A thrice-a-week insulin shot instead of the once-a-day shot at present could soon be a reality.
Doctors from India, Canada, US and South Africa have jointly tested the most promising new form of long- acting insulin ‒ degludec ‒ needed once every 48 hours, and found it to be as good in controlling blood sugar as the presently used insulin of choice, glargine (e.g. Lantus), which is a 24-hour shot.
This means that once in the market, the number of injections needed by a type-2 diabetic patient would be cut by half every week. It will also make insulin shots cheaper for patients. Pharma giant Novo Nordisk of Denmark, which funded the study, hopes to apply for licensing approval to market the drug in 2013.
However, the findings still need to be confirmed in another phase of research, and it's not clear how much the drug would cost if it were approved for this use. The Phase 2 trial results were published this week in the medical journal The Lancet.
Nonetheless, the findings are promising because most patients with diabetes don't want to have injections at all, if they can help it. And those who have to take them would prefer less. Moreover, each additional injection per day is a financial burden.
Announcing the results of their 16-week, phase-II trial of degludec in the medical journal Lancet, scientists said, "In this 16-week randomized trial, participants aged 18-75 years with type-2 diabetes and glycosylated hemoglobin (HbA1C) of 7-11% were enrolled and treated at 28 clinical sites in Canada, India, South Africa and US. At study end, mean HbA1c levels were much the same across treatment groups and insulin degludec provided comparable glycemic control to insulin glargine without additional adverse events. This might reduce dosing frequency due to its ultra-long action profile.”
The novel insulin releases over several days appears as effective as once-daily standard insulin in type 2 diabetes, an open-label trial found. HbA1c levels reached a similar 7.2% to 7.5% over 16 weeks whether patients got the novel insulin degludec three times a week or once daily, or standard insulin glargine (e.g. Lantus) once daily, Bernard Zinman, MD, of Mount Sinai Hospital at the University of Toronto, and colleagues reported online in The Lancet.
Adverse events, including hypoglycemia, were likewise comparable across the insulin groups in the phase II study, mirroring what Zinman initially presented at the American Diabetes Association meeting last summer.
"Insulin degludec is an ultra-long-acting insulin in clinical development. Its features suggest that the risk of hypoglycemia might be reduced and clinical effectiveness might be achievable with dosing three times a week in people with type-2 diabetes who were previously insulin-naive which could help with early initiation of and adherence to insulin treatment," the study says.
"It's an exciting new insulin, it's an ultra-long-acting insulin and the real issue is, of course, this is a small study, a proof-of-concept study, and we have to wait for the results of much larger studies to know where its place will be in a clinical setting," Zinman said in an interview. "It just has a much longer half-life, much more than 24 hours, compared to the other insulin and may provide some additional advantage."
However, Zinman said he doesn't see that three-times-per-week injections will be a common way to treat diabetes. "When you inject three times a week, the doses have to be increased so that it covers the full week, and in those circumstances, the benefits with respect to reducing the rates of hypoglycemia are not there," he said.
"Personally, I wouldn't use it that way. I would use it as once-daily insulin,” said Zinman, but he thinks if people do forget to take their insulin on occasion, this would be more forgiving. "We find people do occasionally forget their insulin, so this may — because it has a longer half-life and hangs around longer — that may be an advantage. I think we need to do studies to really see if that's the case."
However, topline results from a more recent phase III study comparing insulin degludec to insulin glargine again showed virtually identical glycemic control without a significant difference in hypoglycemia between groups.
While it had been hoped that the ultra-long-acting formulation might actually reduce hypoglycemia episodes, the chance to cut down on dosing frequency would be a valuable feature for clinical practice even without a safety or efficacy advantage over current basal insulin choices, Zinman's group suggested.
"A three-times-a-week, weekend-off, dosing regimen might appeal to some people with type 2 diabetes who are inadequately controlled on oral anti-diabetic drug treatments, potentially helping with acceptance and early initiation of insulin therapy," they wrote in the paper.
A longer dosing interval could be important in boosting adherence as well, and with less disruption to patients' lifestyle, Yogish C. Kudva, MBBS, and Ananda Basu, MBBS, both of the Mayo Clinic in Rochester, Minn., noted in an accompanying commentary.
But regardless of increasing numbers of long-acting options in diabetes treatment, lifestyle changes can't be overlooked, they urged.
"It is extremely worthwhile to remember that therapeutic lifestyle changes are inexpensive and favorable on a risk–benefit basis and need persistent re-emphasis, as is being done for the financial benefits accruing to patients from their employer and insurance by doing so," Kudva and Basu wrote in the commentary.
The proof-of-concept study by Zinman's group randomized 245 insulin-naive patients with inadequately controlled type 2 diabetes to open-label treatment at 28 centers internationally with one of the following regimens in combination with metformin:
• Insulin degludec three times a week ‒ Monday, Wednesday, and Friday evenings -- with a starting dose of 20 U per injection
• Insulin degludec in a 600 nmol/mL formulation once a day, with a starting dose of 10 U per injection
• Insulin degludec in a 900 nmol/mL formulation once a day, also at a starting dose of 10 U per injection
• Insulin glargine once a day, at a starting dose of 10 U per injection
Mean reductions in HbA1c over 16 weeks of treatment hit 1.3% to 1.5% in all the groups without significant differences among them. Nor were fasting plasma glucose concentrations any different between groups by the end of the study.
Confirmed hypoglycemia episodes of glucose falling below 55.8 mg/dL or requiring assistance occurred among 23% of patients on thrice-weekly insulin degludec or insulin glargine but 8% to 15% of those on once-daily insulin degludec. Although the difference between the highest and lowest rates was significant, the researchers noted that the 95% confidence intervals overlapped among all the between-group comparisons.
Nocturnal hypoglycemia by the same measure was uncommon, at 0% to 5% across groups, which the researchers attributed in part to the short duration of diabetes in the cohort.
However, as was pointed out at the ADA presentation of the data, the 55.8 mg/dL threshold may have missed hypoglycemia cases by the more standard 70 mg/dL criteria.
Diabetes specialist Dr. Vivian Fonseca, who chairs the endocrinology section at Tulane University Health Sciences Center, cautioned that more research is needed to determine if people who take the drug will face a higher risk of low blood sugar.
That's a major problem for people who currently take insulin medications, she said, as is the unpredictability of the drugs. "You give the same dose to the same person every day, and the next morning you get a different result," Fonseca said. "That is challenging for patients."
The researchers also reported that body weight remained stable throughout the trial for all treatment groups, and they pointed to "no apparent treatment-specific patterns or clustering of adverse events."
However, they cautioned about drawing firm conclusions on safety or efficacy based on the phase II data and noted that the open-label design used because of the different insulin-injection systems for the drugs might have impacted efforts to get glucose under control, as well as reporting of hypoglycemia and adverse events.
Dr Anoop Misra, chairman of Fortis Hospital's Centre of Excellence for Diabetes in New Delhi, India, said, "This is quite a breakthrough. For the first time, we have a ultra-long acting insulin with stable action. This will lead to lesser injections (once in two days) for the patients with good blood sugar control…Till now, all long acting insulin shots are for 24 hours."
It typically takes years for a drug to go through research and get approval from the U.S. government. The three-times-a-week degludec needs just one more phase of research, however, meaning that it could be on the market fairly soon if it's found to be effective. There's no indication of how much it would cost, although Kudva said it's fair to assume that it will be more expensive than insulin is today.
But one thing remains clear, Kudva said: "The most effective treatment for diabetes, a treatment that is worth doing throughout life, is attention to diet and exercise and working on one's weight. These are difficult to achieve, but even as every new medication comes, there's no getting away from that."
The study was sponsored by the drug maker Novo Nordisk of Denmark, and three of the paper's authors are employees of the company and own stock. Zinman, who helped design the study and obtain and interpret the data, has received fees for consultancy and honoraria for membership of advisory boards from Novo Nordisk and a number of other drug companies.
Doctors from India, Canada, US and South Africa have jointly tested the most promising new form of long- acting insulin ‒ degludec ‒ needed once every 48 hours, and found it to be as good in controlling blood sugar as the presently used insulin of choice, glargine (e.g. Lantus), which is a 24-hour shot.
This means that once in the market, the number of injections needed by a type-2 diabetic patient would be cut by half every week. It will also make insulin shots cheaper for patients. Pharma giant Novo Nordisk of Denmark, which funded the study, hopes to apply for licensing approval to market the drug in 2013.
However, the findings still need to be confirmed in another phase of research, and it's not clear how much the drug would cost if it were approved for this use. The Phase 2 trial results were published this week in the medical journal The Lancet.
Nonetheless, the findings are promising because most patients with diabetes don't want to have injections at all, if they can help it. And those who have to take them would prefer less. Moreover, each additional injection per day is a financial burden.
Announcing the results of their 16-week, phase-II trial of degludec in the medical journal Lancet, scientists said, "In this 16-week randomized trial, participants aged 18-75 years with type-2 diabetes and glycosylated hemoglobin (HbA1C) of 7-11% were enrolled and treated at 28 clinical sites in Canada, India, South Africa and US. At study end, mean HbA1c levels were much the same across treatment groups and insulin degludec provided comparable glycemic control to insulin glargine without additional adverse events. This might reduce dosing frequency due to its ultra-long action profile.”
The novel insulin releases over several days appears as effective as once-daily standard insulin in type 2 diabetes, an open-label trial found. HbA1c levels reached a similar 7.2% to 7.5% over 16 weeks whether patients got the novel insulin degludec three times a week or once daily, or standard insulin glargine (e.g. Lantus) once daily, Bernard Zinman, MD, of Mount Sinai Hospital at the University of Toronto, and colleagues reported online in The Lancet.
Adverse events, including hypoglycemia, were likewise comparable across the insulin groups in the phase II study, mirroring what Zinman initially presented at the American Diabetes Association meeting last summer.
"Insulin degludec is an ultra-long-acting insulin in clinical development. Its features suggest that the risk of hypoglycemia might be reduced and clinical effectiveness might be achievable with dosing three times a week in people with type-2 diabetes who were previously insulin-naive which could help with early initiation of and adherence to insulin treatment," the study says.
"It's an exciting new insulin, it's an ultra-long-acting insulin and the real issue is, of course, this is a small study, a proof-of-concept study, and we have to wait for the results of much larger studies to know where its place will be in a clinical setting," Zinman said in an interview. "It just has a much longer half-life, much more than 24 hours, compared to the other insulin and may provide some additional advantage."
However, Zinman said he doesn't see that three-times-per-week injections will be a common way to treat diabetes. "When you inject three times a week, the doses have to be increased so that it covers the full week, and in those circumstances, the benefits with respect to reducing the rates of hypoglycemia are not there," he said.
"Personally, I wouldn't use it that way. I would use it as once-daily insulin,” said Zinman, but he thinks if people do forget to take their insulin on occasion, this would be more forgiving. "We find people do occasionally forget their insulin, so this may — because it has a longer half-life and hangs around longer — that may be an advantage. I think we need to do studies to really see if that's the case."
However, topline results from a more recent phase III study comparing insulin degludec to insulin glargine again showed virtually identical glycemic control without a significant difference in hypoglycemia between groups.
While it had been hoped that the ultra-long-acting formulation might actually reduce hypoglycemia episodes, the chance to cut down on dosing frequency would be a valuable feature for clinical practice even without a safety or efficacy advantage over current basal insulin choices, Zinman's group suggested.
"A three-times-a-week, weekend-off, dosing regimen might appeal to some people with type 2 diabetes who are inadequately controlled on oral anti-diabetic drug treatments, potentially helping with acceptance and early initiation of insulin therapy," they wrote in the paper.
A longer dosing interval could be important in boosting adherence as well, and with less disruption to patients' lifestyle, Yogish C. Kudva, MBBS, and Ananda Basu, MBBS, both of the Mayo Clinic in Rochester, Minn., noted in an accompanying commentary.
But regardless of increasing numbers of long-acting options in diabetes treatment, lifestyle changes can't be overlooked, they urged.
"It is extremely worthwhile to remember that therapeutic lifestyle changes are inexpensive and favorable on a risk–benefit basis and need persistent re-emphasis, as is being done for the financial benefits accruing to patients from their employer and insurance by doing so," Kudva and Basu wrote in the commentary.
The proof-of-concept study by Zinman's group randomized 245 insulin-naive patients with inadequately controlled type 2 diabetes to open-label treatment at 28 centers internationally with one of the following regimens in combination with metformin:
• Insulin degludec three times a week ‒ Monday, Wednesday, and Friday evenings -- with a starting dose of 20 U per injection
• Insulin degludec in a 600 nmol/mL formulation once a day, with a starting dose of 10 U per injection
• Insulin degludec in a 900 nmol/mL formulation once a day, also at a starting dose of 10 U per injection
• Insulin glargine once a day, at a starting dose of 10 U per injection
Mean reductions in HbA1c over 16 weeks of treatment hit 1.3% to 1.5% in all the groups without significant differences among them. Nor were fasting plasma glucose concentrations any different between groups by the end of the study.
Confirmed hypoglycemia episodes of glucose falling below 55.8 mg/dL or requiring assistance occurred among 23% of patients on thrice-weekly insulin degludec or insulin glargine but 8% to 15% of those on once-daily insulin degludec. Although the difference between the highest and lowest rates was significant, the researchers noted that the 95% confidence intervals overlapped among all the between-group comparisons.
Nocturnal hypoglycemia by the same measure was uncommon, at 0% to 5% across groups, which the researchers attributed in part to the short duration of diabetes in the cohort.
However, as was pointed out at the ADA presentation of the data, the 55.8 mg/dL threshold may have missed hypoglycemia cases by the more standard 70 mg/dL criteria.
Diabetes specialist Dr. Vivian Fonseca, who chairs the endocrinology section at Tulane University Health Sciences Center, cautioned that more research is needed to determine if people who take the drug will face a higher risk of low blood sugar.
That's a major problem for people who currently take insulin medications, she said, as is the unpredictability of the drugs. "You give the same dose to the same person every day, and the next morning you get a different result," Fonseca said. "That is challenging for patients."
The researchers also reported that body weight remained stable throughout the trial for all treatment groups, and they pointed to "no apparent treatment-specific patterns or clustering of adverse events."
However, they cautioned about drawing firm conclusions on safety or efficacy based on the phase II data and noted that the open-label design used because of the different insulin-injection systems for the drugs might have impacted efforts to get glucose under control, as well as reporting of hypoglycemia and adverse events.
Dr Anoop Misra, chairman of Fortis Hospital's Centre of Excellence for Diabetes in New Delhi, India, said, "This is quite a breakthrough. For the first time, we have a ultra-long acting insulin with stable action. This will lead to lesser injections (once in two days) for the patients with good blood sugar control…Till now, all long acting insulin shots are for 24 hours."
It typically takes years for a drug to go through research and get approval from the U.S. government. The three-times-a-week degludec needs just one more phase of research, however, meaning that it could be on the market fairly soon if it's found to be effective. There's no indication of how much it would cost, although Kudva said it's fair to assume that it will be more expensive than insulin is today.
But one thing remains clear, Kudva said: "The most effective treatment for diabetes, a treatment that is worth doing throughout life, is attention to diet and exercise and working on one's weight. These are difficult to achieve, but even as every new medication comes, there's no getting away from that."
The study was sponsored by the drug maker Novo Nordisk of Denmark, and three of the paper's authors are employees of the company and own stock. Zinman, who helped design the study and obtain and interpret the data, has received fees for consultancy and honoraria for membership of advisory boards from Novo Nordisk and a number of other drug companies.
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