed ties to several other pharmaceutical companies.
AT THE ADA ANNUAL SCIENTIFIC SESSIONS
Key clinical point: Exenatide/dapagliflozin therapy was more effective than either drug alone in type 2 diabetes that was uncontrolled with metformin.
Major finding: At week 52, dual therapy significantly outperformed exenatide alone in terms of hemoglobin A1c, fasting and 2-hour postprandial glucose, body weight, and systolic blood pressure. Dual therapy also significantly topped dapagliflozin alone on glycemic measures.
Data source: DURATION-8, a double-blind, randomized, active-controlled phase III trial of 695 patients with type 2 diabetes.
Disclosures: AstraZeneca markets Byetta and Farxiga and sponsored the trial. Dr. Guja reported having been on a speakers bureau for AstraZeneca and disclosed ties to several other pharmaceutical companies.
ODYSSEY: Alirocumab improves lipids but not glycemic targets in 2DM
SAN DIEGO – The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab helped correct dyslipidemia but did not improve glucose control in patients with type 2 diabetes mellitus, investigators reported at the annual scientific sessions of the American Diabetes Association.
In the international, double-blind ODYSSEY DM-Insulin trial, 24 weeks of alirocumab (Praluent, Sanofi and Regeneron) therapy cut low-density lipoprotein (LDL) cholesterol levels by an average of 49% more than placebo (P less than .0001), said Lawrence A. Leiter, MD, professor of medicine and nutritional sciences at the University of Toronto. Alirocumab also significantly reduced non–high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a) levels. However, hemoglobin A1c, fasting plasma glucose, total insulin dose, and number of antihyperglycemic drugs remained nearly identical between the trial arms throughout follow-up.
About 94% of patients in each arm completed the trial. Most were in their mid-60s, white, obese, and already on a moderate or high-intensity statin, with baseline fasting plasma glucose levels of about 150 mg per dL and HbA1c levels of 7.5%. The most common treatment-associated adverse events were myalgia (4%) and arthralgia (3%). Rates of local and systemic allergic drug reactions, neurologic or neurocognitive events, and elevated transaminases were low and similar between groups, according to Dr. Leiter, who is also director of the lipid clinic at the Li Ka Shing Knowledge Institute at St. Michael’s Hospital.
Robert R. Henry, MD, who is professor of medicine at the University of California, San Diego, discussed the ODYSSEY DM-Dyslipidemia trial which compared alirocumab with usual care in patients with type 2 diabetes whose mixed dyslipidemia was inadequately controlled with maximum tolerable statin therapy. In all, 413 patients received open-label alirocumab (75 mg–150 mg) or placebo plus optional ezetimibe, fenofibrate, omega-3 fatty acids, or nicotinic acid every 2 weeks for 24 weeks. At the end of treatment, non-HDL cholesterol dropped about 33% more with alirocumab than usual care (P less than .0001). Alirocumab also produced significant declines in LDL cholesterol, apolipoprotein B, total cholesterol, and lipoprotein(a), and a 6% increase in HDL cholesterol as compared with usual care. Once again, alirocumab induced no changes in HbA1c or fasting plasma glucose levels. The most common treatment-related adverse events were urinary tract infections, diarrhea, and nasopharyngitis.
Sanofi US and Regeneron Pharmaceuticals make alirocumab and funded the trials. Dr. Leiter disclosed research grants and consulting relationships with Regeneron, Sanofi, Eli Lilly and Company, and several other pharmaceutical companies. Dr. Henry disclosed consulting and advisory relationships with Sanofi and many other pharmaceutical companies.
SAN DIEGO – The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab helped correct dyslipidemia but did not improve glucose control in patients with type 2 diabetes mellitus, investigators reported at the annual scientific sessions of the American Diabetes Association.
In the international, double-blind ODYSSEY DM-Insulin trial, 24 weeks of alirocumab (Praluent, Sanofi and Regeneron) therapy cut low-density lipoprotein (LDL) cholesterol levels by an average of 49% more than placebo (P less than .0001), said Lawrence A. Leiter, MD, professor of medicine and nutritional sciences at the University of Toronto. Alirocumab also significantly reduced non–high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a) levels. However, hemoglobin A1c, fasting plasma glucose, total insulin dose, and number of antihyperglycemic drugs remained nearly identical between the trial arms throughout follow-up.
About 94% of patients in each arm completed the trial. Most were in their mid-60s, white, obese, and already on a moderate or high-intensity statin, with baseline fasting plasma glucose levels of about 150 mg per dL and HbA1c levels of 7.5%. The most common treatment-associated adverse events were myalgia (4%) and arthralgia (3%). Rates of local and systemic allergic drug reactions, neurologic or neurocognitive events, and elevated transaminases were low and similar between groups, according to Dr. Leiter, who is also director of the lipid clinic at the Li Ka Shing Knowledge Institute at St. Michael’s Hospital.
Robert R. Henry, MD, who is professor of medicine at the University of California, San Diego, discussed the ODYSSEY DM-Dyslipidemia trial which compared alirocumab with usual care in patients with type 2 diabetes whose mixed dyslipidemia was inadequately controlled with maximum tolerable statin therapy. In all, 413 patients received open-label alirocumab (75 mg–150 mg) or placebo plus optional ezetimibe, fenofibrate, omega-3 fatty acids, or nicotinic acid every 2 weeks for 24 weeks. At the end of treatment, non-HDL cholesterol dropped about 33% more with alirocumab than usual care (P less than .0001). Alirocumab also produced significant declines in LDL cholesterol, apolipoprotein B, total cholesterol, and lipoprotein(a), and a 6% increase in HDL cholesterol as compared with usual care. Once again, alirocumab induced no changes in HbA1c or fasting plasma glucose levels. The most common treatment-related adverse events were urinary tract infections, diarrhea, and nasopharyngitis.
Sanofi US and Regeneron Pharmaceuticals make alirocumab and funded the trials. Dr. Leiter disclosed research grants and consulting relationships with Regeneron, Sanofi, Eli Lilly and Company, and several other pharmaceutical companies. Dr. Henry disclosed consulting and advisory relationships with Sanofi and many other pharmaceutical companies.
SAN DIEGO – The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab helped correct dyslipidemia but did not improve glucose control in patients with type 2 diabetes mellitus, investigators reported at the annual scientific sessions of the American Diabetes Association.
In the international, double-blind ODYSSEY DM-Insulin trial, 24 weeks of alirocumab (Praluent, Sanofi and Regeneron) therapy cut low-density lipoprotein (LDL) cholesterol levels by an average of 49% more than placebo (P less than .0001), said Lawrence A. Leiter, MD, professor of medicine and nutritional sciences at the University of Toronto. Alirocumab also significantly reduced non–high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a) levels. However, hemoglobin A1c, fasting plasma glucose, total insulin dose, and number of antihyperglycemic drugs remained nearly identical between the trial arms throughout follow-up.
About 94% of patients in each arm completed the trial. Most were in their mid-60s, white, obese, and already on a moderate or high-intensity statin, with baseline fasting plasma glucose levels of about 150 mg per dL and HbA1c levels of 7.5%. The most common treatment-associated adverse events were myalgia (4%) and arthralgia (3%). Rates of local and systemic allergic drug reactions, neurologic or neurocognitive events, and elevated transaminases were low and similar between groups, according to Dr. Leiter, who is also director of the lipid clinic at the Li Ka Shing Knowledge Institute at St. Michael’s Hospital.
Robert R. Henry, MD, who is professor of medicine at the University of California, San Diego, discussed the ODYSSEY DM-Dyslipidemia trial which compared alirocumab with usual care in patients with type 2 diabetes whose mixed dyslipidemia was inadequately controlled with maximum tolerable statin therapy. In all, 413 patients received open-label alirocumab (75 mg–150 mg) or placebo plus optional ezetimibe, fenofibrate, omega-3 fatty acids, or nicotinic acid every 2 weeks for 24 weeks. At the end of treatment, non-HDL cholesterol dropped about 33% more with alirocumab than usual care (P less than .0001). Alirocumab also produced significant declines in LDL cholesterol, apolipoprotein B, total cholesterol, and lipoprotein(a), and a 6% increase in HDL cholesterol as compared with usual care. Once again, alirocumab induced no changes in HbA1c or fasting plasma glucose levels. The most common treatment-related adverse events were urinary tract infections, diarrhea, and nasopharyngitis.
Sanofi US and Regeneron Pharmaceuticals make alirocumab and funded the trials. Dr. Leiter disclosed research grants and consulting relationships with Regeneron, Sanofi, Eli Lilly and Company, and several other pharmaceutical companies. Dr. Henry disclosed consulting and advisory relationships with Sanofi and many other pharmaceutical companies.
AT THE ADA ANNUAL SCIENTIFIC SESSIONS
Key clinical point:
Major finding: After 24 weeks of treatment, average low-density lipoprotein levels fell by about 43%-49% (P less than .0001, compared with placebo, in each trial).
Data source: ODYSSEY DM-Insulin included 441 patients on insulin for type 2 diabetes who had elevated LDL levels and other cardiovascular risk factors. ODYSSEY DM-Dyslipidemia included 413 patients with type 2 diabetes and mixed dyslipidemia despite maximally tolerated statins.
Disclosures: Sanofi and Regeneron Pharmaceuticals funded the trial. Dr. Leiter disclosed research grants and consulting relationships with Regeneron, Sanofi, Eli Lilly, and several other pharmaceutical companies.
IDegLira equals basal-bolus insulin in HbA1c, lowers hypoglycemia risk
SAN DIEGO – When basal insulin alone does not achieve glucose targets in type 2 diabetes, a single fixed-dose injection of insulin degludec and liraglutide (IDegLira) is as effective as multiple insulin injections and has a significantly lower risk of hypoglycemia, according to a randomized, multicenter, open-label, industry-sponsored trial.
After 26 weeks of treatment, average hemoglobin A1c levels dropped similarly with once-daily IDegLira (1.48%) as with basal insulin glargine U100 plus mealtime injections of short-acting insulin aspart (1.46%; P less than .0001 for noninferiority), reported Liana K. Billings, MD, at the annual scientific sessions of the American Diabetes Association.
Patients also needed significantly less insulin and lost significantly more weight on IDegLira, compared with the basal-bolus regimen. “This is some of the most robust, most impressive data I’ve seen in years,” Julio Rosenstock, MD, director of the Dallas Diabetes and Endocrine Center in Texas, commented from the audience. Dr. Rosenstock was not involved in the trial and has studied other combination regimens for type 2 diabetes.
The advent of new insulins and adjunct therapies gives clinicians many potential algorithms for treating type 2 diabetes patients. The ADA recommends that health care professionals consider dual or triple therapy if patients do not meet glycemic targets with lifestyle changes and metformin alone. However, weight gain, hypoglycemia, and complex treatment regimens can make it difficult to intensify treatment in the real world, Dr. Billings said.
Insulin degludec is an ultra–long-acting basal insulin analogue, while liraglutide is a GLP-1 receptor agonist. The open-label, phase III DUAL VII study compared once-daily IDegLira injection (Xultophy, Novo Nordisk) with once-daily basal insulin glargine (Lantus, Sanofi) U100 plus bolus insulin aspart (NovoLog, Novo Nordisk) at mealtimes in 506 adults with type 2 diabetes. All patients were on metformin and glargine (typically 34 U) at baseline. Most were in their late 50s and obese, with an average 13-year duration of type 2 diabetes and HbA1c levels of 8.2% despite treatment. The IDegLira group started at 16 U and titrated by 2 U twice weekly to reach a fasting glucose target of 72-90 mg/dL. Basal-bolus patients maintained their baseline glargine dose and added 4 U mealtime bolus insulin aspart, titrating to target by 1 U twice weekly. The primary endpoint was change in HbA1c levels after 26 weeks. More than 98% of patients completed the trial. Approximately two-thirds of patients in both arms achieved an HbA1c level below 7%, but IDegLira recipients were significantly more likely to do so without gaining weight or experiencing hypoglycemia during the last 12 weeks of treatment (odds ratio, 10.39; 95% CI, 5.76-18.75). The IDegLira arm received significantly less daily insulin than the basal-bolus arm (40 U versus 84 U; P less than .0001), and IDegLira patients lost an average of 0.93 kg, while the comparison group gained 2.64 kg. Rates of serious adverse events were low and similar between arms. The cumulative rate of nausea was higher with IDegLira (11.1%) than with basal-bolus therapy (1.6%), Dr. Billings said. There were no deaths or unexpected adverse events.
Novo Nordisk makes Xultophy and funded the trial. Dr. Billings reported having served on advisory panels and speaker bureaus for Novo Nordisk.
SAN DIEGO – When basal insulin alone does not achieve glucose targets in type 2 diabetes, a single fixed-dose injection of insulin degludec and liraglutide (IDegLira) is as effective as multiple insulin injections and has a significantly lower risk of hypoglycemia, according to a randomized, multicenter, open-label, industry-sponsored trial.
After 26 weeks of treatment, average hemoglobin A1c levels dropped similarly with once-daily IDegLira (1.48%) as with basal insulin glargine U100 plus mealtime injections of short-acting insulin aspart (1.46%; P less than .0001 for noninferiority), reported Liana K. Billings, MD, at the annual scientific sessions of the American Diabetes Association.
Patients also needed significantly less insulin and lost significantly more weight on IDegLira, compared with the basal-bolus regimen. “This is some of the most robust, most impressive data I’ve seen in years,” Julio Rosenstock, MD, director of the Dallas Diabetes and Endocrine Center in Texas, commented from the audience. Dr. Rosenstock was not involved in the trial and has studied other combination regimens for type 2 diabetes.
The advent of new insulins and adjunct therapies gives clinicians many potential algorithms for treating type 2 diabetes patients. The ADA recommends that health care professionals consider dual or triple therapy if patients do not meet glycemic targets with lifestyle changes and metformin alone. However, weight gain, hypoglycemia, and complex treatment regimens can make it difficult to intensify treatment in the real world, Dr. Billings said.
Insulin degludec is an ultra–long-acting basal insulin analogue, while liraglutide is a GLP-1 receptor agonist. The open-label, phase III DUAL VII study compared once-daily IDegLira injection (Xultophy, Novo Nordisk) with once-daily basal insulin glargine (Lantus, Sanofi) U100 plus bolus insulin aspart (NovoLog, Novo Nordisk) at mealtimes in 506 adults with type 2 diabetes. All patients were on metformin and glargine (typically 34 U) at baseline. Most were in their late 50s and obese, with an average 13-year duration of type 2 diabetes and HbA1c levels of 8.2% despite treatment. The IDegLira group started at 16 U and titrated by 2 U twice weekly to reach a fasting glucose target of 72-90 mg/dL. Basal-bolus patients maintained their baseline glargine dose and added 4 U mealtime bolus insulin aspart, titrating to target by 1 U twice weekly. The primary endpoint was change in HbA1c levels after 26 weeks. More than 98% of patients completed the trial. Approximately two-thirds of patients in both arms achieved an HbA1c level below 7%, but IDegLira recipients were significantly more likely to do so without gaining weight or experiencing hypoglycemia during the last 12 weeks of treatment (odds ratio, 10.39; 95% CI, 5.76-18.75). The IDegLira arm received significantly less daily insulin than the basal-bolus arm (40 U versus 84 U; P less than .0001), and IDegLira patients lost an average of 0.93 kg, while the comparison group gained 2.64 kg. Rates of serious adverse events were low and similar between arms. The cumulative rate of nausea was higher with IDegLira (11.1%) than with basal-bolus therapy (1.6%), Dr. Billings said. There were no deaths or unexpected adverse events.
Novo Nordisk makes Xultophy and funded the trial. Dr. Billings reported having served on advisory panels and speaker bureaus for Novo Nordisk.
SAN DIEGO – When basal insulin alone does not achieve glucose targets in type 2 diabetes, a single fixed-dose injection of insulin degludec and liraglutide (IDegLira) is as effective as multiple insulin injections and has a significantly lower risk of hypoglycemia, according to a randomized, multicenter, open-label, industry-sponsored trial.
After 26 weeks of treatment, average hemoglobin A1c levels dropped similarly with once-daily IDegLira (1.48%) as with basal insulin glargine U100 plus mealtime injections of short-acting insulin aspart (1.46%; P less than .0001 for noninferiority), reported Liana K. Billings, MD, at the annual scientific sessions of the American Diabetes Association.
Patients also needed significantly less insulin and lost significantly more weight on IDegLira, compared with the basal-bolus regimen. “This is some of the most robust, most impressive data I’ve seen in years,” Julio Rosenstock, MD, director of the Dallas Diabetes and Endocrine Center in Texas, commented from the audience. Dr. Rosenstock was not involved in the trial and has studied other combination regimens for type 2 diabetes.
The advent of new insulins and adjunct therapies gives clinicians many potential algorithms for treating type 2 diabetes patients. The ADA recommends that health care professionals consider dual or triple therapy if patients do not meet glycemic targets with lifestyle changes and metformin alone. However, weight gain, hypoglycemia, and complex treatment regimens can make it difficult to intensify treatment in the real world, Dr. Billings said.
Insulin degludec is an ultra–long-acting basal insulin analogue, while liraglutide is a GLP-1 receptor agonist. The open-label, phase III DUAL VII study compared once-daily IDegLira injection (Xultophy, Novo Nordisk) with once-daily basal insulin glargine (Lantus, Sanofi) U100 plus bolus insulin aspart (NovoLog, Novo Nordisk) at mealtimes in 506 adults with type 2 diabetes. All patients were on metformin and glargine (typically 34 U) at baseline. Most were in their late 50s and obese, with an average 13-year duration of type 2 diabetes and HbA1c levels of 8.2% despite treatment. The IDegLira group started at 16 U and titrated by 2 U twice weekly to reach a fasting glucose target of 72-90 mg/dL. Basal-bolus patients maintained their baseline glargine dose and added 4 U mealtime bolus insulin aspart, titrating to target by 1 U twice weekly. The primary endpoint was change in HbA1c levels after 26 weeks. More than 98% of patients completed the trial. Approximately two-thirds of patients in both arms achieved an HbA1c level below 7%, but IDegLira recipients were significantly more likely to do so without gaining weight or experiencing hypoglycemia during the last 12 weeks of treatment (odds ratio, 10.39; 95% CI, 5.76-18.75). The IDegLira arm received significantly less daily insulin than the basal-bolus arm (40 U versus 84 U; P less than .0001), and IDegLira patients lost an average of 0.93 kg, while the comparison group gained 2.64 kg. Rates of serious adverse events were low and similar between arms. The cumulative rate of nausea was higher with IDegLira (11.1%) than with basal-bolus therapy (1.6%), Dr. Billings said. There were no deaths or unexpected adverse events.
Novo Nordisk makes Xultophy and funded the trial. Dr. Billings reported having served on advisory panels and speaker bureaus for Novo Nordisk.
AT THE ADA ANNUAL SCIENTIFIC SESSIONS
Key clinical point: A single daily injection of fixed-dose insulin degludec and liraglutide (IDegLira) improved hemoglobin A1c levels as much as basal-bolus insulin therapy while producing significantly less hypoglycemia.
Major finding: HbA1c levels dropped similarly with IDegLira (1.48%) or basal insulin glargine U100 plus mealtime injections of short-acting insulin aspart (1.46%; P less than .0001 for noninferiority).
Data source: DUAL VII, a multicenter, randomized, open-label, phase III trial of 506 adults with type 2 diabetes who did not reach glucose targets on basal insulin glargine and metformin.
Disclosures: Novo Nordisk makes Xultophy and funded the trial. Dr. Billings reported having served on advisory panels and speaker bureaus for Novo Nordisk.
CANVAS: Canagliflozin cuts cardiovascular events, doubles risk of amputations
SAN DIEGO –
After an average of 188 weeks of follow-up, the combined rate of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke was 26.9 events per 1,000 person-years of canagliflozin treatment and 31.5 events per 1,000 person-years of placebo treatment (hazard ratio, 0.86; 95% confidence interval, 0.75-0.97; P less than .001 for noninferiority; P = .02 for superiority) in the Canagliflozin Cardiovascular Assessment Study (CANVAS) and its sister trial, CANVAS-R, investigators reported at the annual scientific sessions of the American Diabetes Association. The report was published simultaneously in the New England Journal of Medicine (N Engl J Med. 2017 Jun 12. doi: 10.1056/NEJMoa1611925).
But unexpectedly, canagliflozin also doubled the risk of amputations, said Dr. Neal, who is with the University of New South Wales and the George Institute for Global Health in Sydney. Treating 1,000 patients for 5 years would lead to 15 excess amputations, including 10 amputations of the toes or forefoot and five amputations at the ankle or above, he said.
The reason for this heightened risk is unknown. Other sodium-glucose co-transporter 2 (SGLT-2) development programs did not comprehensively monitor amputations, so it is unclear whether this is a class effect, Dr. Neal said. For now, the Food and Drug Administration is requiring a boxed warning for canagliflozin, while its European Union product label recommends carefully monitoring patients, emphasizing foot care and hydration, and considering stopping treatment if patients develop lower-extremity ulcers, infection, osteomyelitis, or gangrene.
Canagliflozin might also increase the risk of fractures, Dr. Bruce and his coinvestigators noted. Hazard ratios for overall and low-trauma fractures reached statistical significance in CANVAS, but not in CANVAS-R. As in other trials of SGLT-2 inhibitors, canagliflozin significantly increased the risk of female and male genital mycotic infections (respective HR, 4.27 and 3.76) and was associated with osmotic diuresis (HR, 2.80), and volume depletion (HR, 1.44). However, canagliflozin was not associated with malignancies, hepatic injury, pancreatitis, diabetic ketoacidosis, photosensitivity, hypersensitivity reactions, hypoglycemia, venous thrombotic events, or urinary tract infections.
Canagliflozin (Invokana, Janssen) inhibits SGLT-2, which is responsible for about 90% of renal glucose reabsorption. The FDA approved the medication in 2013 based on interim results from the CANVAS trial, which included 4,330 adults with type 2 diabetes and a history of symptomatic atherosclerotic cardiovascular disease or multiple cardiovascular risk factors. Patients were usually in their 60s, male, and hypertensive. Two-thirds had atherosclerotic cardiovascular disease and about 14% had heart failure. Background medications included metformin, insulin, sulfonylurea, DPP-4 inhibitors, GLP-1 receptor agonists, and cardioprotective agents. Patients were randomly assigned to receive canagliflozin 300 mg or 100 mg or placebo.
Investigators designed the CANVAS-R trial to further evaluate canagliflozin in another 5,813 patients with type 2 diabetes. The SGLT-2 inhibitor met its primary MACE endpoint in the overall pooled analysis and in numerous demographic and clinical subgroups, Dr. Neal said. Canagliflozin also significantly cut the risk of hospitalization for heart failure (HR, 0.67), and met a “hard” composite endpoint of renal death, end-stage renal disease, or a 40% reduction in estimated glomerular filtration rate (HR, 0.60).
Compared with placebo, treatment induced regression of albuminuria and reduced loss of renal function, said coinvestigator Dick de Zeeuw, MD, PhD, of the University of Groningen (the Netherlands). “These data suggest a potential renoprotective effect of canagliflozin treatment in patients with type 2 diabetes at high cardiovascular risk, on top of treatment with angiotensin-converting-enzyme inhibitors and angiotensin receptor blockers,” he said.
However, patients were twice as likely to undergo amputations on canagliflozin, compared with those on placebo (HR, 1.97; 95% CI, 1.41-2.75). Risks were similar for amputation of the toe or forefoot, at the ankle, below the knee, and above the knee, Dr. Neal said. Predictors of amputation also were similar in all arms of the trials, and included peripheral vascular disease, male sex, neuropathy, and hemoglobin A1c above 8%. Amputation was not associated with non-loop diuretic therapy, smoking, hypertension, or age.
Janssen Research and Development makes canagliflozin and sponsored the trials. Dr. Neal and Dr. Zeeuw disclosed consultancy, travel support, or grants from Janssen paid to their institutions, and ties to several other pharmaceutical companies.
SAN DIEGO –
After an average of 188 weeks of follow-up, the combined rate of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke was 26.9 events per 1,000 person-years of canagliflozin treatment and 31.5 events per 1,000 person-years of placebo treatment (hazard ratio, 0.86; 95% confidence interval, 0.75-0.97; P less than .001 for noninferiority; P = .02 for superiority) in the Canagliflozin Cardiovascular Assessment Study (CANVAS) and its sister trial, CANVAS-R, investigators reported at the annual scientific sessions of the American Diabetes Association. The report was published simultaneously in the New England Journal of Medicine (N Engl J Med. 2017 Jun 12. doi: 10.1056/NEJMoa1611925).
But unexpectedly, canagliflozin also doubled the risk of amputations, said Dr. Neal, who is with the University of New South Wales and the George Institute for Global Health in Sydney. Treating 1,000 patients for 5 years would lead to 15 excess amputations, including 10 amputations of the toes or forefoot and five amputations at the ankle or above, he said.
The reason for this heightened risk is unknown. Other sodium-glucose co-transporter 2 (SGLT-2) development programs did not comprehensively monitor amputations, so it is unclear whether this is a class effect, Dr. Neal said. For now, the Food and Drug Administration is requiring a boxed warning for canagliflozin, while its European Union product label recommends carefully monitoring patients, emphasizing foot care and hydration, and considering stopping treatment if patients develop lower-extremity ulcers, infection, osteomyelitis, or gangrene.
Canagliflozin might also increase the risk of fractures, Dr. Bruce and his coinvestigators noted. Hazard ratios for overall and low-trauma fractures reached statistical significance in CANVAS, but not in CANVAS-R. As in other trials of SGLT-2 inhibitors, canagliflozin significantly increased the risk of female and male genital mycotic infections (respective HR, 4.27 and 3.76) and was associated with osmotic diuresis (HR, 2.80), and volume depletion (HR, 1.44). However, canagliflozin was not associated with malignancies, hepatic injury, pancreatitis, diabetic ketoacidosis, photosensitivity, hypersensitivity reactions, hypoglycemia, venous thrombotic events, or urinary tract infections.
Canagliflozin (Invokana, Janssen) inhibits SGLT-2, which is responsible for about 90% of renal glucose reabsorption. The FDA approved the medication in 2013 based on interim results from the CANVAS trial, which included 4,330 adults with type 2 diabetes and a history of symptomatic atherosclerotic cardiovascular disease or multiple cardiovascular risk factors. Patients were usually in their 60s, male, and hypertensive. Two-thirds had atherosclerotic cardiovascular disease and about 14% had heart failure. Background medications included metformin, insulin, sulfonylurea, DPP-4 inhibitors, GLP-1 receptor agonists, and cardioprotective agents. Patients were randomly assigned to receive canagliflozin 300 mg or 100 mg or placebo.
Investigators designed the CANVAS-R trial to further evaluate canagliflozin in another 5,813 patients with type 2 diabetes. The SGLT-2 inhibitor met its primary MACE endpoint in the overall pooled analysis and in numerous demographic and clinical subgroups, Dr. Neal said. Canagliflozin also significantly cut the risk of hospitalization for heart failure (HR, 0.67), and met a “hard” composite endpoint of renal death, end-stage renal disease, or a 40% reduction in estimated glomerular filtration rate (HR, 0.60).
Compared with placebo, treatment induced regression of albuminuria and reduced loss of renal function, said coinvestigator Dick de Zeeuw, MD, PhD, of the University of Groningen (the Netherlands). “These data suggest a potential renoprotective effect of canagliflozin treatment in patients with type 2 diabetes at high cardiovascular risk, on top of treatment with angiotensin-converting-enzyme inhibitors and angiotensin receptor blockers,” he said.
However, patients were twice as likely to undergo amputations on canagliflozin, compared with those on placebo (HR, 1.97; 95% CI, 1.41-2.75). Risks were similar for amputation of the toe or forefoot, at the ankle, below the knee, and above the knee, Dr. Neal said. Predictors of amputation also were similar in all arms of the trials, and included peripheral vascular disease, male sex, neuropathy, and hemoglobin A1c above 8%. Amputation was not associated with non-loop diuretic therapy, smoking, hypertension, or age.
Janssen Research and Development makes canagliflozin and sponsored the trials. Dr. Neal and Dr. Zeeuw disclosed consultancy, travel support, or grants from Janssen paid to their institutions, and ties to several other pharmaceutical companies.
SAN DIEGO –
After an average of 188 weeks of follow-up, the combined rate of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke was 26.9 events per 1,000 person-years of canagliflozin treatment and 31.5 events per 1,000 person-years of placebo treatment (hazard ratio, 0.86; 95% confidence interval, 0.75-0.97; P less than .001 for noninferiority; P = .02 for superiority) in the Canagliflozin Cardiovascular Assessment Study (CANVAS) and its sister trial, CANVAS-R, investigators reported at the annual scientific sessions of the American Diabetes Association. The report was published simultaneously in the New England Journal of Medicine (N Engl J Med. 2017 Jun 12. doi: 10.1056/NEJMoa1611925).
But unexpectedly, canagliflozin also doubled the risk of amputations, said Dr. Neal, who is with the University of New South Wales and the George Institute for Global Health in Sydney. Treating 1,000 patients for 5 years would lead to 15 excess amputations, including 10 amputations of the toes or forefoot and five amputations at the ankle or above, he said.
The reason for this heightened risk is unknown. Other sodium-glucose co-transporter 2 (SGLT-2) development programs did not comprehensively monitor amputations, so it is unclear whether this is a class effect, Dr. Neal said. For now, the Food and Drug Administration is requiring a boxed warning for canagliflozin, while its European Union product label recommends carefully monitoring patients, emphasizing foot care and hydration, and considering stopping treatment if patients develop lower-extremity ulcers, infection, osteomyelitis, or gangrene.
Canagliflozin might also increase the risk of fractures, Dr. Bruce and his coinvestigators noted. Hazard ratios for overall and low-trauma fractures reached statistical significance in CANVAS, but not in CANVAS-R. As in other trials of SGLT-2 inhibitors, canagliflozin significantly increased the risk of female and male genital mycotic infections (respective HR, 4.27 and 3.76) and was associated with osmotic diuresis (HR, 2.80), and volume depletion (HR, 1.44). However, canagliflozin was not associated with malignancies, hepatic injury, pancreatitis, diabetic ketoacidosis, photosensitivity, hypersensitivity reactions, hypoglycemia, venous thrombotic events, or urinary tract infections.
Canagliflozin (Invokana, Janssen) inhibits SGLT-2, which is responsible for about 90% of renal glucose reabsorption. The FDA approved the medication in 2013 based on interim results from the CANVAS trial, which included 4,330 adults with type 2 diabetes and a history of symptomatic atherosclerotic cardiovascular disease or multiple cardiovascular risk factors. Patients were usually in their 60s, male, and hypertensive. Two-thirds had atherosclerotic cardiovascular disease and about 14% had heart failure. Background medications included metformin, insulin, sulfonylurea, DPP-4 inhibitors, GLP-1 receptor agonists, and cardioprotective agents. Patients were randomly assigned to receive canagliflozin 300 mg or 100 mg or placebo.
Investigators designed the CANVAS-R trial to further evaluate canagliflozin in another 5,813 patients with type 2 diabetes. The SGLT-2 inhibitor met its primary MACE endpoint in the overall pooled analysis and in numerous demographic and clinical subgroups, Dr. Neal said. Canagliflozin also significantly cut the risk of hospitalization for heart failure (HR, 0.67), and met a “hard” composite endpoint of renal death, end-stage renal disease, or a 40% reduction in estimated glomerular filtration rate (HR, 0.60).
Compared with placebo, treatment induced regression of albuminuria and reduced loss of renal function, said coinvestigator Dick de Zeeuw, MD, PhD, of the University of Groningen (the Netherlands). “These data suggest a potential renoprotective effect of canagliflozin treatment in patients with type 2 diabetes at high cardiovascular risk, on top of treatment with angiotensin-converting-enzyme inhibitors and angiotensin receptor blockers,” he said.
However, patients were twice as likely to undergo amputations on canagliflozin, compared with those on placebo (HR, 1.97; 95% CI, 1.41-2.75). Risks were similar for amputation of the toe or forefoot, at the ankle, below the knee, and above the knee, Dr. Neal said. Predictors of amputation also were similar in all arms of the trials, and included peripheral vascular disease, male sex, neuropathy, and hemoglobin A1c above 8%. Amputation was not associated with non-loop diuretic therapy, smoking, hypertension, or age.
Janssen Research and Development makes canagliflozin and sponsored the trials. Dr. Neal and Dr. Zeeuw disclosed consultancy, travel support, or grants from Janssen paid to their institutions, and ties to several other pharmaceutical companies.
AT THE ADA ANNUAL SCIENTIFIC SESSIONS
Key clinical point: Canagliflozin significantly reduced the risk of cardiovascular and renal events but doubled the risk of amputation, compared with placebo, in patients with type 2 diabetes.
Major finding: The hazard ratio for cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke was 0.86 in favor of canagliflozin (P = .02 for superiority). Patients on treatment were twice as likely to undergo amputations, compared to those on placebo (HR, 1.97).
Data source: Two international, randomized, double-blind trials of more than 10,000 adults with type 2 diabetes at high risk of cardiovascular disease.
Disclosures: Janssen Research and Development makes canagliflozin and sponsored the trials. Dr. Neal and Dr. Zeeuw disclosed consultancy, travel support, or grants from Janssen paid to their institutions and ties to several other pharmaceutical companies.
DEVOTE: Degludec and glargine had similar risk with less severe hypoglycemia
SAN DIEGO – For patients with type 2 diabetes at high risk of cardiovascular disease, the ultra–long-acting, once-daily basal insulin degludec produced a similar risk of major adverse cardiovascular events as glargine with a significantly lower risk of severe hypoglycemia, new data show.
Nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death occurred in 325 (8.5%) patients on degludec and 356 (9.3%) patients on glargine (hazard ratio, 0.91; 95% confidence interval, 0.78 to 1.06; P = .21) in DEVOTE (the Trial Comparing Cardiovascular Safety of Insulin Degludec versus Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events). Rates of severe hypoglycemia were 4.9% and 6.6%, respectively (P less than .001), investigators reported at the annual scientific sessions of the American Diabetes Association and simultaneously in the New England Journal of Medicine (2017 Jun 12. doi: 10.1056/NEJMoa1615692).
Insulin degludec injection (Tresiba®, Novo Nordisk) is a basal insulin analog, the long, soluble hexamer chains of which are metabolized only at the ends, yielding at least a 42-hour duration of action, Todd Hobbs, MD, chief medical officer of Novo Nordisk, Princeton, N.J., explained in an interview. In contrast, glargine has about a 12-hour half-life. Previous trials of degludec did not adjudicate cardiovascular endpoints, which the U.S. Food and Drug Administration only recently began requiring for insulins, Dr. Hobbs said. In response to an FDA request, the phase III, international, randomized, double-blind DEVOTE trial compared the cardiovascular safety of daily basal insulin degludec (100 U per mL) with that of glargine U100 in more than 7,600 adults with type 2 diabetes.
Fully 98% of patients completed the 2-year trial. The overall risk of major adverse cardiac events resembled that of each individual component, including cardiovascular death (HR, 0.96; 95% CI, 0.76-1.21; P = .71), nonfatal myocardial infarction (HR, 0.85; 95% CI, 0.68-1.06; P = .15), and nonfatal stroke (HR, 0.90; 95% CI, 0.65-1.23; P =. 50). Degludec remained noninferior to glargine when researchers added unstable angina to the primary endpoint and accounted for patient location, treatment duration, length of follow-up, and age, sex, body mass index, and renal function.
Both insulins produced similar HbA1c levels of about 7.5%, but degludec cut fasting plasma glucose by about 5 mg per mL more, compared with glargine (P less than .001), the investigators reported. Furthermore, the odds ratio for severe hypoglycemia significantly favored degludec (HR, 0.73; 95% CI, 0.60-0.89; P less than .001). In other words, 40 patients would need to receive degludec rather than glargine to prevent one event of severe hypoglycemia. Previous studies have shown similar results, Dr. Buse said. In a pooled analysis of all five trials of type 2 diabetes in the degludec clinical development program, degludec was associated with a significantly lower risk of hypoglycemia, particularly nocturnal episodes, than was glargine (Diabetes Obes Metab. 2013;15:175-84).
Findings were similar in the double-blind SWITCH 2 trial (Diabetologia. 2016;59[Suppl 1]:1-581).
DEVOTE identified no safety issues for degludec, compared with glargine. Each arm had similar rates of serious or severe adverse events, leading to treatment discontinuation, and neoplasms. Nonetheless, DEVOTE had several limitations, said Elizabeth R. Seaquist, MD, of the University of Minnesota, Minneapolis, who was not involved in the study. “Investigators could modify the titration protocol based on clinical judgment, and it isn’t clear whether this modification was applied equally in both arms,” she said at ADA. “Another weakness is that there were no data collected about moderate symptomatic hypoglycemia, the most common type of hypoglycemia that patients experience.” DEVOTE also did not examine how often blood glucose dropped below 54 mg per dL, the point at which patients often do not know they are hypoglycemic. Investigators also should examine whether degludec cuts health care costs or improves sleep or quality of life, whether its glycemic benefits extends to patients who are insulin-naive or have severe kidney disease, and how it compares with glargine U300, she added.
Insulin degludec received FDA approval in September 2015, based on interim results of DEVOTE. Novo Nordisk makes insulin degludec and sponsored the trial. Dr. Buse disclosed consulting fees from Novo Nordisk and ties to many other pharmaceutical companies. Dr. Seaquist disclosed ties to Novo Nordisk, Eli Lilly, Locemia, and Lucera. Dr. Hobbs is chief medical officer for Novo Nordisk.
SAN DIEGO – For patients with type 2 diabetes at high risk of cardiovascular disease, the ultra–long-acting, once-daily basal insulin degludec produced a similar risk of major adverse cardiovascular events as glargine with a significantly lower risk of severe hypoglycemia, new data show.
Nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death occurred in 325 (8.5%) patients on degludec and 356 (9.3%) patients on glargine (hazard ratio, 0.91; 95% confidence interval, 0.78 to 1.06; P = .21) in DEVOTE (the Trial Comparing Cardiovascular Safety of Insulin Degludec versus Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events). Rates of severe hypoglycemia were 4.9% and 6.6%, respectively (P less than .001), investigators reported at the annual scientific sessions of the American Diabetes Association and simultaneously in the New England Journal of Medicine (2017 Jun 12. doi: 10.1056/NEJMoa1615692).
Insulin degludec injection (Tresiba®, Novo Nordisk) is a basal insulin analog, the long, soluble hexamer chains of which are metabolized only at the ends, yielding at least a 42-hour duration of action, Todd Hobbs, MD, chief medical officer of Novo Nordisk, Princeton, N.J., explained in an interview. In contrast, glargine has about a 12-hour half-life. Previous trials of degludec did not adjudicate cardiovascular endpoints, which the U.S. Food and Drug Administration only recently began requiring for insulins, Dr. Hobbs said. In response to an FDA request, the phase III, international, randomized, double-blind DEVOTE trial compared the cardiovascular safety of daily basal insulin degludec (100 U per mL) with that of glargine U100 in more than 7,600 adults with type 2 diabetes.
Fully 98% of patients completed the 2-year trial. The overall risk of major adverse cardiac events resembled that of each individual component, including cardiovascular death (HR, 0.96; 95% CI, 0.76-1.21; P = .71), nonfatal myocardial infarction (HR, 0.85; 95% CI, 0.68-1.06; P = .15), and nonfatal stroke (HR, 0.90; 95% CI, 0.65-1.23; P =. 50). Degludec remained noninferior to glargine when researchers added unstable angina to the primary endpoint and accounted for patient location, treatment duration, length of follow-up, and age, sex, body mass index, and renal function.
Both insulins produced similar HbA1c levels of about 7.5%, but degludec cut fasting plasma glucose by about 5 mg per mL more, compared with glargine (P less than .001), the investigators reported. Furthermore, the odds ratio for severe hypoglycemia significantly favored degludec (HR, 0.73; 95% CI, 0.60-0.89; P less than .001). In other words, 40 patients would need to receive degludec rather than glargine to prevent one event of severe hypoglycemia. Previous studies have shown similar results, Dr. Buse said. In a pooled analysis of all five trials of type 2 diabetes in the degludec clinical development program, degludec was associated with a significantly lower risk of hypoglycemia, particularly nocturnal episodes, than was glargine (Diabetes Obes Metab. 2013;15:175-84).
Findings were similar in the double-blind SWITCH 2 trial (Diabetologia. 2016;59[Suppl 1]:1-581).
DEVOTE identified no safety issues for degludec, compared with glargine. Each arm had similar rates of serious or severe adverse events, leading to treatment discontinuation, and neoplasms. Nonetheless, DEVOTE had several limitations, said Elizabeth R. Seaquist, MD, of the University of Minnesota, Minneapolis, who was not involved in the study. “Investigators could modify the titration protocol based on clinical judgment, and it isn’t clear whether this modification was applied equally in both arms,” she said at ADA. “Another weakness is that there were no data collected about moderate symptomatic hypoglycemia, the most common type of hypoglycemia that patients experience.” DEVOTE also did not examine how often blood glucose dropped below 54 mg per dL, the point at which patients often do not know they are hypoglycemic. Investigators also should examine whether degludec cuts health care costs or improves sleep or quality of life, whether its glycemic benefits extends to patients who are insulin-naive or have severe kidney disease, and how it compares with glargine U300, she added.
Insulin degludec received FDA approval in September 2015, based on interim results of DEVOTE. Novo Nordisk makes insulin degludec and sponsored the trial. Dr. Buse disclosed consulting fees from Novo Nordisk and ties to many other pharmaceutical companies. Dr. Seaquist disclosed ties to Novo Nordisk, Eli Lilly, Locemia, and Lucera. Dr. Hobbs is chief medical officer for Novo Nordisk.
SAN DIEGO – For patients with type 2 diabetes at high risk of cardiovascular disease, the ultra–long-acting, once-daily basal insulin degludec produced a similar risk of major adverse cardiovascular events as glargine with a significantly lower risk of severe hypoglycemia, new data show.
Nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death occurred in 325 (8.5%) patients on degludec and 356 (9.3%) patients on glargine (hazard ratio, 0.91; 95% confidence interval, 0.78 to 1.06; P = .21) in DEVOTE (the Trial Comparing Cardiovascular Safety of Insulin Degludec versus Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events). Rates of severe hypoglycemia were 4.9% and 6.6%, respectively (P less than .001), investigators reported at the annual scientific sessions of the American Diabetes Association and simultaneously in the New England Journal of Medicine (2017 Jun 12. doi: 10.1056/NEJMoa1615692).
Insulin degludec injection (Tresiba®, Novo Nordisk) is a basal insulin analog, the long, soluble hexamer chains of which are metabolized only at the ends, yielding at least a 42-hour duration of action, Todd Hobbs, MD, chief medical officer of Novo Nordisk, Princeton, N.J., explained in an interview. In contrast, glargine has about a 12-hour half-life. Previous trials of degludec did not adjudicate cardiovascular endpoints, which the U.S. Food and Drug Administration only recently began requiring for insulins, Dr. Hobbs said. In response to an FDA request, the phase III, international, randomized, double-blind DEVOTE trial compared the cardiovascular safety of daily basal insulin degludec (100 U per mL) with that of glargine U100 in more than 7,600 adults with type 2 diabetes.
Fully 98% of patients completed the 2-year trial. The overall risk of major adverse cardiac events resembled that of each individual component, including cardiovascular death (HR, 0.96; 95% CI, 0.76-1.21; P = .71), nonfatal myocardial infarction (HR, 0.85; 95% CI, 0.68-1.06; P = .15), and nonfatal stroke (HR, 0.90; 95% CI, 0.65-1.23; P =. 50). Degludec remained noninferior to glargine when researchers added unstable angina to the primary endpoint and accounted for patient location, treatment duration, length of follow-up, and age, sex, body mass index, and renal function.
Both insulins produced similar HbA1c levels of about 7.5%, but degludec cut fasting plasma glucose by about 5 mg per mL more, compared with glargine (P less than .001), the investigators reported. Furthermore, the odds ratio for severe hypoglycemia significantly favored degludec (HR, 0.73; 95% CI, 0.60-0.89; P less than .001). In other words, 40 patients would need to receive degludec rather than glargine to prevent one event of severe hypoglycemia. Previous studies have shown similar results, Dr. Buse said. In a pooled analysis of all five trials of type 2 diabetes in the degludec clinical development program, degludec was associated with a significantly lower risk of hypoglycemia, particularly nocturnal episodes, than was glargine (Diabetes Obes Metab. 2013;15:175-84).
Findings were similar in the double-blind SWITCH 2 trial (Diabetologia. 2016;59[Suppl 1]:1-581).
DEVOTE identified no safety issues for degludec, compared with glargine. Each arm had similar rates of serious or severe adverse events, leading to treatment discontinuation, and neoplasms. Nonetheless, DEVOTE had several limitations, said Elizabeth R. Seaquist, MD, of the University of Minnesota, Minneapolis, who was not involved in the study. “Investigators could modify the titration protocol based on clinical judgment, and it isn’t clear whether this modification was applied equally in both arms,” she said at ADA. “Another weakness is that there were no data collected about moderate symptomatic hypoglycemia, the most common type of hypoglycemia that patients experience.” DEVOTE also did not examine how often blood glucose dropped below 54 mg per dL, the point at which patients often do not know they are hypoglycemic. Investigators also should examine whether degludec cuts health care costs or improves sleep or quality of life, whether its glycemic benefits extends to patients who are insulin-naive or have severe kidney disease, and how it compares with glargine U300, she added.
Insulin degludec received FDA approval in September 2015, based on interim results of DEVOTE. Novo Nordisk makes insulin degludec and sponsored the trial. Dr. Buse disclosed consulting fees from Novo Nordisk and ties to many other pharmaceutical companies. Dr. Seaquist disclosed ties to Novo Nordisk, Eli Lilly, Locemia, and Lucera. Dr. Hobbs is chief medical officer for Novo Nordisk.
AT THE ADA ANNUAL SCIENTIFIC SESSIONS
Key clinical point: The ultra–long-acting basal insulin degludec was noninferior to glargine in terms of cardiovascular risk and was superior in terms of severe hypoglycemia.
Major finding: Nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death occurred in 325 (8.5%) patients on degludec and 356 (9.3%) patients on glargine (HR, 0.91; 95% CI, 0.78-1.06; P = .21). Rates of severe hypoglycemia were 4.9% and 6.6%, respectively (P less than .001).
Data source: A randomized, double-blind, multicenter trial of 7,637 adults with type 2 diabetes at high risk of cardiovascular disease.
Disclosures: Novo Nordisk makes insulin degludec and sponsored the trial. Dr. Buse disclosed consulting fees from Novo Nordisk and ties to many other pharmaceutical companies. Dr. Seaquist disclosed ties to Novo Nordisk, Eli Lilly, Locemia, and Lucera. Dr. Hobbs is chief medical officer for Novo Nordisk.
Providers buck lipid recommendations in high-risk diabetes
SAN DIEGO – In the 3 months before their atherosclerotic cardiovascular event, 40% of high-risk patients with diabetes received no prescription for lipid-lowering therapy, researchers reported at the annual scientific sessions of the American Diabetes Association.
Underprescribing of high-intensity statins was also “particularly apparent for patients with diabetes mellitus alone, although rates improved somewhat over follow-up,” Sarah S. Cohen, PhD, of EpidStat Institute in Ann Arbor, Mich., said in a late-breaking poster. The findings highlight the need to educate providers and patients on the importance of addressing cardiovascular risk factors and disease in the diabetes setting, she wrote with her associates from the Mayo Clinic and Amgen.
Hypertension and dyslipidemia are classic companions of type 2 diabetes and “clear risk factors” for atherosclerotic cardiovascular disease (ASCVD), according to 2017 care guidelines from the American Diabetes Association.
“Diabetes itself confers independent risk,” the guidelines add. To characterize real-world use of lipid-lowering therapies in patients with diabetes, ASCVD, or both conditions, Dr. Cohen and her associates analyzed electronic medical records from more than 7,400 adults in Minnesota with new-onset type 2 diabetes mellitus or ASCVD, or incident ASCVD and existing diabetes between 2005 and 2012. During this period, about 4,500 patients were diagnosed with diabetes and another 570 patients with an existing diagnosis of diabetes were diagnosed with ASCVD based on incident myocardial infarction, unstable angina, stroke, or revascularization. An additional 2,300 patients had ASCVD alone.
Patients with existing diabetes and incident ASCVD tended to be in their 70s, two-thirds had used tobacco, 31% were overweight, and 54% were obese, the investigators found. Nonetheless, 40% of patients received no lipid-lowering therapy in the 3 months before the ASCVD event and 90% received no high-intensity statins. Three months after the event, 75% of patients were on lipid-lowering therapy and 64% were on moderate- or high-intensity statins. Patients with incident diabetes alone tended to be in their late 50s, about 60% had used tobacco, and two-thirds were obese. Only 34%, however, were prescribed moderate or high-intensity statins within 3 months after their diabetes diagnosis, and this proportion rose to just 46% at 2 years.
Diabetes is known to boost the risk of cardiovascular disease, but incident diabetes seldom triggered a prescription for lipid-lowering therapy in this cohort, the researchers concluded. Incident ASCVD was much more likely to elicit a prescription, but comorbid diabetes did not further improve the chances of receiving guideline-recommended therapy.
The ADA recommends screening for and treating modifiable CVD risk factors even in the prediabetes setting. For patients with clinical diabetes, providers should evaluate history of dyslipidemia, obtain a fasting lipid profile, and recommend lifestyle changes to address glycemic, blood pressure, and lipid goals, ADA guidelines state. In addition, comorbid diabetes and ASCVD merit high-intensity statin therapy, and diabetic patients with additional risk factors for CVD merit consideration of moderate- or high-intensity statin therapy, according to the recommendations.
The researchers lacked data on prescription fill rates, so they might have overestimated the proportion of patients taking lipid-lowering therapies, they noted. They also had no data on reasons for not prescribing lipid-lowering therapies.
Amgen and the National Institute on Aging provided funding. Dr. Cohen disclosed research funding from Amgen, which makes evolocumab, a lipid-lowering drug. She had no other conflicts of interest.
SAN DIEGO – In the 3 months before their atherosclerotic cardiovascular event, 40% of high-risk patients with diabetes received no prescription for lipid-lowering therapy, researchers reported at the annual scientific sessions of the American Diabetes Association.
Underprescribing of high-intensity statins was also “particularly apparent for patients with diabetes mellitus alone, although rates improved somewhat over follow-up,” Sarah S. Cohen, PhD, of EpidStat Institute in Ann Arbor, Mich., said in a late-breaking poster. The findings highlight the need to educate providers and patients on the importance of addressing cardiovascular risk factors and disease in the diabetes setting, she wrote with her associates from the Mayo Clinic and Amgen.
Hypertension and dyslipidemia are classic companions of type 2 diabetes and “clear risk factors” for atherosclerotic cardiovascular disease (ASCVD), according to 2017 care guidelines from the American Diabetes Association.
“Diabetes itself confers independent risk,” the guidelines add. To characterize real-world use of lipid-lowering therapies in patients with diabetes, ASCVD, or both conditions, Dr. Cohen and her associates analyzed electronic medical records from more than 7,400 adults in Minnesota with new-onset type 2 diabetes mellitus or ASCVD, or incident ASCVD and existing diabetes between 2005 and 2012. During this period, about 4,500 patients were diagnosed with diabetes and another 570 patients with an existing diagnosis of diabetes were diagnosed with ASCVD based on incident myocardial infarction, unstable angina, stroke, or revascularization. An additional 2,300 patients had ASCVD alone.
Patients with existing diabetes and incident ASCVD tended to be in their 70s, two-thirds had used tobacco, 31% were overweight, and 54% were obese, the investigators found. Nonetheless, 40% of patients received no lipid-lowering therapy in the 3 months before the ASCVD event and 90% received no high-intensity statins. Three months after the event, 75% of patients were on lipid-lowering therapy and 64% were on moderate- or high-intensity statins. Patients with incident diabetes alone tended to be in their late 50s, about 60% had used tobacco, and two-thirds were obese. Only 34%, however, were prescribed moderate or high-intensity statins within 3 months after their diabetes diagnosis, and this proportion rose to just 46% at 2 years.
Diabetes is known to boost the risk of cardiovascular disease, but incident diabetes seldom triggered a prescription for lipid-lowering therapy in this cohort, the researchers concluded. Incident ASCVD was much more likely to elicit a prescription, but comorbid diabetes did not further improve the chances of receiving guideline-recommended therapy.
The ADA recommends screening for and treating modifiable CVD risk factors even in the prediabetes setting. For patients with clinical diabetes, providers should evaluate history of dyslipidemia, obtain a fasting lipid profile, and recommend lifestyle changes to address glycemic, blood pressure, and lipid goals, ADA guidelines state. In addition, comorbid diabetes and ASCVD merit high-intensity statin therapy, and diabetic patients with additional risk factors for CVD merit consideration of moderate- or high-intensity statin therapy, according to the recommendations.
The researchers lacked data on prescription fill rates, so they might have overestimated the proportion of patients taking lipid-lowering therapies, they noted. They also had no data on reasons for not prescribing lipid-lowering therapies.
Amgen and the National Institute on Aging provided funding. Dr. Cohen disclosed research funding from Amgen, which makes evolocumab, a lipid-lowering drug. She had no other conflicts of interest.
SAN DIEGO – In the 3 months before their atherosclerotic cardiovascular event, 40% of high-risk patients with diabetes received no prescription for lipid-lowering therapy, researchers reported at the annual scientific sessions of the American Diabetes Association.
Underprescribing of high-intensity statins was also “particularly apparent for patients with diabetes mellitus alone, although rates improved somewhat over follow-up,” Sarah S. Cohen, PhD, of EpidStat Institute in Ann Arbor, Mich., said in a late-breaking poster. The findings highlight the need to educate providers and patients on the importance of addressing cardiovascular risk factors and disease in the diabetes setting, she wrote with her associates from the Mayo Clinic and Amgen.
Hypertension and dyslipidemia are classic companions of type 2 diabetes and “clear risk factors” for atherosclerotic cardiovascular disease (ASCVD), according to 2017 care guidelines from the American Diabetes Association.
“Diabetes itself confers independent risk,” the guidelines add. To characterize real-world use of lipid-lowering therapies in patients with diabetes, ASCVD, or both conditions, Dr. Cohen and her associates analyzed electronic medical records from more than 7,400 adults in Minnesota with new-onset type 2 diabetes mellitus or ASCVD, or incident ASCVD and existing diabetes between 2005 and 2012. During this period, about 4,500 patients were diagnosed with diabetes and another 570 patients with an existing diagnosis of diabetes were diagnosed with ASCVD based on incident myocardial infarction, unstable angina, stroke, or revascularization. An additional 2,300 patients had ASCVD alone.
Patients with existing diabetes and incident ASCVD tended to be in their 70s, two-thirds had used tobacco, 31% were overweight, and 54% were obese, the investigators found. Nonetheless, 40% of patients received no lipid-lowering therapy in the 3 months before the ASCVD event and 90% received no high-intensity statins. Three months after the event, 75% of patients were on lipid-lowering therapy and 64% were on moderate- or high-intensity statins. Patients with incident diabetes alone tended to be in their late 50s, about 60% had used tobacco, and two-thirds were obese. Only 34%, however, were prescribed moderate or high-intensity statins within 3 months after their diabetes diagnosis, and this proportion rose to just 46% at 2 years.
Diabetes is known to boost the risk of cardiovascular disease, but incident diabetes seldom triggered a prescription for lipid-lowering therapy in this cohort, the researchers concluded. Incident ASCVD was much more likely to elicit a prescription, but comorbid diabetes did not further improve the chances of receiving guideline-recommended therapy.
The ADA recommends screening for and treating modifiable CVD risk factors even in the prediabetes setting. For patients with clinical diabetes, providers should evaluate history of dyslipidemia, obtain a fasting lipid profile, and recommend lifestyle changes to address glycemic, blood pressure, and lipid goals, ADA guidelines state. In addition, comorbid diabetes and ASCVD merit high-intensity statin therapy, and diabetic patients with additional risk factors for CVD merit consideration of moderate- or high-intensity statin therapy, according to the recommendations.
The researchers lacked data on prescription fill rates, so they might have overestimated the proportion of patients taking lipid-lowering therapies, they noted. They also had no data on reasons for not prescribing lipid-lowering therapies.
Amgen and the National Institute on Aging provided funding. Dr. Cohen disclosed research funding from Amgen, which makes evolocumab, a lipid-lowering drug. She had no other conflicts of interest.
AT THE ADA ANNUAL SCIENTIFIC SESSIONS
Key clinical point: Underprescribing of lipid-lowering therapies persists despite guidelines on their importance in patients with diabetes.
Major finding: About 40% of high-risk patients with diabetes were not prescribed lipid-lowering therapy in the 3 months before an atherosclerotic cardiovascular event.
Data source: Analyses of electronic medical records from 7,414 patients diagnosed with diabetes, atherosclerotic cardiovascular disease, or both between 2005 and 2012.
Disclosures: Amgen and the National Institute on Aging provided funding. Dr. Cohen disclosed research funding from Amgen, which makes evolocumab, a lipid-lowering drug. She had no other conflicts of interest.