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Wearing lateral wedge insoles reduces osteoarthritis knee pain
LIVERPOOL, ENGLAND – Lateral wedge insoles reduced osteoarthritis knee pain to a greater extent than did wearing neutral insoles in a randomized, controlled, crossover trial.
An overall significant treatment difference of 0.7 points on a 0-10 numerical rating scale global pain score was observed when patients with painful medial osteoarthritis (OA) wore lateral wedge insoles compared with when they wore neutral insoles in their own shoes (95% confidence interval [CI], 0.1-1.2 points; P = .02).
The study’s findings are in contrast to previous research that has found no benefit of lateral wedge insoles in patients with medial compartment knee OA (JAMA. 2013;310[7]:722-30) because patients were specifically prescreened to find those who would be biomechanical responders, David T. Felson, MD, said at the World Congress on Osteoarthritis.
“There is increased medial load in medial knee OA, and that is thought to cause pain and medial joint damage,” Dr. Felson, of Boston University, said at the congress, sponsored by the Osteoarthritis Research Society International.
There is evidence, however, that by moving the center of pressure laterally during walking with the use of lateral wedge insoles, the external knee adduction movement (KAM) can be reduced by around 5%-6%, which in turn can reduce the load across the medial component.
“We asked the following question: ‘If patients were screened to remove those with painful patellofemoral OA and those who did not show a biomechanical response to lateral wedge insoles, would lateral wedge insoles actually reduce pain?’ ” Dr. Felson noted.
For inclusion in the trial, patients needed to be aged between 40 and 80 years and have x-rays showing Kellgren-Lawrence grade 2-4 OA with definite medial and no lateral joint space narrowing in the last 2 years. They then also needed to have experienced knee pain that was rated at least 4 or more on a 0-10 numerical rating scale in the last week. Patients then had to be examined by an experienced physiotherapist or have x-rays to exclude patellofemoral OA and inflammatory arthritis.
All patients then underwent biomechanical assessment which consisted of motion analysis screening. Patients who did not show at least a 2% decrease in KAM after wearing the lateral wedge insoles versus the neutral insoles were excluded.
Of 112 subjects who were screened for the study, there remained 62 with a mean age of 64 years and body mass index of 28 kg/m2 who could be randomized. The subjects, 73% of whom were male, were randomized to first wear either neutral insoles or insoles with a lateral five-degree wedge for 8 weeks and then, after an 8-week washout period, to wear the other type of insole for a further 8 weeks. Participants wore the insoles for at least 4 hours a day and for a median of 7 hours per day.
Results showed that the lateral wedge insoles reduced KAM by 7.5% versus their own shoes and by 6.6% versus a neutral insole, and of the 62 patients randomized, 56 completed the trial. Two patients in each group stopped participating in the trial because of adverse events, which with lateral wedge insoles were cramps in the calf and foot and increased pain in the knee, and with the neutral insoles included a blister and increased pain in knee and foot.
At baseline, the mean global knee pain score in the last week was 5.46. After use of the lateral wedge or neutral insoles, this fell to a respective 4.2 and 4.9.
Patients were asked to report on the pain experience during a nominated activity. The baseline value for pain was 6.18, which decreased to 4.9 and 5.8 in the two groups, respectively, with an overall treatment difference of 0.9 (P = .001) favoring the use of the lateral wedge insoles.
There was improvement in knee pain assessed by the Knee injury and Osteoarthritis Outcomes Score from a baseline of 55 points to a score of 60.6 for lateral wedge and 58.9 for the neutral insoles, a between group difference of –1.7 (P = .45).
“Lateral wedge insoles reduce knee pain in selected subjects with painful medial OA, those without patellofemoral OA, and those who are biomechanical responders to these insoles,” Dr. Felson said.
“I think the importance of this study is that it opens the door to a treatment that we were frustrated wasn’t working,” Dr. Felson said. Insoles are inexpensive, safe, and potentially widely useful, and the research paves the way for further study of these insoles and for perhaps for shoes that could modify knee loads.
The findings open the door to “stratified approaches to knee OA that may also offer us an avenue toward success in developing treatments,” he added.
The National Institute for Health Research, Arthritis Research U.K., and the National Institutes of Health sponsored the study. Dr. Felson had no disclosures.
SOURCE: Felson D et al. Osteoarthritis Cartilage. 2018:26(1):S17. Abstract 14.
LIVERPOOL, ENGLAND – Lateral wedge insoles reduced osteoarthritis knee pain to a greater extent than did wearing neutral insoles in a randomized, controlled, crossover trial.
An overall significant treatment difference of 0.7 points on a 0-10 numerical rating scale global pain score was observed when patients with painful medial osteoarthritis (OA) wore lateral wedge insoles compared with when they wore neutral insoles in their own shoes (95% confidence interval [CI], 0.1-1.2 points; P = .02).
The study’s findings are in contrast to previous research that has found no benefit of lateral wedge insoles in patients with medial compartment knee OA (JAMA. 2013;310[7]:722-30) because patients were specifically prescreened to find those who would be biomechanical responders, David T. Felson, MD, said at the World Congress on Osteoarthritis.
“There is increased medial load in medial knee OA, and that is thought to cause pain and medial joint damage,” Dr. Felson, of Boston University, said at the congress, sponsored by the Osteoarthritis Research Society International.
There is evidence, however, that by moving the center of pressure laterally during walking with the use of lateral wedge insoles, the external knee adduction movement (KAM) can be reduced by around 5%-6%, which in turn can reduce the load across the medial component.
“We asked the following question: ‘If patients were screened to remove those with painful patellofemoral OA and those who did not show a biomechanical response to lateral wedge insoles, would lateral wedge insoles actually reduce pain?’ ” Dr. Felson noted.
For inclusion in the trial, patients needed to be aged between 40 and 80 years and have x-rays showing Kellgren-Lawrence grade 2-4 OA with definite medial and no lateral joint space narrowing in the last 2 years. They then also needed to have experienced knee pain that was rated at least 4 or more on a 0-10 numerical rating scale in the last week. Patients then had to be examined by an experienced physiotherapist or have x-rays to exclude patellofemoral OA and inflammatory arthritis.
All patients then underwent biomechanical assessment which consisted of motion analysis screening. Patients who did not show at least a 2% decrease in KAM after wearing the lateral wedge insoles versus the neutral insoles were excluded.
Of 112 subjects who were screened for the study, there remained 62 with a mean age of 64 years and body mass index of 28 kg/m2 who could be randomized. The subjects, 73% of whom were male, were randomized to first wear either neutral insoles or insoles with a lateral five-degree wedge for 8 weeks and then, after an 8-week washout period, to wear the other type of insole for a further 8 weeks. Participants wore the insoles for at least 4 hours a day and for a median of 7 hours per day.
Results showed that the lateral wedge insoles reduced KAM by 7.5% versus their own shoes and by 6.6% versus a neutral insole, and of the 62 patients randomized, 56 completed the trial. Two patients in each group stopped participating in the trial because of adverse events, which with lateral wedge insoles were cramps in the calf and foot and increased pain in the knee, and with the neutral insoles included a blister and increased pain in knee and foot.
At baseline, the mean global knee pain score in the last week was 5.46. After use of the lateral wedge or neutral insoles, this fell to a respective 4.2 and 4.9.
Patients were asked to report on the pain experience during a nominated activity. The baseline value for pain was 6.18, which decreased to 4.9 and 5.8 in the two groups, respectively, with an overall treatment difference of 0.9 (P = .001) favoring the use of the lateral wedge insoles.
There was improvement in knee pain assessed by the Knee injury and Osteoarthritis Outcomes Score from a baseline of 55 points to a score of 60.6 for lateral wedge and 58.9 for the neutral insoles, a between group difference of –1.7 (P = .45).
“Lateral wedge insoles reduce knee pain in selected subjects with painful medial OA, those without patellofemoral OA, and those who are biomechanical responders to these insoles,” Dr. Felson said.
“I think the importance of this study is that it opens the door to a treatment that we were frustrated wasn’t working,” Dr. Felson said. Insoles are inexpensive, safe, and potentially widely useful, and the research paves the way for further study of these insoles and for perhaps for shoes that could modify knee loads.
The findings open the door to “stratified approaches to knee OA that may also offer us an avenue toward success in developing treatments,” he added.
The National Institute for Health Research, Arthritis Research U.K., and the National Institutes of Health sponsored the study. Dr. Felson had no disclosures.
SOURCE: Felson D et al. Osteoarthritis Cartilage. 2018:26(1):S17. Abstract 14.
LIVERPOOL, ENGLAND – Lateral wedge insoles reduced osteoarthritis knee pain to a greater extent than did wearing neutral insoles in a randomized, controlled, crossover trial.
An overall significant treatment difference of 0.7 points on a 0-10 numerical rating scale global pain score was observed when patients with painful medial osteoarthritis (OA) wore lateral wedge insoles compared with when they wore neutral insoles in their own shoes (95% confidence interval [CI], 0.1-1.2 points; P = .02).
The study’s findings are in contrast to previous research that has found no benefit of lateral wedge insoles in patients with medial compartment knee OA (JAMA. 2013;310[7]:722-30) because patients were specifically prescreened to find those who would be biomechanical responders, David T. Felson, MD, said at the World Congress on Osteoarthritis.
“There is increased medial load in medial knee OA, and that is thought to cause pain and medial joint damage,” Dr. Felson, of Boston University, said at the congress, sponsored by the Osteoarthritis Research Society International.
There is evidence, however, that by moving the center of pressure laterally during walking with the use of lateral wedge insoles, the external knee adduction movement (KAM) can be reduced by around 5%-6%, which in turn can reduce the load across the medial component.
“We asked the following question: ‘If patients were screened to remove those with painful patellofemoral OA and those who did not show a biomechanical response to lateral wedge insoles, would lateral wedge insoles actually reduce pain?’ ” Dr. Felson noted.
For inclusion in the trial, patients needed to be aged between 40 and 80 years and have x-rays showing Kellgren-Lawrence grade 2-4 OA with definite medial and no lateral joint space narrowing in the last 2 years. They then also needed to have experienced knee pain that was rated at least 4 or more on a 0-10 numerical rating scale in the last week. Patients then had to be examined by an experienced physiotherapist or have x-rays to exclude patellofemoral OA and inflammatory arthritis.
All patients then underwent biomechanical assessment which consisted of motion analysis screening. Patients who did not show at least a 2% decrease in KAM after wearing the lateral wedge insoles versus the neutral insoles were excluded.
Of 112 subjects who were screened for the study, there remained 62 with a mean age of 64 years and body mass index of 28 kg/m2 who could be randomized. The subjects, 73% of whom were male, were randomized to first wear either neutral insoles or insoles with a lateral five-degree wedge for 8 weeks and then, after an 8-week washout period, to wear the other type of insole for a further 8 weeks. Participants wore the insoles for at least 4 hours a day and for a median of 7 hours per day.
Results showed that the lateral wedge insoles reduced KAM by 7.5% versus their own shoes and by 6.6% versus a neutral insole, and of the 62 patients randomized, 56 completed the trial. Two patients in each group stopped participating in the trial because of adverse events, which with lateral wedge insoles were cramps in the calf and foot and increased pain in the knee, and with the neutral insoles included a blister and increased pain in knee and foot.
At baseline, the mean global knee pain score in the last week was 5.46. After use of the lateral wedge or neutral insoles, this fell to a respective 4.2 and 4.9.
Patients were asked to report on the pain experience during a nominated activity. The baseline value for pain was 6.18, which decreased to 4.9 and 5.8 in the two groups, respectively, with an overall treatment difference of 0.9 (P = .001) favoring the use of the lateral wedge insoles.
There was improvement in knee pain assessed by the Knee injury and Osteoarthritis Outcomes Score from a baseline of 55 points to a score of 60.6 for lateral wedge and 58.9 for the neutral insoles, a between group difference of –1.7 (P = .45).
“Lateral wedge insoles reduce knee pain in selected subjects with painful medial OA, those without patellofemoral OA, and those who are biomechanical responders to these insoles,” Dr. Felson said.
“I think the importance of this study is that it opens the door to a treatment that we were frustrated wasn’t working,” Dr. Felson said. Insoles are inexpensive, safe, and potentially widely useful, and the research paves the way for further study of these insoles and for perhaps for shoes that could modify knee loads.
The findings open the door to “stratified approaches to knee OA that may also offer us an avenue toward success in developing treatments,” he added.
The National Institute for Health Research, Arthritis Research U.K., and the National Institutes of Health sponsored the study. Dr. Felson had no disclosures.
SOURCE: Felson D et al. Osteoarthritis Cartilage. 2018:26(1):S17. Abstract 14.
REPORTING FROM OARSI 2018
Key clinical point:
Major finding: There was a mean treatment difference of 0.7 points in a global pain score favoring lateral wedge over neutral insoles (P = .02).
Study details: Randomized, controlled, crossover study of 62 patients with painful medial knee OA.
Disclosures: The National Institute for Health Research, Arthritis Research U.K., and the National Institutes of Health sponsored the study. Dr. Felson had no disclosures.
Source: Felson D et al. Osteoarthritis Cartilage. 2018:26(1):S17. Abstract 14.
Cathepsin K inhibitor exhibits bone protecting effects in osteoarthritis
LIVERPOOL, ENGLAND – The investigational cathepsin K inhibitor MIV-711 had positive effects on both bone and cartilage at 6 months in patients with knee osteoarthritis (OA) in a phase 2a study.
The MRI measures of the “area of bone in the medial femur region” and “average cartilage thickness” showed reduced progression with MIV-711 versus placebo.
MIV-711 also produced rapid and sustained reductions in the bone biomarkers CTX-I and CTX-II, study investigator Philip Conaghan, MBBS, PhD, reported at the World Congress on Osteoarthritis.
The primary endpoint of the trial – the change in average knee pain over 26 weeks assessed using an 11-point numerical rating scale (NRS) – was not met, however, with no differences between MIV-711 treatment and placebo.
While there were also no statistical differences in Western Ontario and McMaster Universities Osteoarthritis Index pain scores, one of several secondary endpoints assessed, there was a trend for less pain with MIV-711 than with placebo.
“The lack of symptom benefits may reflect that the study duration was not sufficient to see symptom reduction following structure modification,” Dr. Conaghan and his coauthors stated in their abstract.
“That’s something we’re seeing with all the drugs that are trying to get DMOAD [disease modifying osteoarthritis drug] licenses at present,“ Dr. Conaghan said at the Congress, sponsored by the Osteoarthritis Research Society International.
Dr. Conaghan, who is professor of musculoskeletal medicine and director of the Leeds (England) Institute of Rheumatic and Musculoskeletal Medicine, noted: “Cathepsin K is a cysteine protease that degrades the collagen matrix and stops bone resorption, so it’s got a number of potential actions,” in the development of OA.
MIV-711 is a potent, selective, and reversible inhibitor of cathepsin K, he added, which has previously been shown to have bone structure–modifying properties in preclinical models. It also has been shown to reduce CTX-I and CTX-II in healthy volunteers.
The current randomized, double-blind, placebo-controlled phase 2a study included two active treatment (100 mg and 200 mg, once daily) arms and one placebo arm. For inclusion, patients had to have knee pain rated as 4 or higher on an 11-point NRS and Kellgren-Lawrence grade 2 or 3 knee OA.
Patients also were allowed to remain on any analgesic medication they were currently taking, provided this was stable. “That enables recruitment as a trialist, and it’s more like my usual practice as it’s unlikely I’d stop an analgesic before starting a new one,” Dr. Conaghan said.
In all, 240 patients were enrolled at six European sites. They had a mean age of 62 years, a body mass index of 32 kg/m2, and 77% were women. MRIs were assessed at baseline and at week 26, with additional clinic visits scheduled at 2, 4, 8, 14, and 20 weeks.
“Overall, there are not any great safety signals,” Dr. Conaghan said. The placebo, 100-mg, and 200-mg MIV-117 arms had similar rates of any adverse event (55%, 54.9%, and 52.4%) or treatment-related adverse events (21.2%, 20.7%, and 24.4%). There were more serious adverse events in the 100-mg and 200-mg MIV-711 treatment arms (3.7% and 2.4%) than in the placebo arm (1.3%), and more discontinuations (7.3%, 4.9%, and 3.8%).
“The primary endpoint of knee pain was not met, but there was a consistent trend, and it looks like there’s a benefit, but the statistically endpoint was not achieved,” Dr. Conaghan summarized.
“MRI measures do show structural modification in terms of bone shape and probably an effect on cartilage,” although the study was not powered to show an effect on the latter, Dr. Conaghan noted.
“The overall data, and from what we’ve seen regarding structural effects, do warrant this drug moving forward into further trials,” he added.
The study was sponsored by Medivir. Dr. Conaghan disclosed being a member of the speaker’s bureau for Kolon TissueGene and Samumed and on advisory boards for AbbVie, Centrexion, Flexion Therapeutics, Medivir, Novartis, and ONO Pharmaceutical.
SOURCE: Conaghan P et al. Osteoarthritis Cartilage. 2018 Apr 16:26(1):S25-26. Abstract 29.
LIVERPOOL, ENGLAND – The investigational cathepsin K inhibitor MIV-711 had positive effects on both bone and cartilage at 6 months in patients with knee osteoarthritis (OA) in a phase 2a study.
The MRI measures of the “area of bone in the medial femur region” and “average cartilage thickness” showed reduced progression with MIV-711 versus placebo.
MIV-711 also produced rapid and sustained reductions in the bone biomarkers CTX-I and CTX-II, study investigator Philip Conaghan, MBBS, PhD, reported at the World Congress on Osteoarthritis.
The primary endpoint of the trial – the change in average knee pain over 26 weeks assessed using an 11-point numerical rating scale (NRS) – was not met, however, with no differences between MIV-711 treatment and placebo.
While there were also no statistical differences in Western Ontario and McMaster Universities Osteoarthritis Index pain scores, one of several secondary endpoints assessed, there was a trend for less pain with MIV-711 than with placebo.
“The lack of symptom benefits may reflect that the study duration was not sufficient to see symptom reduction following structure modification,” Dr. Conaghan and his coauthors stated in their abstract.
“That’s something we’re seeing with all the drugs that are trying to get DMOAD [disease modifying osteoarthritis drug] licenses at present,“ Dr. Conaghan said at the Congress, sponsored by the Osteoarthritis Research Society International.
Dr. Conaghan, who is professor of musculoskeletal medicine and director of the Leeds (England) Institute of Rheumatic and Musculoskeletal Medicine, noted: “Cathepsin K is a cysteine protease that degrades the collagen matrix and stops bone resorption, so it’s got a number of potential actions,” in the development of OA.
MIV-711 is a potent, selective, and reversible inhibitor of cathepsin K, he added, which has previously been shown to have bone structure–modifying properties in preclinical models. It also has been shown to reduce CTX-I and CTX-II in healthy volunteers.
The current randomized, double-blind, placebo-controlled phase 2a study included two active treatment (100 mg and 200 mg, once daily) arms and one placebo arm. For inclusion, patients had to have knee pain rated as 4 or higher on an 11-point NRS and Kellgren-Lawrence grade 2 or 3 knee OA.
Patients also were allowed to remain on any analgesic medication they were currently taking, provided this was stable. “That enables recruitment as a trialist, and it’s more like my usual practice as it’s unlikely I’d stop an analgesic before starting a new one,” Dr. Conaghan said.
In all, 240 patients were enrolled at six European sites. They had a mean age of 62 years, a body mass index of 32 kg/m2, and 77% were women. MRIs were assessed at baseline and at week 26, with additional clinic visits scheduled at 2, 4, 8, 14, and 20 weeks.
“Overall, there are not any great safety signals,” Dr. Conaghan said. The placebo, 100-mg, and 200-mg MIV-117 arms had similar rates of any adverse event (55%, 54.9%, and 52.4%) or treatment-related adverse events (21.2%, 20.7%, and 24.4%). There were more serious adverse events in the 100-mg and 200-mg MIV-711 treatment arms (3.7% and 2.4%) than in the placebo arm (1.3%), and more discontinuations (7.3%, 4.9%, and 3.8%).
“The primary endpoint of knee pain was not met, but there was a consistent trend, and it looks like there’s a benefit, but the statistically endpoint was not achieved,” Dr. Conaghan summarized.
“MRI measures do show structural modification in terms of bone shape and probably an effect on cartilage,” although the study was not powered to show an effect on the latter, Dr. Conaghan noted.
“The overall data, and from what we’ve seen regarding structural effects, do warrant this drug moving forward into further trials,” he added.
The study was sponsored by Medivir. Dr. Conaghan disclosed being a member of the speaker’s bureau for Kolon TissueGene and Samumed and on advisory boards for AbbVie, Centrexion, Flexion Therapeutics, Medivir, Novartis, and ONO Pharmaceutical.
SOURCE: Conaghan P et al. Osteoarthritis Cartilage. 2018 Apr 16:26(1):S25-26. Abstract 29.
LIVERPOOL, ENGLAND – The investigational cathepsin K inhibitor MIV-711 had positive effects on both bone and cartilage at 6 months in patients with knee osteoarthritis (OA) in a phase 2a study.
The MRI measures of the “area of bone in the medial femur region” and “average cartilage thickness” showed reduced progression with MIV-711 versus placebo.
MIV-711 also produced rapid and sustained reductions in the bone biomarkers CTX-I and CTX-II, study investigator Philip Conaghan, MBBS, PhD, reported at the World Congress on Osteoarthritis.
The primary endpoint of the trial – the change in average knee pain over 26 weeks assessed using an 11-point numerical rating scale (NRS) – was not met, however, with no differences between MIV-711 treatment and placebo.
While there were also no statistical differences in Western Ontario and McMaster Universities Osteoarthritis Index pain scores, one of several secondary endpoints assessed, there was a trend for less pain with MIV-711 than with placebo.
“The lack of symptom benefits may reflect that the study duration was not sufficient to see symptom reduction following structure modification,” Dr. Conaghan and his coauthors stated in their abstract.
“That’s something we’re seeing with all the drugs that are trying to get DMOAD [disease modifying osteoarthritis drug] licenses at present,“ Dr. Conaghan said at the Congress, sponsored by the Osteoarthritis Research Society International.
Dr. Conaghan, who is professor of musculoskeletal medicine and director of the Leeds (England) Institute of Rheumatic and Musculoskeletal Medicine, noted: “Cathepsin K is a cysteine protease that degrades the collagen matrix and stops bone resorption, so it’s got a number of potential actions,” in the development of OA.
MIV-711 is a potent, selective, and reversible inhibitor of cathepsin K, he added, which has previously been shown to have bone structure–modifying properties in preclinical models. It also has been shown to reduce CTX-I and CTX-II in healthy volunteers.
The current randomized, double-blind, placebo-controlled phase 2a study included two active treatment (100 mg and 200 mg, once daily) arms and one placebo arm. For inclusion, patients had to have knee pain rated as 4 or higher on an 11-point NRS and Kellgren-Lawrence grade 2 or 3 knee OA.
Patients also were allowed to remain on any analgesic medication they were currently taking, provided this was stable. “That enables recruitment as a trialist, and it’s more like my usual practice as it’s unlikely I’d stop an analgesic before starting a new one,” Dr. Conaghan said.
In all, 240 patients were enrolled at six European sites. They had a mean age of 62 years, a body mass index of 32 kg/m2, and 77% were women. MRIs were assessed at baseline and at week 26, with additional clinic visits scheduled at 2, 4, 8, 14, and 20 weeks.
“Overall, there are not any great safety signals,” Dr. Conaghan said. The placebo, 100-mg, and 200-mg MIV-117 arms had similar rates of any adverse event (55%, 54.9%, and 52.4%) or treatment-related adverse events (21.2%, 20.7%, and 24.4%). There were more serious adverse events in the 100-mg and 200-mg MIV-711 treatment arms (3.7% and 2.4%) than in the placebo arm (1.3%), and more discontinuations (7.3%, 4.9%, and 3.8%).
“The primary endpoint of knee pain was not met, but there was a consistent trend, and it looks like there’s a benefit, but the statistically endpoint was not achieved,” Dr. Conaghan summarized.
“MRI measures do show structural modification in terms of bone shape and probably an effect on cartilage,” although the study was not powered to show an effect on the latter, Dr. Conaghan noted.
“The overall data, and from what we’ve seen regarding structural effects, do warrant this drug moving forward into further trials,” he added.
The study was sponsored by Medivir. Dr. Conaghan disclosed being a member of the speaker’s bureau for Kolon TissueGene and Samumed and on advisory boards for AbbVie, Centrexion, Flexion Therapeutics, Medivir, Novartis, and ONO Pharmaceutical.
SOURCE: Conaghan P et al. Osteoarthritis Cartilage. 2018 Apr 16:26(1):S25-26. Abstract 29.
REPORTING FROM OARSI 2018
Key clinical point:
Major finding: A 63%-66% reduction in the medial femur bone area was observed with MIV-711, compared with placebo.
Study details: Randomized, double-blind, placebo-controlled phase 2a study of 240 patients with osteoarthritis knee pain.
Disclosures: The study was sponsored by Medivir. Dr. Conaghan disclosed being a member of the speakers bureau for Kolon TissueGene and Samumed and on advisory boards for AbbVie, Centrexion, Flexion Therapeutics, Medivir, Novartis, and ONO Pharmaceutical.
Source: Conaghan P et al. Osteoarthritis Cartilage. 2018 Apr 16:26(1):S25-26. Abstract 29.
Patient-reported outcomes show impairment decades after acute knee injury
LIVERPOOL, ENGLAND – Decades after they were sustained, acute knee injuries caused clinically significant impairments in patient-reported outcomes, as well as upped the risk for knee osteoarthritis (OA) in an observational study.
Results of the study, which followed up individuals 32-37 years after they were treated for a ruptured anterior cruciate ligament (ACL) injury between 1980 and 1985, showed that, compared with the general population, they experienced greater levels of knee pain, participated less in physical activities, and had a reduced quality of life.
The link between OA and ACL injury is not new, with prior estimates suggesting that up to half of all patients with ACL injury develop OA within 10 years of the injury, said Stephanie Filbay, PhD, who presented the results of the study at the World Congress on Osteoarthritis. There have also been reports of knee pain and other symptoms, and poor quality of life more than 5 years later. What’s not been known until now, however, is what happens with even longer term follow-up, said Dr. Filbay, a postdoctoral research fellow in sport, exercise, and osteoarthritis at the University of Oxford, England.
The aims of the study were to compare patient-reported outcomes at 32-37-years’ follow-up against the general population, then to see if the baseline injury or treatment approach, or knee function 3-7 years after the initial injury had any influence on outcomes.
The study included 223 patients who were between aged 15 and 40 years at the time of the acute ACL injury between 1980 and 1985 and who had been seen within 2 weeks of ACL rupture at Linköping University Hospital in Linköping, Sweden. Patients had been allocated to early surgical or non-surgical treatment based on having an odd or even birth year. They had then been assessed 3-7 years later using a variety of tests to determine the strength of their quadriceps and hamstrings and the ability to hop on one leg.
All patients were then invited 32-37 years later after the initial injury to complete questionnaires and undergo clinical examination and X-rays. Only four people declined and 38 did not answer, leaving 181 (81%) people who agreed to participate and complete the Knee injury and Osteoarthritis Outcome Score (KOOS) and the ACL quality of life questionnaire (ACL-QOL).
The average age of participants at follow-up was 59 years (range, 47-74 years); 30% were female. 58% of all patients had been treated non-surgically initially, and 38% remained non-surgically treated at the longterm follow-up. At baseline, 58% had a meniscus injury.
Compared with an age- and sex-matched Swedish population, patients with ACL injuries had a lower KOOS for pain, sport/recreational activities, and quality of life. For example, KOOS for knee pain was around 65-70 for those with prior ACL injuries, compared with 80-90 for those without ACL injuries, where 100 indicates the best outcome or least pain and zero the worst.
KOOS was not affected by whether or not patients had initial ACL surgery or surgery at any point in their follow up. It also did not appear to matter if patients had a meniscal injury at baseline or not.
Quadriceps and hamstring strength at the 3-7 year postinjury assessment did not affect the longterm KOOS, but the ability to hop on one leg did: Those who were not able to hop on one leg for more than 90% of the time on the unaffected limb at the 3-7 years follow-up had worse pain, symptoms, function, and quality of life at the longterm follow-up point.
With regards to OA, “overall, more than one in two individuals had Kellgren-Lawrence grade 4 that could be considered severe radiographic changes in at least one compartment,” Dr. Filbay said at the meeting, which is sponsored by the Osteoarthritis Research Society International.
Severe radiographic changes were most common in the tibiofemoral joint, with around 47% having Kellgren-Lawrence (KL) grade 4. About 35% of tibiofemoral joints and about 60% of patellofemoral joints were KL grade 1.
Interestingly, different factors were found to be associated with OA in the tibiofemoral and patellofemoral joints, according to Dr. Filbay. Patients who had been treated non-surgically, whether initially or at any time during the 32-37 year follow-up, were more likely to have tibiofemoral OA, whereas those who had been treated surgically tended to have patellofemoral OA.
“Perhaps not surprisingly, meniscal injury at baseline was related to a higher percentage of tibiofemoral OA at long-term follow-up,” Dr. Filbay said.
Another finding was that patients with weaker hamstrings 3-7 years after the injury were more likely to develop patellofemoral joint OA.
Dr. Filbay had no disclosures.
SOURCE: Filbay S, et al. Osteoarthritis Cartilage 2018:26(1):S52-3. Abstract 80.
LIVERPOOL, ENGLAND – Decades after they were sustained, acute knee injuries caused clinically significant impairments in patient-reported outcomes, as well as upped the risk for knee osteoarthritis (OA) in an observational study.
Results of the study, which followed up individuals 32-37 years after they were treated for a ruptured anterior cruciate ligament (ACL) injury between 1980 and 1985, showed that, compared with the general population, they experienced greater levels of knee pain, participated less in physical activities, and had a reduced quality of life.
The link between OA and ACL injury is not new, with prior estimates suggesting that up to half of all patients with ACL injury develop OA within 10 years of the injury, said Stephanie Filbay, PhD, who presented the results of the study at the World Congress on Osteoarthritis. There have also been reports of knee pain and other symptoms, and poor quality of life more than 5 years later. What’s not been known until now, however, is what happens with even longer term follow-up, said Dr. Filbay, a postdoctoral research fellow in sport, exercise, and osteoarthritis at the University of Oxford, England.
The aims of the study were to compare patient-reported outcomes at 32-37-years’ follow-up against the general population, then to see if the baseline injury or treatment approach, or knee function 3-7 years after the initial injury had any influence on outcomes.
The study included 223 patients who were between aged 15 and 40 years at the time of the acute ACL injury between 1980 and 1985 and who had been seen within 2 weeks of ACL rupture at Linköping University Hospital in Linköping, Sweden. Patients had been allocated to early surgical or non-surgical treatment based on having an odd or even birth year. They had then been assessed 3-7 years later using a variety of tests to determine the strength of their quadriceps and hamstrings and the ability to hop on one leg.
All patients were then invited 32-37 years later after the initial injury to complete questionnaires and undergo clinical examination and X-rays. Only four people declined and 38 did not answer, leaving 181 (81%) people who agreed to participate and complete the Knee injury and Osteoarthritis Outcome Score (KOOS) and the ACL quality of life questionnaire (ACL-QOL).
The average age of participants at follow-up was 59 years (range, 47-74 years); 30% were female. 58% of all patients had been treated non-surgically initially, and 38% remained non-surgically treated at the longterm follow-up. At baseline, 58% had a meniscus injury.
Compared with an age- and sex-matched Swedish population, patients with ACL injuries had a lower KOOS for pain, sport/recreational activities, and quality of life. For example, KOOS for knee pain was around 65-70 for those with prior ACL injuries, compared with 80-90 for those without ACL injuries, where 100 indicates the best outcome or least pain and zero the worst.
KOOS was not affected by whether or not patients had initial ACL surgery or surgery at any point in their follow up. It also did not appear to matter if patients had a meniscal injury at baseline or not.
Quadriceps and hamstring strength at the 3-7 year postinjury assessment did not affect the longterm KOOS, but the ability to hop on one leg did: Those who were not able to hop on one leg for more than 90% of the time on the unaffected limb at the 3-7 years follow-up had worse pain, symptoms, function, and quality of life at the longterm follow-up point.
With regards to OA, “overall, more than one in two individuals had Kellgren-Lawrence grade 4 that could be considered severe radiographic changes in at least one compartment,” Dr. Filbay said at the meeting, which is sponsored by the Osteoarthritis Research Society International.
Severe radiographic changes were most common in the tibiofemoral joint, with around 47% having Kellgren-Lawrence (KL) grade 4. About 35% of tibiofemoral joints and about 60% of patellofemoral joints were KL grade 1.
Interestingly, different factors were found to be associated with OA in the tibiofemoral and patellofemoral joints, according to Dr. Filbay. Patients who had been treated non-surgically, whether initially or at any time during the 32-37 year follow-up, were more likely to have tibiofemoral OA, whereas those who had been treated surgically tended to have patellofemoral OA.
“Perhaps not surprisingly, meniscal injury at baseline was related to a higher percentage of tibiofemoral OA at long-term follow-up,” Dr. Filbay said.
Another finding was that patients with weaker hamstrings 3-7 years after the injury were more likely to develop patellofemoral joint OA.
Dr. Filbay had no disclosures.
SOURCE: Filbay S, et al. Osteoarthritis Cartilage 2018:26(1):S52-3. Abstract 80.
LIVERPOOL, ENGLAND – Decades after they were sustained, acute knee injuries caused clinically significant impairments in patient-reported outcomes, as well as upped the risk for knee osteoarthritis (OA) in an observational study.
Results of the study, which followed up individuals 32-37 years after they were treated for a ruptured anterior cruciate ligament (ACL) injury between 1980 and 1985, showed that, compared with the general population, they experienced greater levels of knee pain, participated less in physical activities, and had a reduced quality of life.
The link between OA and ACL injury is not new, with prior estimates suggesting that up to half of all patients with ACL injury develop OA within 10 years of the injury, said Stephanie Filbay, PhD, who presented the results of the study at the World Congress on Osteoarthritis. There have also been reports of knee pain and other symptoms, and poor quality of life more than 5 years later. What’s not been known until now, however, is what happens with even longer term follow-up, said Dr. Filbay, a postdoctoral research fellow in sport, exercise, and osteoarthritis at the University of Oxford, England.
The aims of the study were to compare patient-reported outcomes at 32-37-years’ follow-up against the general population, then to see if the baseline injury or treatment approach, or knee function 3-7 years after the initial injury had any influence on outcomes.
The study included 223 patients who were between aged 15 and 40 years at the time of the acute ACL injury between 1980 and 1985 and who had been seen within 2 weeks of ACL rupture at Linköping University Hospital in Linköping, Sweden. Patients had been allocated to early surgical or non-surgical treatment based on having an odd or even birth year. They had then been assessed 3-7 years later using a variety of tests to determine the strength of their quadriceps and hamstrings and the ability to hop on one leg.
All patients were then invited 32-37 years later after the initial injury to complete questionnaires and undergo clinical examination and X-rays. Only four people declined and 38 did not answer, leaving 181 (81%) people who agreed to participate and complete the Knee injury and Osteoarthritis Outcome Score (KOOS) and the ACL quality of life questionnaire (ACL-QOL).
The average age of participants at follow-up was 59 years (range, 47-74 years); 30% were female. 58% of all patients had been treated non-surgically initially, and 38% remained non-surgically treated at the longterm follow-up. At baseline, 58% had a meniscus injury.
Compared with an age- and sex-matched Swedish population, patients with ACL injuries had a lower KOOS for pain, sport/recreational activities, and quality of life. For example, KOOS for knee pain was around 65-70 for those with prior ACL injuries, compared with 80-90 for those without ACL injuries, where 100 indicates the best outcome or least pain and zero the worst.
KOOS was not affected by whether or not patients had initial ACL surgery or surgery at any point in their follow up. It also did not appear to matter if patients had a meniscal injury at baseline or not.
Quadriceps and hamstring strength at the 3-7 year postinjury assessment did not affect the longterm KOOS, but the ability to hop on one leg did: Those who were not able to hop on one leg for more than 90% of the time on the unaffected limb at the 3-7 years follow-up had worse pain, symptoms, function, and quality of life at the longterm follow-up point.
With regards to OA, “overall, more than one in two individuals had Kellgren-Lawrence grade 4 that could be considered severe radiographic changes in at least one compartment,” Dr. Filbay said at the meeting, which is sponsored by the Osteoarthritis Research Society International.
Severe radiographic changes were most common in the tibiofemoral joint, with around 47% having Kellgren-Lawrence (KL) grade 4. About 35% of tibiofemoral joints and about 60% of patellofemoral joints were KL grade 1.
Interestingly, different factors were found to be associated with OA in the tibiofemoral and patellofemoral joints, according to Dr. Filbay. Patients who had been treated non-surgically, whether initially or at any time during the 32-37 year follow-up, were more likely to have tibiofemoral OA, whereas those who had been treated surgically tended to have patellofemoral OA.
“Perhaps not surprisingly, meniscal injury at baseline was related to a higher percentage of tibiofemoral OA at long-term follow-up,” Dr. Filbay said.
Another finding was that patients with weaker hamstrings 3-7 years after the injury were more likely to develop patellofemoral joint OA.
Dr. Filbay had no disclosures.
SOURCE: Filbay S, et al. Osteoarthritis Cartilage 2018:26(1):S52-3. Abstract 80.
REPORTING FROM OARSI 2018
Key clinical point: Decades after rupturing the anterior cruciate ligament (ACL), patients can experience significant impairments.
Major finding: 70% of 136 of the patients in the study developed knee osteoarthritis 32-37 years after an ACL injury.Study details: A population-based, observational follow-up study of 181 individuals who had an acute ACL injury in 1980-1985. Disclosures: Stephanie Filbay, PhD., had no disclosures. Source: Filbay S, et al. Osteoarthritis Cartilage 2018:26(1):S52-53. Abstract 80.
Targeting inactivity, mood, and cognition could be key to reducing OA mortality
LIVERPOOL, ENGLAND – Osteoarthritis is associated with an increased risk in mortality, but three factors – inactivity, low mood, and cognitive ability – could be important targets to reduce this risk, according to the results of a study presented at the World Congress on Osteoarthritis.
“There’s recently been increasing interest in whether osteoarthritis (OA) is associated with mortality as the literature has failed to find a consistent link,” said Simran Parmar, a third-year medical student at Keele University, Newcastle-Under-Lyme, U.K.
Three years later, data from another study (BMJ. 2011;342:d1165) suggested an increased risk, with standardized mortality ratios calculated to be 1.55 for all-cause mortality and 1.71 for cardiovascular-specific mortality when comparing those with OA to those without OA in the general population.
However, more recent meta-analyses, performed in 2016, have failed to show a relationship between mortality and OA (Semin Arthritis Rheum. 2016;46[2]:160–7; Sci Rep. 2016;6:24393).
“This could be because of heterogeneity among the studies,” Mr. Parmar reasoned, adding that there was still an unclear relationship between OA and mortality.
So the aim of the current study was not only to take another look at the association to determine its strength but also to see what factors might be mediating the association in order to perhaps explain why OA might be associated with an increased risk of death.
The analysis used data on more than 8,000 individuals participating in the NorStOP (North Staffordshire Osteoarthritis Project). This is a large, population-based, prospective cohort initiated in 2002 that includes adults aged 50 years or older who are registered at any of six general practices.
At baseline, the mean age of participants was 65 years, 51% were female, and just under 30% had OA. During 10 years of follow-up, 1,188 (14.7%) participants died.
Osteoarthritis was significantly associated with mortality in both unadjusted and adjusted analyses.
“For the average person presenting to general practice in North Staffordshire, there’s a 39.4% increased risk of mortality if they have osteoarthritis compared to if they don’t,” Mr. Parmar said.
After adjustment for potential confounding factors, such as age, NSAID use, and common comorbidities, the increased mortality risk remained, with around a 15% increased risk of death for those with OA versus those without.
“We proposed six different mediators of this relationship,” Mr. Parmar said. These were depression, anxiety, low walking frequency, cognitive impairment, insomnia, and obesity. “The reason we chose these is because they can be targets for therapy in primary care.”
Three mediators significantly affected the relationship: low walking frequency, depression, and cognitive impairment; the respective hazard ratios and 95% confidence intervals were 1.12 (1.09-1.15), 1.11 (1.08-1.15), and 1.06 (1.03-1.09).
“This tells us that these could possibly be on the pathway between osteoarthritis and mortality, and this could provide further evidence that they could be used for targeted therapy of osteoarthritis,” Mr. Parmar suggested.
“This type of mediation analysis has not been done in the osteoarthritis field before,” Mr. Parmar observed. He conceded that the mediators found might actually have contributed to the development of OA and that pain interference used in the definition of OA could have been caused by other factors.
Nevertheless, these data suggest that there may be actionable factors that could be used in primary care to reduce mortality in OA.
Mr. Parmar suggested that “encouraging physical activity and considering the impact of comorbidities can help reduce the risk of mortality in adults with osteoarthritis.”
The study was funded by Arthritis Research UK, the North Staffordshire Primary Care Consortium, and the Medical Research Council. Mr. Parmar had no conflicts of interest to disclose.
SOURCE: Parmar S et al. Osteoarthritis Cartilage. 2018;26(1):S14-15.
LIVERPOOL, ENGLAND – Osteoarthritis is associated with an increased risk in mortality, but three factors – inactivity, low mood, and cognitive ability – could be important targets to reduce this risk, according to the results of a study presented at the World Congress on Osteoarthritis.
“There’s recently been increasing interest in whether osteoarthritis (OA) is associated with mortality as the literature has failed to find a consistent link,” said Simran Parmar, a third-year medical student at Keele University, Newcastle-Under-Lyme, U.K.
Three years later, data from another study (BMJ. 2011;342:d1165) suggested an increased risk, with standardized mortality ratios calculated to be 1.55 for all-cause mortality and 1.71 for cardiovascular-specific mortality when comparing those with OA to those without OA in the general population.
However, more recent meta-analyses, performed in 2016, have failed to show a relationship between mortality and OA (Semin Arthritis Rheum. 2016;46[2]:160–7; Sci Rep. 2016;6:24393).
“This could be because of heterogeneity among the studies,” Mr. Parmar reasoned, adding that there was still an unclear relationship between OA and mortality.
So the aim of the current study was not only to take another look at the association to determine its strength but also to see what factors might be mediating the association in order to perhaps explain why OA might be associated with an increased risk of death.
The analysis used data on more than 8,000 individuals participating in the NorStOP (North Staffordshire Osteoarthritis Project). This is a large, population-based, prospective cohort initiated in 2002 that includes adults aged 50 years or older who are registered at any of six general practices.
At baseline, the mean age of participants was 65 years, 51% were female, and just under 30% had OA. During 10 years of follow-up, 1,188 (14.7%) participants died.
Osteoarthritis was significantly associated with mortality in both unadjusted and adjusted analyses.
“For the average person presenting to general practice in North Staffordshire, there’s a 39.4% increased risk of mortality if they have osteoarthritis compared to if they don’t,” Mr. Parmar said.
After adjustment for potential confounding factors, such as age, NSAID use, and common comorbidities, the increased mortality risk remained, with around a 15% increased risk of death for those with OA versus those without.
“We proposed six different mediators of this relationship,” Mr. Parmar said. These were depression, anxiety, low walking frequency, cognitive impairment, insomnia, and obesity. “The reason we chose these is because they can be targets for therapy in primary care.”
Three mediators significantly affected the relationship: low walking frequency, depression, and cognitive impairment; the respective hazard ratios and 95% confidence intervals were 1.12 (1.09-1.15), 1.11 (1.08-1.15), and 1.06 (1.03-1.09).
“This tells us that these could possibly be on the pathway between osteoarthritis and mortality, and this could provide further evidence that they could be used for targeted therapy of osteoarthritis,” Mr. Parmar suggested.
“This type of mediation analysis has not been done in the osteoarthritis field before,” Mr. Parmar observed. He conceded that the mediators found might actually have contributed to the development of OA and that pain interference used in the definition of OA could have been caused by other factors.
Nevertheless, these data suggest that there may be actionable factors that could be used in primary care to reduce mortality in OA.
Mr. Parmar suggested that “encouraging physical activity and considering the impact of comorbidities can help reduce the risk of mortality in adults with osteoarthritis.”
The study was funded by Arthritis Research UK, the North Staffordshire Primary Care Consortium, and the Medical Research Council. Mr. Parmar had no conflicts of interest to disclose.
SOURCE: Parmar S et al. Osteoarthritis Cartilage. 2018;26(1):S14-15.
LIVERPOOL, ENGLAND – Osteoarthritis is associated with an increased risk in mortality, but three factors – inactivity, low mood, and cognitive ability – could be important targets to reduce this risk, according to the results of a study presented at the World Congress on Osteoarthritis.
“There’s recently been increasing interest in whether osteoarthritis (OA) is associated with mortality as the literature has failed to find a consistent link,” said Simran Parmar, a third-year medical student at Keele University, Newcastle-Under-Lyme, U.K.
Three years later, data from another study (BMJ. 2011;342:d1165) suggested an increased risk, with standardized mortality ratios calculated to be 1.55 for all-cause mortality and 1.71 for cardiovascular-specific mortality when comparing those with OA to those without OA in the general population.
However, more recent meta-analyses, performed in 2016, have failed to show a relationship between mortality and OA (Semin Arthritis Rheum. 2016;46[2]:160–7; Sci Rep. 2016;6:24393).
“This could be because of heterogeneity among the studies,” Mr. Parmar reasoned, adding that there was still an unclear relationship between OA and mortality.
So the aim of the current study was not only to take another look at the association to determine its strength but also to see what factors might be mediating the association in order to perhaps explain why OA might be associated with an increased risk of death.
The analysis used data on more than 8,000 individuals participating in the NorStOP (North Staffordshire Osteoarthritis Project). This is a large, population-based, prospective cohort initiated in 2002 that includes adults aged 50 years or older who are registered at any of six general practices.
At baseline, the mean age of participants was 65 years, 51% were female, and just under 30% had OA. During 10 years of follow-up, 1,188 (14.7%) participants died.
Osteoarthritis was significantly associated with mortality in both unadjusted and adjusted analyses.
“For the average person presenting to general practice in North Staffordshire, there’s a 39.4% increased risk of mortality if they have osteoarthritis compared to if they don’t,” Mr. Parmar said.
After adjustment for potential confounding factors, such as age, NSAID use, and common comorbidities, the increased mortality risk remained, with around a 15% increased risk of death for those with OA versus those without.
“We proposed six different mediators of this relationship,” Mr. Parmar said. These were depression, anxiety, low walking frequency, cognitive impairment, insomnia, and obesity. “The reason we chose these is because they can be targets for therapy in primary care.”
Three mediators significantly affected the relationship: low walking frequency, depression, and cognitive impairment; the respective hazard ratios and 95% confidence intervals were 1.12 (1.09-1.15), 1.11 (1.08-1.15), and 1.06 (1.03-1.09).
“This tells us that these could possibly be on the pathway between osteoarthritis and mortality, and this could provide further evidence that they could be used for targeted therapy of osteoarthritis,” Mr. Parmar suggested.
“This type of mediation analysis has not been done in the osteoarthritis field before,” Mr. Parmar observed. He conceded that the mediators found might actually have contributed to the development of OA and that pain interference used in the definition of OA could have been caused by other factors.
Nevertheless, these data suggest that there may be actionable factors that could be used in primary care to reduce mortality in OA.
Mr. Parmar suggested that “encouraging physical activity and considering the impact of comorbidities can help reduce the risk of mortality in adults with osteoarthritis.”
The study was funded by Arthritis Research UK, the North Staffordshire Primary Care Consortium, and the Medical Research Council. Mr. Parmar had no conflicts of interest to disclose.
SOURCE: Parmar S et al. Osteoarthritis Cartilage. 2018;26(1):S14-15.
REPORTING FROM OARSI 2018
Key clinical point:
Major finding: OA is associated with a 15% increased risk of mortality in the general population.
Study details: A large, prospective cohort study that included more than 8,000 adults older than 50 years in the general population who participated.
Disclosures: The study was funded by Arthritis Research UK, the North Staffordshire Primary Care Consortium, and the Medical Research Council. Mr. Parmar had no conflicts of interest to disclose.
Source: Parmar S et al. Osteoarthritis Cartilage. 2018;26(1):S14-15.
Siponimod trial ‘first’ to show delayed disability in secondary progressive MS
Phase 3 data with siponimod, Novartis’ investigational treatment for multiple sclerosis, show a 21% reduction in the time to disease progression versus placebo in patients with the secondary progressive subtype of the disease.
A significantly lower percentage of patients with secondary progressive multiple sclerosis (SPMS) treated with siponimod met the primary endpoint of confirmed disease progression (CDP) at 3 months, compared with those who received placebo in the EXPAND trial (26% vs. 32% of patients; hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.65–0.95; P = .013).
No significant difference between siponimod and placebo was seen in one of the two main secondary outcomes of the study – the time to 3-month confirmed worsening of the timed 25-foot walk test (T25FW). This result led Luanne Metz, MD, and Wei-Qiao Liu, MD, both of the department of clinical neurosciences and the Hotchkiss Brain Institute at the University of Calgary (Alta.), to take a cautionary view of the findings in an editorial about the trial’s results.
“Although siponimod seems to reduce the time to confirmed disability in SPMS, the treatment effect was small,” Dr. Metz and Dr. Liu argued.
“In our opinion, the reduction in the proportion of participants reaching the primary endpoint of only 6% and the absence of a significant difference for the key secondary clinical outcome [T25FW] are disappointing results and do not suggest that siponimod is an effective treatment for SPMS,” the two wrote.
“Confidence in the treatment benefit of siponimod in progressive MS will, in our opinion, require confirmation in a second trial. Trials of other novel treatments that target noninflammatory mechanisms are still needed,” they said.
EXPAND (Exploring the efficacy and safety of siponimod in patients with secondary progressive multiple sclerosis) was an event- and exposure-driven double-blind trial that recruited patients with SPMS over a 2-year period starting in February 2013. Of 1,651 patients who were recruited, randomized, and actually received treatment, 1,099 were treated with oral siponimod, 2 mg once daily, and 546 were given a matching placebo.
Treatment was for up to 3 years or until 374 CDP events assessed via the Expanded Disability Status Scale (EDSS) had occurred. Patients who had CDP after 6 months in the double-blind trial could be re-consented and continue with double-blind treatment, switch to open-label siponimod, or stop study treatment and either remain on no treatment or receive another disease-modifying treatment.
On average, the patients had been diagnosed with SPMS for a mean of 3.8 years and had been first diagnosed with MS around 17 years prior to this.
The primary endpoint of the trial – CDP at 3 months – was first reported in 2016 at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). CDP was defined as a 0.5- to 1-point increase in EDSS depending on the baseline score.
A host of additional secondary endpoints were studied, with the risk of 6-month CDP being significantly reduced by siponimod versus placebo (HR, 0.74; 95% CI, 0.60-0.92; P = .0058).
The change from baseline in T2 lesion volume – the second of the two main secondary endpoints studied – showed a potential benefit of siponimod treatment over placebo, with a lower mean-adjusted increase in lesion volume over months 12 and 24 (183.9 mm3 vs. 879.2 mm3; P less than .0001).
More patients receiving siponimod than placebo were free from new or enlarging T2 lesions (57% vs. 37%) or T1 gadolinium-enhancing lesions (89% vs. 67%), and brain volume decreased at a lower rate with siponimod than with placebo.
Adverse events occurred at a higher rate with siponimod than with placebo (89% of patients vs. 82%), of which 18% and 15%, respectively, were defined as serious.
Adverse events seen more commonly in siponimod- than in placebo-treated patients were lymphopenia (1% vs. 0%), abnormal liver-related investigations (12% vs. 4%), hypertension (10% vs. 8%), and bradycardia (4% vs. 3%) and bradyarrhythmia (3% vs. 0.4%) at the start of treatment, which were mitigated by dose titration. Other adverse events that occurred less often but more frequently with siponimod included macular edema (2% vs. less than 1%), reactivation of varicella zoster (2% vs. 1%), and convulsions (2% vs. less than 1%).
“The safety profile of siponimod in EXPAND was generally aligned with that of other drugs in the class,” Dr. Kappos and his colleagues observed.
Siponimod, also known as BAF312, is a selective sphingosine 1-phosphate (S1P) receptor modulator that targets the targets the S1P 1 and 5 receptor subtypes; the other currently approved drug in its class is fingolimod (Gilenya), which is currently indicated for treating the relapsing-remitting form of multiple sclerosis (RRMS).
Phase 2 data have shown that siponimod could also be a promising treatment for RRMS, with reduced relapse rates and fewer brain lesions seen versus placebo (JAMA Neurol. 2016;73[9]:1089-98).
The EXPAND study was funded by Novartis. The lead author Dr. Kappos has received research and educational support funding via his institution from Novartis and multiple other pharmaceutical companies. Editorial author Dr. Metz has received grants from Roche and Biogen and personal fees from EMD Serono. The other editorial author, Dr. Liu, reported receiving personal fees from Novartis and personal fees and grants from EMD Serono. Dr. Liu was a back-up treating neurologist in the EXPAND trial.
SOURCE: Kappos L et al. Lancet. 2018 Mar 22. doi: 10.1016/S0140-6736(18)30475-6, and Metz L and Liu W. Lancet. 2018 Mar 22. doi: 10.1016/S0140-6736(18)30426-4.
Phase 3 data with siponimod, Novartis’ investigational treatment for multiple sclerosis, show a 21% reduction in the time to disease progression versus placebo in patients with the secondary progressive subtype of the disease.
A significantly lower percentage of patients with secondary progressive multiple sclerosis (SPMS) treated with siponimod met the primary endpoint of confirmed disease progression (CDP) at 3 months, compared with those who received placebo in the EXPAND trial (26% vs. 32% of patients; hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.65–0.95; P = .013).
No significant difference between siponimod and placebo was seen in one of the two main secondary outcomes of the study – the time to 3-month confirmed worsening of the timed 25-foot walk test (T25FW). This result led Luanne Metz, MD, and Wei-Qiao Liu, MD, both of the department of clinical neurosciences and the Hotchkiss Brain Institute at the University of Calgary (Alta.), to take a cautionary view of the findings in an editorial about the trial’s results.
“Although siponimod seems to reduce the time to confirmed disability in SPMS, the treatment effect was small,” Dr. Metz and Dr. Liu argued.
“In our opinion, the reduction in the proportion of participants reaching the primary endpoint of only 6% and the absence of a significant difference for the key secondary clinical outcome [T25FW] are disappointing results and do not suggest that siponimod is an effective treatment for SPMS,” the two wrote.
“Confidence in the treatment benefit of siponimod in progressive MS will, in our opinion, require confirmation in a second trial. Trials of other novel treatments that target noninflammatory mechanisms are still needed,” they said.
EXPAND (Exploring the efficacy and safety of siponimod in patients with secondary progressive multiple sclerosis) was an event- and exposure-driven double-blind trial that recruited patients with SPMS over a 2-year period starting in February 2013. Of 1,651 patients who were recruited, randomized, and actually received treatment, 1,099 were treated with oral siponimod, 2 mg once daily, and 546 were given a matching placebo.
Treatment was for up to 3 years or until 374 CDP events assessed via the Expanded Disability Status Scale (EDSS) had occurred. Patients who had CDP after 6 months in the double-blind trial could be re-consented and continue with double-blind treatment, switch to open-label siponimod, or stop study treatment and either remain on no treatment or receive another disease-modifying treatment.
On average, the patients had been diagnosed with SPMS for a mean of 3.8 years and had been first diagnosed with MS around 17 years prior to this.
The primary endpoint of the trial – CDP at 3 months – was first reported in 2016 at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). CDP was defined as a 0.5- to 1-point increase in EDSS depending on the baseline score.
A host of additional secondary endpoints were studied, with the risk of 6-month CDP being significantly reduced by siponimod versus placebo (HR, 0.74; 95% CI, 0.60-0.92; P = .0058).
The change from baseline in T2 lesion volume – the second of the two main secondary endpoints studied – showed a potential benefit of siponimod treatment over placebo, with a lower mean-adjusted increase in lesion volume over months 12 and 24 (183.9 mm3 vs. 879.2 mm3; P less than .0001).
More patients receiving siponimod than placebo were free from new or enlarging T2 lesions (57% vs. 37%) or T1 gadolinium-enhancing lesions (89% vs. 67%), and brain volume decreased at a lower rate with siponimod than with placebo.
Adverse events occurred at a higher rate with siponimod than with placebo (89% of patients vs. 82%), of which 18% and 15%, respectively, were defined as serious.
Adverse events seen more commonly in siponimod- than in placebo-treated patients were lymphopenia (1% vs. 0%), abnormal liver-related investigations (12% vs. 4%), hypertension (10% vs. 8%), and bradycardia (4% vs. 3%) and bradyarrhythmia (3% vs. 0.4%) at the start of treatment, which were mitigated by dose titration. Other adverse events that occurred less often but more frequently with siponimod included macular edema (2% vs. less than 1%), reactivation of varicella zoster (2% vs. 1%), and convulsions (2% vs. less than 1%).
“The safety profile of siponimod in EXPAND was generally aligned with that of other drugs in the class,” Dr. Kappos and his colleagues observed.
Siponimod, also known as BAF312, is a selective sphingosine 1-phosphate (S1P) receptor modulator that targets the targets the S1P 1 and 5 receptor subtypes; the other currently approved drug in its class is fingolimod (Gilenya), which is currently indicated for treating the relapsing-remitting form of multiple sclerosis (RRMS).
Phase 2 data have shown that siponimod could also be a promising treatment for RRMS, with reduced relapse rates and fewer brain lesions seen versus placebo (JAMA Neurol. 2016;73[9]:1089-98).
The EXPAND study was funded by Novartis. The lead author Dr. Kappos has received research and educational support funding via his institution from Novartis and multiple other pharmaceutical companies. Editorial author Dr. Metz has received grants from Roche and Biogen and personal fees from EMD Serono. The other editorial author, Dr. Liu, reported receiving personal fees from Novartis and personal fees and grants from EMD Serono. Dr. Liu was a back-up treating neurologist in the EXPAND trial.
SOURCE: Kappos L et al. Lancet. 2018 Mar 22. doi: 10.1016/S0140-6736(18)30475-6, and Metz L and Liu W. Lancet. 2018 Mar 22. doi: 10.1016/S0140-6736(18)30426-4.
Phase 3 data with siponimod, Novartis’ investigational treatment for multiple sclerosis, show a 21% reduction in the time to disease progression versus placebo in patients with the secondary progressive subtype of the disease.
A significantly lower percentage of patients with secondary progressive multiple sclerosis (SPMS) treated with siponimod met the primary endpoint of confirmed disease progression (CDP) at 3 months, compared with those who received placebo in the EXPAND trial (26% vs. 32% of patients; hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.65–0.95; P = .013).
No significant difference between siponimod and placebo was seen in one of the two main secondary outcomes of the study – the time to 3-month confirmed worsening of the timed 25-foot walk test (T25FW). This result led Luanne Metz, MD, and Wei-Qiao Liu, MD, both of the department of clinical neurosciences and the Hotchkiss Brain Institute at the University of Calgary (Alta.), to take a cautionary view of the findings in an editorial about the trial’s results.
“Although siponimod seems to reduce the time to confirmed disability in SPMS, the treatment effect was small,” Dr. Metz and Dr. Liu argued.
“In our opinion, the reduction in the proportion of participants reaching the primary endpoint of only 6% and the absence of a significant difference for the key secondary clinical outcome [T25FW] are disappointing results and do not suggest that siponimod is an effective treatment for SPMS,” the two wrote.
“Confidence in the treatment benefit of siponimod in progressive MS will, in our opinion, require confirmation in a second trial. Trials of other novel treatments that target noninflammatory mechanisms are still needed,” they said.
EXPAND (Exploring the efficacy and safety of siponimod in patients with secondary progressive multiple sclerosis) was an event- and exposure-driven double-blind trial that recruited patients with SPMS over a 2-year period starting in February 2013. Of 1,651 patients who were recruited, randomized, and actually received treatment, 1,099 were treated with oral siponimod, 2 mg once daily, and 546 were given a matching placebo.
Treatment was for up to 3 years or until 374 CDP events assessed via the Expanded Disability Status Scale (EDSS) had occurred. Patients who had CDP after 6 months in the double-blind trial could be re-consented and continue with double-blind treatment, switch to open-label siponimod, or stop study treatment and either remain on no treatment or receive another disease-modifying treatment.
On average, the patients had been diagnosed with SPMS for a mean of 3.8 years and had been first diagnosed with MS around 17 years prior to this.
The primary endpoint of the trial – CDP at 3 months – was first reported in 2016 at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). CDP was defined as a 0.5- to 1-point increase in EDSS depending on the baseline score.
A host of additional secondary endpoints were studied, with the risk of 6-month CDP being significantly reduced by siponimod versus placebo (HR, 0.74; 95% CI, 0.60-0.92; P = .0058).
The change from baseline in T2 lesion volume – the second of the two main secondary endpoints studied – showed a potential benefit of siponimod treatment over placebo, with a lower mean-adjusted increase in lesion volume over months 12 and 24 (183.9 mm3 vs. 879.2 mm3; P less than .0001).
More patients receiving siponimod than placebo were free from new or enlarging T2 lesions (57% vs. 37%) or T1 gadolinium-enhancing lesions (89% vs. 67%), and brain volume decreased at a lower rate with siponimod than with placebo.
Adverse events occurred at a higher rate with siponimod than with placebo (89% of patients vs. 82%), of which 18% and 15%, respectively, were defined as serious.
Adverse events seen more commonly in siponimod- than in placebo-treated patients were lymphopenia (1% vs. 0%), abnormal liver-related investigations (12% vs. 4%), hypertension (10% vs. 8%), and bradycardia (4% vs. 3%) and bradyarrhythmia (3% vs. 0.4%) at the start of treatment, which were mitigated by dose titration. Other adverse events that occurred less often but more frequently with siponimod included macular edema (2% vs. less than 1%), reactivation of varicella zoster (2% vs. 1%), and convulsions (2% vs. less than 1%).
“The safety profile of siponimod in EXPAND was generally aligned with that of other drugs in the class,” Dr. Kappos and his colleagues observed.
Siponimod, also known as BAF312, is a selective sphingosine 1-phosphate (S1P) receptor modulator that targets the targets the S1P 1 and 5 receptor subtypes; the other currently approved drug in its class is fingolimod (Gilenya), which is currently indicated for treating the relapsing-remitting form of multiple sclerosis (RRMS).
Phase 2 data have shown that siponimod could also be a promising treatment for RRMS, with reduced relapse rates and fewer brain lesions seen versus placebo (JAMA Neurol. 2016;73[9]:1089-98).
The EXPAND study was funded by Novartis. The lead author Dr. Kappos has received research and educational support funding via his institution from Novartis and multiple other pharmaceutical companies. Editorial author Dr. Metz has received grants from Roche and Biogen and personal fees from EMD Serono. The other editorial author, Dr. Liu, reported receiving personal fees from Novartis and personal fees and grants from EMD Serono. Dr. Liu was a back-up treating neurologist in the EXPAND trial.
SOURCE: Kappos L et al. Lancet. 2018 Mar 22. doi: 10.1016/S0140-6736(18)30475-6, and Metz L and Liu W. Lancet. 2018 Mar 22. doi: 10.1016/S0140-6736(18)30426-4.
FROM THE LANCET
Key clinical point:
Major finding: A significantly lower percentage of patients had confirmed disease progression at 3 months if treated with siponimod (26% vs. 32% with placebo; hazard ratio, 0.79; 95% confidence interval, 0.65–0.95; P = .013).
Study details: A double-blind, randomized, multicenter, placebo-controlled, phase 3 study of siponimod involving 1,651 patients with SPMS.
Disclosures: The EXPAND study was funded by Novartis. The lead author Dr. Kappos has received research and educational support funding via his institution from Novartis and multiple other pharmaceutical companies. Editorial author Dr. Metz has received grants from Roche and Biogen and personal fees from EMD Serono. The other editorial author, Dr. Liu, reported receiving personal fees from Novartis and personal fees and grants from EMD Serono. Dr. Liu was a back-up treating neurologist in the EXPAND trial.
Source: Kappos L et al. Lancet. 2018 Mar 22. doi: 10.1016/S0140-6736(18)30475-6, and Metz L and Liu W. Lancet. 2018 Mar 22. doi: 10.1016/S0140-6736(18)30426-4.
Accelerated breast irradiation advocated by ASTRO guideline
Hypofractionation is the preferred means of giving whole breast irradiation to women with invasive breast cancer, according to updated guidance from the American Society for Radiation Oncology.
A dose of 4,000 cGy given in 15 fractions or 4,250 cGy in 16 fractions is recommended, with or without inclusion of the low axilla, and regardless of a variety of factors such as tumor grade, prior chemotherapy, and patient age.
“Previously, accelerated treatment was recommended only for certain patients, including older patients and those with less advanced disease,” Benjamin Smith, MD, one of the cochairs of the guideline task force, said in an ASTRO news release.
Dr. Smith, of the University of Texas MD Anderson Cancer Center, Houston, added that recent long-term data from several large trials “strongly support the safety and efficacy of accelerated treatment for most breast cancer patients.”
Treatment decisions and plans still need to be individualized, but the updated ASTRO guidance notes that whole breast irradiation (WBI) can be offered to most women with invasive breast cancer independent of breast size and whether or not the cancer is in the left or right breast, provided that homogeneous dosing can be achieved. Hormone receptor, HER2 status, and postsurgical margin status also appear not to matter.
Historically, conventional fractionation (CF) with or without a tumor bed boost was used for WBI, Dr. Smith and associates wrote in the guidelines, which were published online in Practical Radiation Oncology. This consisted of daily doses of 180-200 cGy for a total dose of 4,500-5,000 cGy.
“Recognizing the limitations of CF for convenience and cost, randomized trials in the 1990s and 2000s investigated if moderate hypofractionation [HF], defined as daily doses of 265-330 cGy, could yield oncologic and functional/cosmetic outcomes similar to CF-WBI,” they said.
Initial results of these trials “supported the safety and effectiveness of HF-WBI” and were then used to form ASTRO’s 2011 guideline on dose fractionation for WBI. With longer term data from these trials now available, it was time to review the evidence again. A systematic literature review was thus conducted to identify all relevant studies published during 2009-2016, and 100 articles met the task force criteria and were used to create the updated guideline.
Aside from the delivery and dosing of WBI, other key recommendations look at the use of a radiation boost to the tumor bed, and preferred techniques for treatment planning.
With regards to a radiation boost, this needs to be considered on an individual basis but can be independent of any previous WBI. A radiation boost is recommended if patients have any grade invasive cancer and are aged 50 years or younger, have a high-grade tumor and are aged 51-70 years, or if there is a positive margin following surgery. A radiation boost also is recommended in women with ductal carcinoma in situ if they are aged 50 years or younger, have a high-grade tumor, and positive or close postsurgical margins.
As for treatment planning, 3-dimensional conformal treatment planning with a “field-in-field” technique is recommended as the initial approach. This is to minimize the volume of breast tissue that receives more than 105% of the radiation dose. The guideline also covers optimal patient positioning and how to avoid nearby tissues and organs, such as the heart, lungs and contralateral breast.
ASTRO hopes that the updated guideline will increase the use of hypofractionation, which has been reportedly low in recent years, with as few as 35% of eligible patients received hypofractionation in one study (JAMA. 2014;312[23]:2542-50).
“We hope that this guideline encourages providers to counsel their patients on options including hypofractionation,” said Reshma Jagsi, MD, DPhil, professor of radiation oncology at the University of Michigan, Ann Arbor, who cochaired the guideline task force with Dr. Smith.
“Hypofractionated radiation therapy offers patients a more convenient and lower cost option for their treatment without compromising the likelihood that their cancer will return or increasing their risk of side effects,” Dr. Jagsi noted. Furthermore, “a shorter course of radiation equates to more time with family, less time away from work and lower treatment costs.”
SOURCE: Smith BD et al. Pract Radiat Oncol. 2018 March 12. doi: 10.1016/j.prro.2018.01.012.
Hypofractionation is the preferred means of giving whole breast irradiation to women with invasive breast cancer, according to updated guidance from the American Society for Radiation Oncology.
A dose of 4,000 cGy given in 15 fractions or 4,250 cGy in 16 fractions is recommended, with or without inclusion of the low axilla, and regardless of a variety of factors such as tumor grade, prior chemotherapy, and patient age.
“Previously, accelerated treatment was recommended only for certain patients, including older patients and those with less advanced disease,” Benjamin Smith, MD, one of the cochairs of the guideline task force, said in an ASTRO news release.
Dr. Smith, of the University of Texas MD Anderson Cancer Center, Houston, added that recent long-term data from several large trials “strongly support the safety and efficacy of accelerated treatment for most breast cancer patients.”
Treatment decisions and plans still need to be individualized, but the updated ASTRO guidance notes that whole breast irradiation (WBI) can be offered to most women with invasive breast cancer independent of breast size and whether or not the cancer is in the left or right breast, provided that homogeneous dosing can be achieved. Hormone receptor, HER2 status, and postsurgical margin status also appear not to matter.
Historically, conventional fractionation (CF) with or without a tumor bed boost was used for WBI, Dr. Smith and associates wrote in the guidelines, which were published online in Practical Radiation Oncology. This consisted of daily doses of 180-200 cGy for a total dose of 4,500-5,000 cGy.
“Recognizing the limitations of CF for convenience and cost, randomized trials in the 1990s and 2000s investigated if moderate hypofractionation [HF], defined as daily doses of 265-330 cGy, could yield oncologic and functional/cosmetic outcomes similar to CF-WBI,” they said.
Initial results of these trials “supported the safety and effectiveness of HF-WBI” and were then used to form ASTRO’s 2011 guideline on dose fractionation for WBI. With longer term data from these trials now available, it was time to review the evidence again. A systematic literature review was thus conducted to identify all relevant studies published during 2009-2016, and 100 articles met the task force criteria and were used to create the updated guideline.
Aside from the delivery and dosing of WBI, other key recommendations look at the use of a radiation boost to the tumor bed, and preferred techniques for treatment planning.
With regards to a radiation boost, this needs to be considered on an individual basis but can be independent of any previous WBI. A radiation boost is recommended if patients have any grade invasive cancer and are aged 50 years or younger, have a high-grade tumor and are aged 51-70 years, or if there is a positive margin following surgery. A radiation boost also is recommended in women with ductal carcinoma in situ if they are aged 50 years or younger, have a high-grade tumor, and positive or close postsurgical margins.
As for treatment planning, 3-dimensional conformal treatment planning with a “field-in-field” technique is recommended as the initial approach. This is to minimize the volume of breast tissue that receives more than 105% of the radiation dose. The guideline also covers optimal patient positioning and how to avoid nearby tissues and organs, such as the heart, lungs and contralateral breast.
ASTRO hopes that the updated guideline will increase the use of hypofractionation, which has been reportedly low in recent years, with as few as 35% of eligible patients received hypofractionation in one study (JAMA. 2014;312[23]:2542-50).
“We hope that this guideline encourages providers to counsel their patients on options including hypofractionation,” said Reshma Jagsi, MD, DPhil, professor of radiation oncology at the University of Michigan, Ann Arbor, who cochaired the guideline task force with Dr. Smith.
“Hypofractionated radiation therapy offers patients a more convenient and lower cost option for their treatment without compromising the likelihood that their cancer will return or increasing their risk of side effects,” Dr. Jagsi noted. Furthermore, “a shorter course of radiation equates to more time with family, less time away from work and lower treatment costs.”
SOURCE: Smith BD et al. Pract Radiat Oncol. 2018 March 12. doi: 10.1016/j.prro.2018.01.012.
Hypofractionation is the preferred means of giving whole breast irradiation to women with invasive breast cancer, according to updated guidance from the American Society for Radiation Oncology.
A dose of 4,000 cGy given in 15 fractions or 4,250 cGy in 16 fractions is recommended, with or without inclusion of the low axilla, and regardless of a variety of factors such as tumor grade, prior chemotherapy, and patient age.
“Previously, accelerated treatment was recommended only for certain patients, including older patients and those with less advanced disease,” Benjamin Smith, MD, one of the cochairs of the guideline task force, said in an ASTRO news release.
Dr. Smith, of the University of Texas MD Anderson Cancer Center, Houston, added that recent long-term data from several large trials “strongly support the safety and efficacy of accelerated treatment for most breast cancer patients.”
Treatment decisions and plans still need to be individualized, but the updated ASTRO guidance notes that whole breast irradiation (WBI) can be offered to most women with invasive breast cancer independent of breast size and whether or not the cancer is in the left or right breast, provided that homogeneous dosing can be achieved. Hormone receptor, HER2 status, and postsurgical margin status also appear not to matter.
Historically, conventional fractionation (CF) with or without a tumor bed boost was used for WBI, Dr. Smith and associates wrote in the guidelines, which were published online in Practical Radiation Oncology. This consisted of daily doses of 180-200 cGy for a total dose of 4,500-5,000 cGy.
“Recognizing the limitations of CF for convenience and cost, randomized trials in the 1990s and 2000s investigated if moderate hypofractionation [HF], defined as daily doses of 265-330 cGy, could yield oncologic and functional/cosmetic outcomes similar to CF-WBI,” they said.
Initial results of these trials “supported the safety and effectiveness of HF-WBI” and were then used to form ASTRO’s 2011 guideline on dose fractionation for WBI. With longer term data from these trials now available, it was time to review the evidence again. A systematic literature review was thus conducted to identify all relevant studies published during 2009-2016, and 100 articles met the task force criteria and were used to create the updated guideline.
Aside from the delivery and dosing of WBI, other key recommendations look at the use of a radiation boost to the tumor bed, and preferred techniques for treatment planning.
With regards to a radiation boost, this needs to be considered on an individual basis but can be independent of any previous WBI. A radiation boost is recommended if patients have any grade invasive cancer and are aged 50 years or younger, have a high-grade tumor and are aged 51-70 years, or if there is a positive margin following surgery. A radiation boost also is recommended in women with ductal carcinoma in situ if they are aged 50 years or younger, have a high-grade tumor, and positive or close postsurgical margins.
As for treatment planning, 3-dimensional conformal treatment planning with a “field-in-field” technique is recommended as the initial approach. This is to minimize the volume of breast tissue that receives more than 105% of the radiation dose. The guideline also covers optimal patient positioning and how to avoid nearby tissues and organs, such as the heart, lungs and contralateral breast.
ASTRO hopes that the updated guideline will increase the use of hypofractionation, which has been reportedly low in recent years, with as few as 35% of eligible patients received hypofractionation in one study (JAMA. 2014;312[23]:2542-50).
“We hope that this guideline encourages providers to counsel their patients on options including hypofractionation,” said Reshma Jagsi, MD, DPhil, professor of radiation oncology at the University of Michigan, Ann Arbor, who cochaired the guideline task force with Dr. Smith.
“Hypofractionated radiation therapy offers patients a more convenient and lower cost option for their treatment without compromising the likelihood that their cancer will return or increasing their risk of side effects,” Dr. Jagsi noted. Furthermore, “a shorter course of radiation equates to more time with family, less time away from work and lower treatment costs.”
SOURCE: Smith BD et al. Pract Radiat Oncol. 2018 March 12. doi: 10.1016/j.prro.2018.01.012.
FROM PRACTICAL RADIATION ONCOLOGY
Key clinical point: For invasive cancer, the preferred scheme is hypofractionated whole breast irradiation (HF-WBI).
Major finding: HF-WBI should be given to a total dose of 4,000 cGy in 15 fractions or 4,250 cGy in 16 fractions.
Study details: A systematic literature review of all relevant studies published during 2009-2016.
Disclosures: The guidelines were sponsored by the American Society for Radiation Oncology.
Source: Smith BD et al. Pract Radiat Oncol. 2018 March 12. doi: 10.1016/j.prro.2018.01.012.
Real-world data support extended cervical cancer screening interval
A cervical cancer screening interval of 5 years or longer may be safe for women with one or more negative cotests using the high-risk human papillomavirus (HPV) test and cervical cytology, according to the results of a large observational study.
The findings also suggest that one or two negative HPV tests, regardless of cytology, may be enough to extend the screening interval, the researchers noted.
The 5-year risk decreased with each successive HPV-negative and cytology-negative result, falling from 0.098% in the first cotesting round, to 0.052% in the second round, and 0.035% in the third round. The 5-year risks were similar with an HPV-negative cotest result, regardless of the outcome of cytology: 0.114%, 0.061%, and 0.041%.
The results are based on data from more than 990,000 women in the Kaiser Permanente Northern California health care system who had one or more cotests from 2003 to 2014.
These findings come as the U.S. Preventive Services Task Force (USPSTF) has issued draft recommendations that would call for either HPV testing alone every 5 years starting at age 30 years or cytology every 3 years, but no cotesting. The American College of Obstetricians and Gynecologists currently recommends cotesting with cytology and HPV testing every 5 years or cytology alone every 3 years in women aged 30-65 years (Obstet Gynecol. 2016;128[4]:e111-30).
The study was partially funded by the National Cancer Institute. Some of the researchers are employees of the National Cancer Institute. The researchers reported receiving cervical screening tests and diagnostics at reduced or no cost from Roche, BD Biosciences, Cepheid, Arbor Vita, and Hologic.
The study by Castle et al provides important insight into the effects of repeated testing of HPV, cervical cytology, and testing both together. The authors are to be commended for performing their analysis, which involved almost 1 million women.
There are several important observations that can be made. One is that the risk of detecting cancer is decreased after cotesting HPV and cervical cytology both show a negative result, and that this risk is further reduced after the second and third negative HPV/cytology test. This could mean less frequent screening could be safely adopted in women who are HPV and cytology negative, which would lead to fewer women referred for unnecessary colposcopy and treatment, reducing their stress and discomfort.
These data could alter how women are triaged on the basis of the HPV test. In HPV-positive women, for example, current practices are appropriate for the first and perhaps second round of HPV testing, but perhaps subsequent rounds could become less stringent. Conversely, when there is an HPV-negative result, even in the presence of a positive or equivocal cytology, screening intervals may still be safe to lengthen as there is only a small increase in risk versus being both HPV and cytology negative.
Guglielmo Ronco, MD, PhD, is formerly of the City of Health and Science University Hospital of Turin (Italy). Silvia Franceschi, MD, PhD, is with the International Agency for Research on Cancer in Lyon, France. They reported having no relevant financial disclosures. Their comments were adapted from an accompanying editorial (Ann Intern Med. 2017. doi: 10.7326/M17-2872).
The study by Castle et al provides important insight into the effects of repeated testing of HPV, cervical cytology, and testing both together. The authors are to be commended for performing their analysis, which involved almost 1 million women.
There are several important observations that can be made. One is that the risk of detecting cancer is decreased after cotesting HPV and cervical cytology both show a negative result, and that this risk is further reduced after the second and third negative HPV/cytology test. This could mean less frequent screening could be safely adopted in women who are HPV and cytology negative, which would lead to fewer women referred for unnecessary colposcopy and treatment, reducing their stress and discomfort.
These data could alter how women are triaged on the basis of the HPV test. In HPV-positive women, for example, current practices are appropriate for the first and perhaps second round of HPV testing, but perhaps subsequent rounds could become less stringent. Conversely, when there is an HPV-negative result, even in the presence of a positive or equivocal cytology, screening intervals may still be safe to lengthen as there is only a small increase in risk versus being both HPV and cytology negative.
Guglielmo Ronco, MD, PhD, is formerly of the City of Health and Science University Hospital of Turin (Italy). Silvia Franceschi, MD, PhD, is with the International Agency for Research on Cancer in Lyon, France. They reported having no relevant financial disclosures. Their comments were adapted from an accompanying editorial (Ann Intern Med. 2017. doi: 10.7326/M17-2872).
The study by Castle et al provides important insight into the effects of repeated testing of HPV, cervical cytology, and testing both together. The authors are to be commended for performing their analysis, which involved almost 1 million women.
There are several important observations that can be made. One is that the risk of detecting cancer is decreased after cotesting HPV and cervical cytology both show a negative result, and that this risk is further reduced after the second and third negative HPV/cytology test. This could mean less frequent screening could be safely adopted in women who are HPV and cytology negative, which would lead to fewer women referred for unnecessary colposcopy and treatment, reducing their stress and discomfort.
These data could alter how women are triaged on the basis of the HPV test. In HPV-positive women, for example, current practices are appropriate for the first and perhaps second round of HPV testing, but perhaps subsequent rounds could become less stringent. Conversely, when there is an HPV-negative result, even in the presence of a positive or equivocal cytology, screening intervals may still be safe to lengthen as there is only a small increase in risk versus being both HPV and cytology negative.
Guglielmo Ronco, MD, PhD, is formerly of the City of Health and Science University Hospital of Turin (Italy). Silvia Franceschi, MD, PhD, is with the International Agency for Research on Cancer in Lyon, France. They reported having no relevant financial disclosures. Their comments were adapted from an accompanying editorial (Ann Intern Med. 2017. doi: 10.7326/M17-2872).
A cervical cancer screening interval of 5 years or longer may be safe for women with one or more negative cotests using the high-risk human papillomavirus (HPV) test and cervical cytology, according to the results of a large observational study.
The findings also suggest that one or two negative HPV tests, regardless of cytology, may be enough to extend the screening interval, the researchers noted.
The 5-year risk decreased with each successive HPV-negative and cytology-negative result, falling from 0.098% in the first cotesting round, to 0.052% in the second round, and 0.035% in the third round. The 5-year risks were similar with an HPV-negative cotest result, regardless of the outcome of cytology: 0.114%, 0.061%, and 0.041%.
The results are based on data from more than 990,000 women in the Kaiser Permanente Northern California health care system who had one or more cotests from 2003 to 2014.
These findings come as the U.S. Preventive Services Task Force (USPSTF) has issued draft recommendations that would call for either HPV testing alone every 5 years starting at age 30 years or cytology every 3 years, but no cotesting. The American College of Obstetricians and Gynecologists currently recommends cotesting with cytology and HPV testing every 5 years or cytology alone every 3 years in women aged 30-65 years (Obstet Gynecol. 2016;128[4]:e111-30).
The study was partially funded by the National Cancer Institute. Some of the researchers are employees of the National Cancer Institute. The researchers reported receiving cervical screening tests and diagnostics at reduced or no cost from Roche, BD Biosciences, Cepheid, Arbor Vita, and Hologic.
A cervical cancer screening interval of 5 years or longer may be safe for women with one or more negative cotests using the high-risk human papillomavirus (HPV) test and cervical cytology, according to the results of a large observational study.
The findings also suggest that one or two negative HPV tests, regardless of cytology, may be enough to extend the screening interval, the researchers noted.
The 5-year risk decreased with each successive HPV-negative and cytology-negative result, falling from 0.098% in the first cotesting round, to 0.052% in the second round, and 0.035% in the third round. The 5-year risks were similar with an HPV-negative cotest result, regardless of the outcome of cytology: 0.114%, 0.061%, and 0.041%.
The results are based on data from more than 990,000 women in the Kaiser Permanente Northern California health care system who had one or more cotests from 2003 to 2014.
These findings come as the U.S. Preventive Services Task Force (USPSTF) has issued draft recommendations that would call for either HPV testing alone every 5 years starting at age 30 years or cytology every 3 years, but no cotesting. The American College of Obstetricians and Gynecologists currently recommends cotesting with cytology and HPV testing every 5 years or cytology alone every 3 years in women aged 30-65 years (Obstet Gynecol. 2016;128[4]:e111-30).
The study was partially funded by the National Cancer Institute. Some of the researchers are employees of the National Cancer Institute. The researchers reported receiving cervical screening tests and diagnostics at reduced or no cost from Roche, BD Biosciences, Cepheid, Arbor Vita, and Hologic.
FROM ANNALS OF INTERNAL MEDICINE
Key clinical point:
Major finding: The 5-year cumulative detection of invasive cervical cancer, CIN3, and adenocarcinoma in situ decreased with each successive HPV-negative and cytology-negative result (0.098%, 0.052%, and 0.035%).
Data source: Data on more than 990,000 women who received cotesting between 2003 and 2014.
Disclosures: The research was partially supported by the National Cancer Institute. Some of the researchers are employees of the National Cancer Institute. The researchers reported receiving cervical screening tests and diagnostics at reduced or no cost from Roche, BD Biosciences, Cepheid, Arbor Vita, and Hologic.
CV outcomes better with SGLT2 inhibitor than DPP4 inhibitor in T2DM study
LISBON – The sodium-glucose co-transporter 2 (SGLT-2) inhibitor dapagliflozin (Farxiga) posed a lower risk of cardiovascular events and all-cause mortality in patients with type 2 diabetes mellitus (T2DM) compared with dipeptidyl peptidase-4 inhibitors in a large real-world, observational study.
In CVD-REAL NORDIC, treatment with the SGLT-2 inhibitor reduced the incidence of major cardiovascular adverse events by 21% as compared to DDP-4 inhibitors (hazard ratio, 0.79; 95% confidence interval, 0.67-0.94; P = .006).
Anna Norhammar, MD, PhD, of the Institute of Medicine, Cardiology Unit, at Karolinska Institutet in Stockholm, presented the findings at the annual meeting of the European Association for the Study of Diabetes.
She said: “These results are in line with previous clinical trials and meta-analyses, but extend the results to a broader CV risk population and with a commonly used comparator.”
Indeed, the findings build on those from the widely reported EMPA-REG Outcome (New Engl J Med. 2015;373;2117-8) and CANVAS (New Engl J Med. 2017;377:644-7) randomized controlled trials. These trials respectively showed empagliflozin and canagliflozin significantly reduced the risk for MACE and heart failure in patients with T2DM versus placebo. As the majority of patients in these trials had established CV disease, this suggested a class effect for SGLT2 inhibitors, Dr. Norhammar explained.
CVD-REAL NORDIC is part of a larger, multinational, observational, comparative effectiveness study looking at the real-world effect of SGLT2 inhibitors versus other glucose-lowering drugs on CV outcomes in patients with T2DM. Altogether around 90,000 patients have been recruited in Sweden, Norway, and Denmark.
Previously, Dr. Norhammar and co-investigators have reported that SGLT2 inhibitors lowered MACE (HR, 0.78; 95% CI 0.69–0.87, P less than .0001) and heart failure hospitalization (HR, 0.70; 95% CI 0.61–0.81, P less than .0001) relative to all glucose-lowering drugs (Lancet Diabetes Endocrinol. 2017;709–17).
“However, the comparator group used in that study, other [glucose-lowering drugs], consisted of almost 50% patients with T2DM treated with insulin or sul[f]onylureas,” they wrote in Diabetes, Obesity and Metabolism (8 Sep., doi: 10.1111/dom.13077). Insulin or sulfonylureas, they add, “have been shown to have increased associated CV risks” compared with DPP4 inhibitors and it is “not fully clear to what extent this could have influenced risk estimates.”
Furthermore, the CVD-NORDIC investigators note that the comparator group reflected real-world practice and it is important to look at treatment strategies more specifically, hence why they decided to do an analysis comparing SGLT2 and DPP4 inhibitors.
The study population for the current analysis consisted of 40,909 patients with T2DM who were newly initiated on either dapagliflozin (n=10,227) or a DPP4 inhibitor (n=30,682) between 2012 and 2015. The mean age was 61 years, and around 23% had prior CV disease and 5% had previous heart failure.
After a mean follow-up of 11.3 months, 177 MACE events had occurred among the 10,227 dapagliflozin-treated patients and 695 among the 30,681 DPP4 inhibitor-treated patients, giving respective event rates of 1.86 and 2.34 per 100 patient years. MACE was defined as a composite of nonfatal myocardial infarction, nonfatal stroke, and CV mortality.
“Dapagliflozin is the most commonly used SGLT2 inhibitor in the Nordic countries,” Dr. Norhammar said, explaining why this particular SGLT2 inhibitor was used in the analysis.
While there was a clear benefit of using dapagliflozin over DPP4 inhibitors in terms of MACE, heart failure hospitalization, and all-cause mortality, there was a “neutral” effect on atrial fibrillation and severe hypoglycaemia, with respective HRs of 0.92 (95% CI 0.76–1.12; P = .41) and 0.94 (95% CI 0.74–1.19; P = .62).
Dr. Norhammar said these “neutral results for atrial fibrillation and severe hypoglycaemia,” were “in line with expectations, and suggest a low likelihood of confounding.”
As this was an observational study, one of the limitations is that could be confounding factors that could not be adequately matched in the analysis. The events were not adjudicated and the study didn’t look at safety.
Dr. Norhammar noted that the results of the DECLARE-TIMI 58 trials were now needed to see if the potential CV benefits of using an SGLT2 inhibitor over other gluc0se-lowering medications might extend into patients at lower CV risk.
AstraZeneca supported the study.
Dr. Norhammar disclosed acting as a consultant to and receiving honoraria from AstraZeneca, Boehringer-Ingelheim, Eli Lilly, Novo Nordisk, and MSD Sweden.
LISBON – The sodium-glucose co-transporter 2 (SGLT-2) inhibitor dapagliflozin (Farxiga) posed a lower risk of cardiovascular events and all-cause mortality in patients with type 2 diabetes mellitus (T2DM) compared with dipeptidyl peptidase-4 inhibitors in a large real-world, observational study.
In CVD-REAL NORDIC, treatment with the SGLT-2 inhibitor reduced the incidence of major cardiovascular adverse events by 21% as compared to DDP-4 inhibitors (hazard ratio, 0.79; 95% confidence interval, 0.67-0.94; P = .006).
Anna Norhammar, MD, PhD, of the Institute of Medicine, Cardiology Unit, at Karolinska Institutet in Stockholm, presented the findings at the annual meeting of the European Association for the Study of Diabetes.
She said: “These results are in line with previous clinical trials and meta-analyses, but extend the results to a broader CV risk population and with a commonly used comparator.”
Indeed, the findings build on those from the widely reported EMPA-REG Outcome (New Engl J Med. 2015;373;2117-8) and CANVAS (New Engl J Med. 2017;377:644-7) randomized controlled trials. These trials respectively showed empagliflozin and canagliflozin significantly reduced the risk for MACE and heart failure in patients with T2DM versus placebo. As the majority of patients in these trials had established CV disease, this suggested a class effect for SGLT2 inhibitors, Dr. Norhammar explained.
CVD-REAL NORDIC is part of a larger, multinational, observational, comparative effectiveness study looking at the real-world effect of SGLT2 inhibitors versus other glucose-lowering drugs on CV outcomes in patients with T2DM. Altogether around 90,000 patients have been recruited in Sweden, Norway, and Denmark.
Previously, Dr. Norhammar and co-investigators have reported that SGLT2 inhibitors lowered MACE (HR, 0.78; 95% CI 0.69–0.87, P less than .0001) and heart failure hospitalization (HR, 0.70; 95% CI 0.61–0.81, P less than .0001) relative to all glucose-lowering drugs (Lancet Diabetes Endocrinol. 2017;709–17).
“However, the comparator group used in that study, other [glucose-lowering drugs], consisted of almost 50% patients with T2DM treated with insulin or sul[f]onylureas,” they wrote in Diabetes, Obesity and Metabolism (8 Sep., doi: 10.1111/dom.13077). Insulin or sulfonylureas, they add, “have been shown to have increased associated CV risks” compared with DPP4 inhibitors and it is “not fully clear to what extent this could have influenced risk estimates.”
Furthermore, the CVD-NORDIC investigators note that the comparator group reflected real-world practice and it is important to look at treatment strategies more specifically, hence why they decided to do an analysis comparing SGLT2 and DPP4 inhibitors.
The study population for the current analysis consisted of 40,909 patients with T2DM who were newly initiated on either dapagliflozin (n=10,227) or a DPP4 inhibitor (n=30,682) between 2012 and 2015. The mean age was 61 years, and around 23% had prior CV disease and 5% had previous heart failure.
After a mean follow-up of 11.3 months, 177 MACE events had occurred among the 10,227 dapagliflozin-treated patients and 695 among the 30,681 DPP4 inhibitor-treated patients, giving respective event rates of 1.86 and 2.34 per 100 patient years. MACE was defined as a composite of nonfatal myocardial infarction, nonfatal stroke, and CV mortality.
“Dapagliflozin is the most commonly used SGLT2 inhibitor in the Nordic countries,” Dr. Norhammar said, explaining why this particular SGLT2 inhibitor was used in the analysis.
While there was a clear benefit of using dapagliflozin over DPP4 inhibitors in terms of MACE, heart failure hospitalization, and all-cause mortality, there was a “neutral” effect on atrial fibrillation and severe hypoglycaemia, with respective HRs of 0.92 (95% CI 0.76–1.12; P = .41) and 0.94 (95% CI 0.74–1.19; P = .62).
Dr. Norhammar said these “neutral results for atrial fibrillation and severe hypoglycaemia,” were “in line with expectations, and suggest a low likelihood of confounding.”
As this was an observational study, one of the limitations is that could be confounding factors that could not be adequately matched in the analysis. The events were not adjudicated and the study didn’t look at safety.
Dr. Norhammar noted that the results of the DECLARE-TIMI 58 trials were now needed to see if the potential CV benefits of using an SGLT2 inhibitor over other gluc0se-lowering medications might extend into patients at lower CV risk.
AstraZeneca supported the study.
Dr. Norhammar disclosed acting as a consultant to and receiving honoraria from AstraZeneca, Boehringer-Ingelheim, Eli Lilly, Novo Nordisk, and MSD Sweden.
LISBON – The sodium-glucose co-transporter 2 (SGLT-2) inhibitor dapagliflozin (Farxiga) posed a lower risk of cardiovascular events and all-cause mortality in patients with type 2 diabetes mellitus (T2DM) compared with dipeptidyl peptidase-4 inhibitors in a large real-world, observational study.
In CVD-REAL NORDIC, treatment with the SGLT-2 inhibitor reduced the incidence of major cardiovascular adverse events by 21% as compared to DDP-4 inhibitors (hazard ratio, 0.79; 95% confidence interval, 0.67-0.94; P = .006).
Anna Norhammar, MD, PhD, of the Institute of Medicine, Cardiology Unit, at Karolinska Institutet in Stockholm, presented the findings at the annual meeting of the European Association for the Study of Diabetes.
She said: “These results are in line with previous clinical trials and meta-analyses, but extend the results to a broader CV risk population and with a commonly used comparator.”
Indeed, the findings build on those from the widely reported EMPA-REG Outcome (New Engl J Med. 2015;373;2117-8) and CANVAS (New Engl J Med. 2017;377:644-7) randomized controlled trials. These trials respectively showed empagliflozin and canagliflozin significantly reduced the risk for MACE and heart failure in patients with T2DM versus placebo. As the majority of patients in these trials had established CV disease, this suggested a class effect for SGLT2 inhibitors, Dr. Norhammar explained.
CVD-REAL NORDIC is part of a larger, multinational, observational, comparative effectiveness study looking at the real-world effect of SGLT2 inhibitors versus other glucose-lowering drugs on CV outcomes in patients with T2DM. Altogether around 90,000 patients have been recruited in Sweden, Norway, and Denmark.
Previously, Dr. Norhammar and co-investigators have reported that SGLT2 inhibitors lowered MACE (HR, 0.78; 95% CI 0.69–0.87, P less than .0001) and heart failure hospitalization (HR, 0.70; 95% CI 0.61–0.81, P less than .0001) relative to all glucose-lowering drugs (Lancet Diabetes Endocrinol. 2017;709–17).
“However, the comparator group used in that study, other [glucose-lowering drugs], consisted of almost 50% patients with T2DM treated with insulin or sul[f]onylureas,” they wrote in Diabetes, Obesity and Metabolism (8 Sep., doi: 10.1111/dom.13077). Insulin or sulfonylureas, they add, “have been shown to have increased associated CV risks” compared with DPP4 inhibitors and it is “not fully clear to what extent this could have influenced risk estimates.”
Furthermore, the CVD-NORDIC investigators note that the comparator group reflected real-world practice and it is important to look at treatment strategies more specifically, hence why they decided to do an analysis comparing SGLT2 and DPP4 inhibitors.
The study population for the current analysis consisted of 40,909 patients with T2DM who were newly initiated on either dapagliflozin (n=10,227) or a DPP4 inhibitor (n=30,682) between 2012 and 2015. The mean age was 61 years, and around 23% had prior CV disease and 5% had previous heart failure.
After a mean follow-up of 11.3 months, 177 MACE events had occurred among the 10,227 dapagliflozin-treated patients and 695 among the 30,681 DPP4 inhibitor-treated patients, giving respective event rates of 1.86 and 2.34 per 100 patient years. MACE was defined as a composite of nonfatal myocardial infarction, nonfatal stroke, and CV mortality.
“Dapagliflozin is the most commonly used SGLT2 inhibitor in the Nordic countries,” Dr. Norhammar said, explaining why this particular SGLT2 inhibitor was used in the analysis.
While there was a clear benefit of using dapagliflozin over DPP4 inhibitors in terms of MACE, heart failure hospitalization, and all-cause mortality, there was a “neutral” effect on atrial fibrillation and severe hypoglycaemia, with respective HRs of 0.92 (95% CI 0.76–1.12; P = .41) and 0.94 (95% CI 0.74–1.19; P = .62).
Dr. Norhammar said these “neutral results for atrial fibrillation and severe hypoglycaemia,” were “in line with expectations, and suggest a low likelihood of confounding.”
As this was an observational study, one of the limitations is that could be confounding factors that could not be adequately matched in the analysis. The events were not adjudicated and the study didn’t look at safety.
Dr. Norhammar noted that the results of the DECLARE-TIMI 58 trials were now needed to see if the potential CV benefits of using an SGLT2 inhibitor over other gluc0se-lowering medications might extend into patients at lower CV risk.
AstraZeneca supported the study.
Dr. Norhammar disclosed acting as a consultant to and receiving honoraria from AstraZeneca, Boehringer-Ingelheim, Eli Lilly, Novo Nordisk, and MSD Sweden.
AT EASD 2017
Key clinical point:
Major finding: Hazard ratios for MACE, heart failure hospitalization, and all-cause mortality were a respective 0.79, 0.62, and 0.59, comparing SGLT2 with DPP4 inhibitors.
Data source: CVD-NORDIC, part of a multinational, observational study comparing the real-world effect of SGLT2 inhibitors versus other glucose-lowering drugs on CV outcomes in patients with T2DM.
Disclosures: AstraZeneca supported the study. The presenting author disclosed acting as a consultant to and receiving honoraria from AstraZeneca, Boehringer-Ingelheim, Eli Lilly, Novo Nordisk, and MSD Sweden.
Care needed using sotagliflozin as add-on to insulin in T1DM
LISBON – Further phase 3 trial data show that the investigational dual sodium-glucose cotransporter 1 and 2 (SGLT1/2) inhibitor according to results reported at the annual meeting of the European Association for the Study of Diabetes.
In the inTandem3 trial, 28.6% of 699 people with T1DM treated with sotagliflozin on top of their usual insulin therapy achieved the primary composite endpoint, which was a glycated hemoglobin (HbA1c) level of 7% or lower at Week 24, with no episodes of severe hypoglycemia or diabetic ketoacidosis (DKA). In comparison, 15.2% of the 703 individuals who received a placebo in addition to their insulin therapy achieved this endpoint (P less than .001), according to Melanie J. Davies, MD, who presented the inTandem3 study results during a symposium on the sotagliflozin clinical program. The results were published online in the New England Journal of Medicine (2017 Sep 15. doi: 10.1056/NEJMoa1708337) to coincide with their presentation at the meeting.
However, the overall rate of DKA was higher in the patients treated with sotagliflozin than in those on placebo, at 3% versus 0.6%, respectively. DKA events most often occurred in persons using insulin pumps (4.4% vs. 9.7%) than in those taking insulin via multiple daily injections (2.1% vs 0.5%). Furthermore, in a post-hoc analysis, it was found that the rate of at least one episode of DKA was significantly higher in sotagliflozin- than placebo-treated patients who failed to reach the HbA1c target of below 7% (P less than .003), reported Dr. Davies.
The study findings “build on data seen inTandem 1 and inTandem 2 but in a more pragmatic design,” said study investigator Melanie Davies, MD, professor of diabetes medicine at the University of Leicester (England).
The inTandem studies
Dr. Davies observed that the sotagliflozin clinical trials program in persons with T1DM involved three phase 2 and three phase 3 studies. The latter, inTandem1, inTandem2, and inTandem3, were all 24-week trials, but there were some differences in the design.
inTandem1 and inTandem2 were the pivotal studies, one conducted in 793 patients in North America and the other in 782 patients in Europe and Israel. After a 2-week screening period, participants underwent a 6-week insulin optimization program before they were randomized to one of two doses of sotagliflozin (200 mg or 400 mg) or placebo for 24 weeks, with follow-up out to 52 weeks. The primary endpoint of these studies was the reduction in HbA1c versus placebo at 24 weeks.
By comparison, inTandem3 was a global study involving 1,405 individuals with T1DM who did not undergo the 6-week insulin optimization period. Instead there was a 2-week run-in period after the initial screening, and the study ran for only 24 weeks. Only one dose (400 mg) of sotagliflozin was used and the primary endpoint was a composite to try to see what the net clinical benefit would be, Dr. Davies explained.
The results of inTandem1 and inTandem2 were reported earlier this year at the American Diabetes Association Scientific Sessions, Dr. Davies noted, and sotagliflozin had “a good efficacy and safety profile as an adjunct to insulin in type 1 diabetes.”
The quest for adjunctive treatment
“For years we’ve been looking for adjunctive therapy for people with type 1 diabetes,” said Julio Rosenstock, MD, at the EASD meeting. Dr. Rosenstock, who is the director of the Dallas Diabetes Research Center at Medical City and involved in the sotagliflozin clinical trials program, noted that the quest for an adjunctive treatment was because “glucose control in type 1 diabetes remains tough and costly, despite multiple advances in insulin therapy, delivery systems, and monitoring methods over the years.”
Several approaches to adjunctive treatment had been proposed, but so far all with limited value, Dr. Rosenstock maintained. Despite no evidence for a benefit of adding metformin, for example, registry data suggest that up to 5% of people with T1DM are using it.
The recent findings of the REMOVAL trial showed metformin did not help change the HbA1c over time and there was no change in the primary outcome, he observed but a small improvement in a tertiary endpoint. “I can’t think of a more negative cardiovascular outcomes trial,” Dr. Rosenstock asserted. “There is not enough justification to use metformin in type 1 diabetes.”
By contrast there is a strong rationale for using SGLT inhibition, partly as the glucose-lowering effects are independent of insulin’s activity. Through inhibition of SGLT1, sotagliflozin reduces glucose absorption in the proximal intestine, thus blunting or delaying rising postprandial glucose levels. By also targeting SGLT2, sotagliflozin can reduce glucose resorption by the kidneys.
Risks and clinical implications
In an editorial accompanying the published findings, David Nathan, MD, of Massachusetts General Hospital and Harvard Medical School in Boston, is not convinced that using adjunctive treatment is the future for better glycemic control in T1DM and that better automated insulin delivery systems will likely make adjunctive therapy unnecessary.
Dr. Nathan also observed “the rate of severe hypoglycemia in the whole sotagliflozin group was not significantly different from the rate in the placebo group,” and the risks and benefits of any adjunctive therapy for T1DM need to be carefully balanced.
While risks remain, one of the chairs of the session, Chantal Mathieu, MD, professor of medicine at the Katholieke Universiteit Leuven (Belgium), observed that “these are exciting times for all of us and hopefully for our patients.” She cautioned clinicians to remember, however, that “type 1 diabetes is a very different disease from type 2 diabetes, and so when we listen to [information about] all these adjunct[ive] therapies, when we read the papers, please interpret the data carefully.”
The trial was funded by Lexicon Pharmaceuticals. Sotagliflozin is being codeveloped with Sanofi. Dr. Davies disclosed acting as an advisor, consultant, or being a member of a speaker’s bureau for Sanofi-Aventis and several other companies. She was an investigator in the inTandem trials and her institution received funding from Lexicon to conduct the inTandem 2 and 3 clinical trials. Dr. Rosenstock disclosed research support and acting as an advisor to multiple pharmaceutical companies. Dr. Nathan had nothing to disclose. Dr. Mathieu chaired the session and did not present disclosures.
LISBON – Further phase 3 trial data show that the investigational dual sodium-glucose cotransporter 1 and 2 (SGLT1/2) inhibitor according to results reported at the annual meeting of the European Association for the Study of Diabetes.
In the inTandem3 trial, 28.6% of 699 people with T1DM treated with sotagliflozin on top of their usual insulin therapy achieved the primary composite endpoint, which was a glycated hemoglobin (HbA1c) level of 7% or lower at Week 24, with no episodes of severe hypoglycemia or diabetic ketoacidosis (DKA). In comparison, 15.2% of the 703 individuals who received a placebo in addition to their insulin therapy achieved this endpoint (P less than .001), according to Melanie J. Davies, MD, who presented the inTandem3 study results during a symposium on the sotagliflozin clinical program. The results were published online in the New England Journal of Medicine (2017 Sep 15. doi: 10.1056/NEJMoa1708337) to coincide with their presentation at the meeting.
However, the overall rate of DKA was higher in the patients treated with sotagliflozin than in those on placebo, at 3% versus 0.6%, respectively. DKA events most often occurred in persons using insulin pumps (4.4% vs. 9.7%) than in those taking insulin via multiple daily injections (2.1% vs 0.5%). Furthermore, in a post-hoc analysis, it was found that the rate of at least one episode of DKA was significantly higher in sotagliflozin- than placebo-treated patients who failed to reach the HbA1c target of below 7% (P less than .003), reported Dr. Davies.
The study findings “build on data seen inTandem 1 and inTandem 2 but in a more pragmatic design,” said study investigator Melanie Davies, MD, professor of diabetes medicine at the University of Leicester (England).
The inTandem studies
Dr. Davies observed that the sotagliflozin clinical trials program in persons with T1DM involved three phase 2 and three phase 3 studies. The latter, inTandem1, inTandem2, and inTandem3, were all 24-week trials, but there were some differences in the design.
inTandem1 and inTandem2 were the pivotal studies, one conducted in 793 patients in North America and the other in 782 patients in Europe and Israel. After a 2-week screening period, participants underwent a 6-week insulin optimization program before they were randomized to one of two doses of sotagliflozin (200 mg or 400 mg) or placebo for 24 weeks, with follow-up out to 52 weeks. The primary endpoint of these studies was the reduction in HbA1c versus placebo at 24 weeks.
By comparison, inTandem3 was a global study involving 1,405 individuals with T1DM who did not undergo the 6-week insulin optimization period. Instead there was a 2-week run-in period after the initial screening, and the study ran for only 24 weeks. Only one dose (400 mg) of sotagliflozin was used and the primary endpoint was a composite to try to see what the net clinical benefit would be, Dr. Davies explained.
The results of inTandem1 and inTandem2 were reported earlier this year at the American Diabetes Association Scientific Sessions, Dr. Davies noted, and sotagliflozin had “a good efficacy and safety profile as an adjunct to insulin in type 1 diabetes.”
The quest for adjunctive treatment
“For years we’ve been looking for adjunctive therapy for people with type 1 diabetes,” said Julio Rosenstock, MD, at the EASD meeting. Dr. Rosenstock, who is the director of the Dallas Diabetes Research Center at Medical City and involved in the sotagliflozin clinical trials program, noted that the quest for an adjunctive treatment was because “glucose control in type 1 diabetes remains tough and costly, despite multiple advances in insulin therapy, delivery systems, and monitoring methods over the years.”
Several approaches to adjunctive treatment had been proposed, but so far all with limited value, Dr. Rosenstock maintained. Despite no evidence for a benefit of adding metformin, for example, registry data suggest that up to 5% of people with T1DM are using it.
The recent findings of the REMOVAL trial showed metformin did not help change the HbA1c over time and there was no change in the primary outcome, he observed but a small improvement in a tertiary endpoint. “I can’t think of a more negative cardiovascular outcomes trial,” Dr. Rosenstock asserted. “There is not enough justification to use metformin in type 1 diabetes.”
By contrast there is a strong rationale for using SGLT inhibition, partly as the glucose-lowering effects are independent of insulin’s activity. Through inhibition of SGLT1, sotagliflozin reduces glucose absorption in the proximal intestine, thus blunting or delaying rising postprandial glucose levels. By also targeting SGLT2, sotagliflozin can reduce glucose resorption by the kidneys.
Risks and clinical implications
In an editorial accompanying the published findings, David Nathan, MD, of Massachusetts General Hospital and Harvard Medical School in Boston, is not convinced that using adjunctive treatment is the future for better glycemic control in T1DM and that better automated insulin delivery systems will likely make adjunctive therapy unnecessary.
Dr. Nathan also observed “the rate of severe hypoglycemia in the whole sotagliflozin group was not significantly different from the rate in the placebo group,” and the risks and benefits of any adjunctive therapy for T1DM need to be carefully balanced.
While risks remain, one of the chairs of the session, Chantal Mathieu, MD, professor of medicine at the Katholieke Universiteit Leuven (Belgium), observed that “these are exciting times for all of us and hopefully for our patients.” She cautioned clinicians to remember, however, that “type 1 diabetes is a very different disease from type 2 diabetes, and so when we listen to [information about] all these adjunct[ive] therapies, when we read the papers, please interpret the data carefully.”
The trial was funded by Lexicon Pharmaceuticals. Sotagliflozin is being codeveloped with Sanofi. Dr. Davies disclosed acting as an advisor, consultant, or being a member of a speaker’s bureau for Sanofi-Aventis and several other companies. She was an investigator in the inTandem trials and her institution received funding from Lexicon to conduct the inTandem 2 and 3 clinical trials. Dr. Rosenstock disclosed research support and acting as an advisor to multiple pharmaceutical companies. Dr. Nathan had nothing to disclose. Dr. Mathieu chaired the session and did not present disclosures.
LISBON – Further phase 3 trial data show that the investigational dual sodium-glucose cotransporter 1 and 2 (SGLT1/2) inhibitor according to results reported at the annual meeting of the European Association for the Study of Diabetes.
In the inTandem3 trial, 28.6% of 699 people with T1DM treated with sotagliflozin on top of their usual insulin therapy achieved the primary composite endpoint, which was a glycated hemoglobin (HbA1c) level of 7% or lower at Week 24, with no episodes of severe hypoglycemia or diabetic ketoacidosis (DKA). In comparison, 15.2% of the 703 individuals who received a placebo in addition to their insulin therapy achieved this endpoint (P less than .001), according to Melanie J. Davies, MD, who presented the inTandem3 study results during a symposium on the sotagliflozin clinical program. The results were published online in the New England Journal of Medicine (2017 Sep 15. doi: 10.1056/NEJMoa1708337) to coincide with their presentation at the meeting.
However, the overall rate of DKA was higher in the patients treated with sotagliflozin than in those on placebo, at 3% versus 0.6%, respectively. DKA events most often occurred in persons using insulin pumps (4.4% vs. 9.7%) than in those taking insulin via multiple daily injections (2.1% vs 0.5%). Furthermore, in a post-hoc analysis, it was found that the rate of at least one episode of DKA was significantly higher in sotagliflozin- than placebo-treated patients who failed to reach the HbA1c target of below 7% (P less than .003), reported Dr. Davies.
The study findings “build on data seen inTandem 1 and inTandem 2 but in a more pragmatic design,” said study investigator Melanie Davies, MD, professor of diabetes medicine at the University of Leicester (England).
The inTandem studies
Dr. Davies observed that the sotagliflozin clinical trials program in persons with T1DM involved three phase 2 and three phase 3 studies. The latter, inTandem1, inTandem2, and inTandem3, were all 24-week trials, but there were some differences in the design.
inTandem1 and inTandem2 were the pivotal studies, one conducted in 793 patients in North America and the other in 782 patients in Europe and Israel. After a 2-week screening period, participants underwent a 6-week insulin optimization program before they were randomized to one of two doses of sotagliflozin (200 mg or 400 mg) or placebo for 24 weeks, with follow-up out to 52 weeks. The primary endpoint of these studies was the reduction in HbA1c versus placebo at 24 weeks.
By comparison, inTandem3 was a global study involving 1,405 individuals with T1DM who did not undergo the 6-week insulin optimization period. Instead there was a 2-week run-in period after the initial screening, and the study ran for only 24 weeks. Only one dose (400 mg) of sotagliflozin was used and the primary endpoint was a composite to try to see what the net clinical benefit would be, Dr. Davies explained.
The results of inTandem1 and inTandem2 were reported earlier this year at the American Diabetes Association Scientific Sessions, Dr. Davies noted, and sotagliflozin had “a good efficacy and safety profile as an adjunct to insulin in type 1 diabetes.”
The quest for adjunctive treatment
“For years we’ve been looking for adjunctive therapy for people with type 1 diabetes,” said Julio Rosenstock, MD, at the EASD meeting. Dr. Rosenstock, who is the director of the Dallas Diabetes Research Center at Medical City and involved in the sotagliflozin clinical trials program, noted that the quest for an adjunctive treatment was because “glucose control in type 1 diabetes remains tough and costly, despite multiple advances in insulin therapy, delivery systems, and monitoring methods over the years.”
Several approaches to adjunctive treatment had been proposed, but so far all with limited value, Dr. Rosenstock maintained. Despite no evidence for a benefit of adding metformin, for example, registry data suggest that up to 5% of people with T1DM are using it.
The recent findings of the REMOVAL trial showed metformin did not help change the HbA1c over time and there was no change in the primary outcome, he observed but a small improvement in a tertiary endpoint. “I can’t think of a more negative cardiovascular outcomes trial,” Dr. Rosenstock asserted. “There is not enough justification to use metformin in type 1 diabetes.”
By contrast there is a strong rationale for using SGLT inhibition, partly as the glucose-lowering effects are independent of insulin’s activity. Through inhibition of SGLT1, sotagliflozin reduces glucose absorption in the proximal intestine, thus blunting or delaying rising postprandial glucose levels. By also targeting SGLT2, sotagliflozin can reduce glucose resorption by the kidneys.
Risks and clinical implications
In an editorial accompanying the published findings, David Nathan, MD, of Massachusetts General Hospital and Harvard Medical School in Boston, is not convinced that using adjunctive treatment is the future for better glycemic control in T1DM and that better automated insulin delivery systems will likely make adjunctive therapy unnecessary.
Dr. Nathan also observed “the rate of severe hypoglycemia in the whole sotagliflozin group was not significantly different from the rate in the placebo group,” and the risks and benefits of any adjunctive therapy for T1DM need to be carefully balanced.
While risks remain, one of the chairs of the session, Chantal Mathieu, MD, professor of medicine at the Katholieke Universiteit Leuven (Belgium), observed that “these are exciting times for all of us and hopefully for our patients.” She cautioned clinicians to remember, however, that “type 1 diabetes is a very different disease from type 2 diabetes, and so when we listen to [information about] all these adjunct[ive] therapies, when we read the papers, please interpret the data carefully.”
The trial was funded by Lexicon Pharmaceuticals. Sotagliflozin is being codeveloped with Sanofi. Dr. Davies disclosed acting as an advisor, consultant, or being a member of a speaker’s bureau for Sanofi-Aventis and several other companies. She was an investigator in the inTandem trials and her institution received funding from Lexicon to conduct the inTandem 2 and 3 clinical trials. Dr. Rosenstock disclosed research support and acting as an advisor to multiple pharmaceutical companies. Dr. Nathan had nothing to disclose. Dr. Mathieu chaired the session and did not present disclosures.
AT EASD 2017
Key clinical point: A higher proportion of people with type 1 diabetes mellitus (T1DM) treated with sotagliflozin than placebo achieved the primary composite endpoint, but there is the risk of diabetic ketoacidosis (DKA) in some.
Major finding: 28.6% versus 15.2% of sotaglifozin- and placebo-treated individuals achieved an HbA1c less than 7% at week 24, with no episodes of severe hypoglycemia or DKA (P less than .001).
Data source: The phase 3, randomized, controlled, multicenter inTandem3 trial in 1,402 people with type 1 diabetes on stable insulin therapy but with poor glycemic control.
Disclosures: The trial was funded by Lexicon Pharmaceuticals. Sotagliflozin is being codeveloped with Sanofi. Two presenters have received research support to perform clinical studies. The commentators had nothing to disclose.
SGLT inhibition back on track in phase 3 type T1DM trial
LISBON – Despite some earlier concerns over safety, sodium-glucose cotransporter (SGLT) inhibitors appear to be back on track for adjunctive use in people with type 1 diabetes (T1DM), according to phase 3 study findings presented at the annual meeting of the European Association for the Study of Diabetes.
Results of the DEPICT-1 study, showed improved glycemic control, greater weight loss, and no increased risk for either hypoglycemia or ketoacidosis in people treated with the SGLT2 inhibitor dapagliflozin (Farxiga) versus those treated with placebo.
When researchers compared the two dapagliflozin doses with placebo, the mean difference in body weight from baseline to week 24 was –2.96% and –3.72% (both P less than .0001).
Rates of any hypoglycemia in the placebo, 5-mg dapagliflozin, and 10-mg dapagliflozin groups were a respective 79.6%, 79.4%, and 79.4%, and rates of severe hypoglycemia were 7.3%, 7.6%, and 6.4%.
Diabetic ketoacidosis occurred in a respective 1.2%, 1.4%, and 1.7% of patients treated with placebo, dapagliflozin 5 mg, and dapagliflozin 10 mg, respectively.
“Based on this 24-week study, dapagliflozin may be considered as a good candidate as an adjunct to insulin to improve glycemic control in type 1 diabetes,” said the lead investigator for the DEPICT-1 trial, Paresh Dandona, MD, PhD, at the EASD 2017 meeting.
“There may also be other potential long-term cardiovascular and renal benefits, which have recently been demonstrated in type 2 diabetes,” suggested Dr. Dandona, who is a distinguished professor of medicine and chief of the division of endocrinology at the State University of New York at Buffalo. “Of course, that’s an open question, which needs to be investigated and determined in future.”
DEPICT-1 is the first phase 3, randomized, blinded, clinical trial of a selective SGLT2 inhibitor in T1DM, the study’s investigators said in an early online publication (Lancet Diabetes Endocrinol. 2017 Sep 13. doi: 10.1016/S2213-8587[17]30308-X). The study was conducted at 143 sites in 17 centers and involved 833 people with T1DM who were not achieving optimal blood glucose control.
Adults with an HbA1c of 7.7% or higher who had been taking insulin for at least 12 months were recruited and underwent an 8-week lead-in period to optimize their diabetes management before being randomized to take placebo or dapagliflozin 5 mg or 10 mg for 52 weeks. The primary endpoint was the change in HbA1c at Week 24.
DEPICT-1 “provides encouraging short-term data for the efficacy of adjunct SGLT2 inhibition in type 1 diabetes but might also provide insights into how the risk of ketoacidosis can be minimized,” John Petrie, MD, commented in an editorial that accompanied the published findings.
Dr. Petrie, professor of diabetic medicine at the Institute of Cardiovascular and Medical Sciences at the University of Glasgow, observed, however, that the results needed to be considered in the context of similar, and also recently presented, findings from the inTandem3 trial (N Engl J Med. 2017 Sep 13. doi: 10.1056/NEJMoa1708337) with the investigational dual SGLT1/SGLT2 inhibitor sotagliflozin. Other trials are expected to report soon with another SGLT2 inhibitor, empagliflozin.
In inTandem3, sotagliflozin helped more people who had T1DM and were on stable insulin to achieve an HbA1c level of 7% or lower at week 24 with no episodes of severe hypoglycemia or diabetic ketoacidosis, compared with those who took insulin alone (28.6% vs. 15.2%; P less than .001). However, the overall rates of ketoacidosis were higher in the patients treated with sotagliflozin than in those treated with placebo, at 3% versus 0.6%, respectively.
In both inTandem3 and DEPICT-1, strategies were in place to help carefully monitor and manage ketoacidosis. Dr. Petrie observed that patients in the latter trial were given a meter that measured both their blood glucose and ketones and were seen in a clinic regularly to assess the risk of ketoacidosis. These frequent visits, which occurred every 2 weeks, were shown to have an independent effect on HbA1c, he pointed out.
“Nevertheless, the investigators kept real-world clinical practice in mind by providing a very simple rule that insulin doses should be reduced by no more than 20% when study medication was started and that they should subsequently be titrated back towards the initial dose,” Dr. Petrie said. “This rule seemed to be quite effective in mitigating ketoacidosis and is feasible to implement in modern clinical practice since meters that measure ketones are increasingly available.
So does this mean a license for SGLT-targeting agents in T1DM could be coming soon? Not yet, Dr. Petrie suggests. “Regulators are likely to await at least the results of the 12-month follow-up, and data from other ongoing trials, before considering an indication for SGLT2 inhibitors in type 1 diabetes,” he said.
Adjunct treatment with these drugs also may require that individuals have “a good understanding of the early-warning symptoms of ketoacidosis” and be prepared to undertake regular home monitoring of both their blood glucose and ketones, as well as having a high level of communication with their diabetes health care providers.
AstraZeneca and Bristol-Myers Squibb funded the study.
Dr. Dandona received research support from AstraZeneca, Novo Nordisk, Boehringer Ingelheim, and AbbVie and was a consultant to AstraZeneca, Novo Nordisk, Sanofi-Aventis, and others.
Dr. Petrie disclosed receiving personal fees and travel expenses from Novo Nordisk; grants and personal fees from Sanofi-Aventis, Quintiles, and Janssen; nonfinancial support from Merck and Itamar Medical; and personal fees from Lilly, ACI Clinical, and Pfizer.
LISBON – Despite some earlier concerns over safety, sodium-glucose cotransporter (SGLT) inhibitors appear to be back on track for adjunctive use in people with type 1 diabetes (T1DM), according to phase 3 study findings presented at the annual meeting of the European Association for the Study of Diabetes.
Results of the DEPICT-1 study, showed improved glycemic control, greater weight loss, and no increased risk for either hypoglycemia or ketoacidosis in people treated with the SGLT2 inhibitor dapagliflozin (Farxiga) versus those treated with placebo.
When researchers compared the two dapagliflozin doses with placebo, the mean difference in body weight from baseline to week 24 was –2.96% and –3.72% (both P less than .0001).
Rates of any hypoglycemia in the placebo, 5-mg dapagliflozin, and 10-mg dapagliflozin groups were a respective 79.6%, 79.4%, and 79.4%, and rates of severe hypoglycemia were 7.3%, 7.6%, and 6.4%.
Diabetic ketoacidosis occurred in a respective 1.2%, 1.4%, and 1.7% of patients treated with placebo, dapagliflozin 5 mg, and dapagliflozin 10 mg, respectively.
“Based on this 24-week study, dapagliflozin may be considered as a good candidate as an adjunct to insulin to improve glycemic control in type 1 diabetes,” said the lead investigator for the DEPICT-1 trial, Paresh Dandona, MD, PhD, at the EASD 2017 meeting.
“There may also be other potential long-term cardiovascular and renal benefits, which have recently been demonstrated in type 2 diabetes,” suggested Dr. Dandona, who is a distinguished professor of medicine and chief of the division of endocrinology at the State University of New York at Buffalo. “Of course, that’s an open question, which needs to be investigated and determined in future.”
DEPICT-1 is the first phase 3, randomized, blinded, clinical trial of a selective SGLT2 inhibitor in T1DM, the study’s investigators said in an early online publication (Lancet Diabetes Endocrinol. 2017 Sep 13. doi: 10.1016/S2213-8587[17]30308-X). The study was conducted at 143 sites in 17 centers and involved 833 people with T1DM who were not achieving optimal blood glucose control.
Adults with an HbA1c of 7.7% or higher who had been taking insulin for at least 12 months were recruited and underwent an 8-week lead-in period to optimize their diabetes management before being randomized to take placebo or dapagliflozin 5 mg or 10 mg for 52 weeks. The primary endpoint was the change in HbA1c at Week 24.
DEPICT-1 “provides encouraging short-term data for the efficacy of adjunct SGLT2 inhibition in type 1 diabetes but might also provide insights into how the risk of ketoacidosis can be minimized,” John Petrie, MD, commented in an editorial that accompanied the published findings.
Dr. Petrie, professor of diabetic medicine at the Institute of Cardiovascular and Medical Sciences at the University of Glasgow, observed, however, that the results needed to be considered in the context of similar, and also recently presented, findings from the inTandem3 trial (N Engl J Med. 2017 Sep 13. doi: 10.1056/NEJMoa1708337) with the investigational dual SGLT1/SGLT2 inhibitor sotagliflozin. Other trials are expected to report soon with another SGLT2 inhibitor, empagliflozin.
In inTandem3, sotagliflozin helped more people who had T1DM and were on stable insulin to achieve an HbA1c level of 7% or lower at week 24 with no episodes of severe hypoglycemia or diabetic ketoacidosis, compared with those who took insulin alone (28.6% vs. 15.2%; P less than .001). However, the overall rates of ketoacidosis were higher in the patients treated with sotagliflozin than in those treated with placebo, at 3% versus 0.6%, respectively.
In both inTandem3 and DEPICT-1, strategies were in place to help carefully monitor and manage ketoacidosis. Dr. Petrie observed that patients in the latter trial were given a meter that measured both their blood glucose and ketones and were seen in a clinic regularly to assess the risk of ketoacidosis. These frequent visits, which occurred every 2 weeks, were shown to have an independent effect on HbA1c, he pointed out.
“Nevertheless, the investigators kept real-world clinical practice in mind by providing a very simple rule that insulin doses should be reduced by no more than 20% when study medication was started and that they should subsequently be titrated back towards the initial dose,” Dr. Petrie said. “This rule seemed to be quite effective in mitigating ketoacidosis and is feasible to implement in modern clinical practice since meters that measure ketones are increasingly available.
So does this mean a license for SGLT-targeting agents in T1DM could be coming soon? Not yet, Dr. Petrie suggests. “Regulators are likely to await at least the results of the 12-month follow-up, and data from other ongoing trials, before considering an indication for SGLT2 inhibitors in type 1 diabetes,” he said.
Adjunct treatment with these drugs also may require that individuals have “a good understanding of the early-warning symptoms of ketoacidosis” and be prepared to undertake regular home monitoring of both their blood glucose and ketones, as well as having a high level of communication with their diabetes health care providers.
AstraZeneca and Bristol-Myers Squibb funded the study.
Dr. Dandona received research support from AstraZeneca, Novo Nordisk, Boehringer Ingelheim, and AbbVie and was a consultant to AstraZeneca, Novo Nordisk, Sanofi-Aventis, and others.
Dr. Petrie disclosed receiving personal fees and travel expenses from Novo Nordisk; grants and personal fees from Sanofi-Aventis, Quintiles, and Janssen; nonfinancial support from Merck and Itamar Medical; and personal fees from Lilly, ACI Clinical, and Pfizer.
LISBON – Despite some earlier concerns over safety, sodium-glucose cotransporter (SGLT) inhibitors appear to be back on track for adjunctive use in people with type 1 diabetes (T1DM), according to phase 3 study findings presented at the annual meeting of the European Association for the Study of Diabetes.
Results of the DEPICT-1 study, showed improved glycemic control, greater weight loss, and no increased risk for either hypoglycemia or ketoacidosis in people treated with the SGLT2 inhibitor dapagliflozin (Farxiga) versus those treated with placebo.
When researchers compared the two dapagliflozin doses with placebo, the mean difference in body weight from baseline to week 24 was –2.96% and –3.72% (both P less than .0001).
Rates of any hypoglycemia in the placebo, 5-mg dapagliflozin, and 10-mg dapagliflozin groups were a respective 79.6%, 79.4%, and 79.4%, and rates of severe hypoglycemia were 7.3%, 7.6%, and 6.4%.
Diabetic ketoacidosis occurred in a respective 1.2%, 1.4%, and 1.7% of patients treated with placebo, dapagliflozin 5 mg, and dapagliflozin 10 mg, respectively.
“Based on this 24-week study, dapagliflozin may be considered as a good candidate as an adjunct to insulin to improve glycemic control in type 1 diabetes,” said the lead investigator for the DEPICT-1 trial, Paresh Dandona, MD, PhD, at the EASD 2017 meeting.
“There may also be other potential long-term cardiovascular and renal benefits, which have recently been demonstrated in type 2 diabetes,” suggested Dr. Dandona, who is a distinguished professor of medicine and chief of the division of endocrinology at the State University of New York at Buffalo. “Of course, that’s an open question, which needs to be investigated and determined in future.”
DEPICT-1 is the first phase 3, randomized, blinded, clinical trial of a selective SGLT2 inhibitor in T1DM, the study’s investigators said in an early online publication (Lancet Diabetes Endocrinol. 2017 Sep 13. doi: 10.1016/S2213-8587[17]30308-X). The study was conducted at 143 sites in 17 centers and involved 833 people with T1DM who were not achieving optimal blood glucose control.
Adults with an HbA1c of 7.7% or higher who had been taking insulin for at least 12 months were recruited and underwent an 8-week lead-in period to optimize their diabetes management before being randomized to take placebo or dapagliflozin 5 mg or 10 mg for 52 weeks. The primary endpoint was the change in HbA1c at Week 24.
DEPICT-1 “provides encouraging short-term data for the efficacy of adjunct SGLT2 inhibition in type 1 diabetes but might also provide insights into how the risk of ketoacidosis can be minimized,” John Petrie, MD, commented in an editorial that accompanied the published findings.
Dr. Petrie, professor of diabetic medicine at the Institute of Cardiovascular and Medical Sciences at the University of Glasgow, observed, however, that the results needed to be considered in the context of similar, and also recently presented, findings from the inTandem3 trial (N Engl J Med. 2017 Sep 13. doi: 10.1056/NEJMoa1708337) with the investigational dual SGLT1/SGLT2 inhibitor sotagliflozin. Other trials are expected to report soon with another SGLT2 inhibitor, empagliflozin.
In inTandem3, sotagliflozin helped more people who had T1DM and were on stable insulin to achieve an HbA1c level of 7% or lower at week 24 with no episodes of severe hypoglycemia or diabetic ketoacidosis, compared with those who took insulin alone (28.6% vs. 15.2%; P less than .001). However, the overall rates of ketoacidosis were higher in the patients treated with sotagliflozin than in those treated with placebo, at 3% versus 0.6%, respectively.
In both inTandem3 and DEPICT-1, strategies were in place to help carefully monitor and manage ketoacidosis. Dr. Petrie observed that patients in the latter trial were given a meter that measured both their blood glucose and ketones and were seen in a clinic regularly to assess the risk of ketoacidosis. These frequent visits, which occurred every 2 weeks, were shown to have an independent effect on HbA1c, he pointed out.
“Nevertheless, the investigators kept real-world clinical practice in mind by providing a very simple rule that insulin doses should be reduced by no more than 20% when study medication was started and that they should subsequently be titrated back towards the initial dose,” Dr. Petrie said. “This rule seemed to be quite effective in mitigating ketoacidosis and is feasible to implement in modern clinical practice since meters that measure ketones are increasingly available.
So does this mean a license for SGLT-targeting agents in T1DM could be coming soon? Not yet, Dr. Petrie suggests. “Regulators are likely to await at least the results of the 12-month follow-up, and data from other ongoing trials, before considering an indication for SGLT2 inhibitors in type 1 diabetes,” he said.
Adjunct treatment with these drugs also may require that individuals have “a good understanding of the early-warning symptoms of ketoacidosis” and be prepared to undertake regular home monitoring of both their blood glucose and ketones, as well as having a high level of communication with their diabetes health care providers.
AstraZeneca and Bristol-Myers Squibb funded the study.
Dr. Dandona received research support from AstraZeneca, Novo Nordisk, Boehringer Ingelheim, and AbbVie and was a consultant to AstraZeneca, Novo Nordisk, Sanofi-Aventis, and others.
Dr. Petrie disclosed receiving personal fees and travel expenses from Novo Nordisk; grants and personal fees from Sanofi-Aventis, Quintiles, and Janssen; nonfinancial support from Merck and Itamar Medical; and personal fees from Lilly, ACI Clinical, and Pfizer.
AT EASD 2017
Key clinical point:
Major finding: Dapagliflozin 5 mg and 10 mg reduced HbA1c from Week 0 to Week 24 more (0.42% and 0.45%, respectively) than did placebo (both P less than .0001).
Data source: A phase 3 randomized, double-blind, parallel-controlled, multicenter trial conducted in 833 people with type 1 diabetes.
Disclosures: AstraZeneca and Bristol-Myers Squibb funded the study. Dr. Dandona disclosed acting as a consultant to AstraZeneca, Novo Nordisk, Sanofi-Aventis, Merck, Intarcia, and AbbVie, as well as receiving research support from AstraZeneca, Novo Nordisk, Boehringer Ingelheim, and AbbVie. Dr. Petrie disclosed receiving personal fees and travel expenses from Novo Nordisk; grants and personal fees from Sanofi-Aventis, Quintiles, and Janssen; nonfinancial support from Merck and Itamar Medical; and personal fees from Lilly, ACI Clinical, and Pfizer.