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Mitchel is a reporter for MDedge based in the Philadelphia area. He started with the company in 1992, when it was International Medical News Group (IMNG), and has since covered a range of medical specialties. Mitchel trained as a virologist at Roswell Park Memorial Institute in Buffalo, and then worked briefly as a researcher at Boston Children's Hospital before pivoting to journalism as a AAAS Mass Media Fellow in 1980. His first reporting job was with Science Digest magazine, and from the mid-1980s to early-1990s he was a reporter with Medical World News. @mitchelzoler
More from DAPA-HF: Dapagliflozin quickly reduces heart failure events
Dapagliflozin’s benefits in patients with heart failure with reduced ejection fraction appeared quickly after treatment began, and patients who had been hospitalized for heart failure within the prior year got the biggest boost from the drug, according to secondary analyses of the more than 4,700-patient DAPA-HF trial.
Dapagliflozin’s significant reduction of the incidence of cardiovascular death or worsening heart failure became apparent in DAPA-HF within 28 days after patients started treatment, by which time those on the study drug had a 49% cut in this combined endpoint, compared with patients on placebo, David D. Berg, MD, and associates said in a recent report published in JAMA Cardiology.
Their analyses also showed that the absolute reduction linked with dapagliflozin treatment for this primary endpoint of the study (which classified worsening heart failure as either hospitalization for heart failure or an urgent visit because of heart failure that required intravenous therapy) was greatest, 10% during 2 years of follow-up, among the roughly one-quarter of enrolled patients who had been hospitalized for heart failure within 12 months of entering the study. Patients previously hospitalized for heart failure more than 12 months before they entered DAPA-HF had a 4% absolute cut in their primary-outcome events during the trial, and those who had never been hospitalized for heart failure had a 2% absolute benefit, compared with placebo, during 2 years of follow-up.
These findings were consistent with the timing of benefits for patients with heart failure with reduced ejection fraction (HFrEF) in recent studies of two other drugs from the same class, the sodium-glucose cotransporter (SGLT) inhibitors, including empagliflozin (Jardiance, which inhibits SGLT-2) in the EMPEROR-Reduced trial, and sotagliflozin (Zynquista, which inhibits both SGLT1 and -2) in the SOLOIST-WHF trial, noted Gregg C. Fonarow, MD, and Clyde W. Yancy, MD, in an editor’s note that accompanied the new report.
The new findings show “the opportunity to expeditiously implement this remarkable class of therapy for HFrEF is now compelling and deserves disruptive efforts to ensure comprehensive treatment and the best patient outcomes,” wrote Dr. Fonarow, a professor of medicine at the University of California, Los Angeles, and Dr. Yancy, a professor of medicine at Northwestern University, Chicago.
But despite these new findings, their exact meaning remains unclear in terms of when to start dapagliflozin (or a different drug from the same class), compared with the other drug classes that have proven highly effective in patients with HFrEF, and exactly how long after hospitalization for heart failure dapagliflozin can safely and effectively begin.
Data needed on starting an SGLT inhibitor soon after hospitalization in patients without diabetes
“DAPA-HF showed that, in patients with or without diabetes, an SGLT2 inhibitor reduced the risk of cardiovascular death or worsening heart failure in patients with stable HFrEF. SOLOIST-WHF looked strictly at patients with diabetes, and showed that a combined SGLT1 and SGLT2 inhibitor could reduce the risk of cardiovascular death or worsening heart failure in patients with recently decompensated heart failure,” Dr. Berg, a cardiologist at Brigham and Women’s Hospital in Boston, noted in an interview. “What we don’t have is a trial focused exclusively on enrolling patients while hospitalized with acute heart failure, irrespective of whether they have diabetes, and testing the immediate clinical efficacy and safety of starting an SGLT2 inhibitor. That is what we are testing with the ongoing DAPA ACT HF-TIMI 68 trial.”
In addition, updated recommendations from the American College of Cardiology on initiating drug therapy in patients newly diagnosed with HFrEF that appeared in early 2021 promoted a sequence that starts most patients on sacubitril/valsartan (Entresto) and a beta-blocker, followed by a diuretic (when needed), a mineralocorticoid receptor agonist, and then an SGLT inhibitor. The recommendations note that starting a patient on all these drug classes could take 3-6 months.
“There are intense debates about the optimal sequence for introducing these therapies, and I don’t think we have solid data to suggest that one sequence is clearly better than another,” noted Dr. Berg. “A one-size-fits-all approach probably doesn’t make sense. For example, each of these therapies has a different set of effects on heart rate and blood pressure, and each has a unique side effect profile, so clinicians will often need to tailor the treatment approach to the patient. And, of course, cost is an important consideration. Although the optimal time to start an SGLT2 inhibitor remains uncertain, the results of our analysis suggest that waiting may result in preventable adverse heart failure events.”
DAPA-HF randomized 4,744 patients with HFrEF and in New York Heart Association functional class II-IV at 410 sites in 20 countries. The incidence of the primary, combined endpoint fell by 26% with dapagliflozin treatment, compared with placebo, during a median 18-month follow-up. Among the study cohort 27% of patients had been hospitalized for heart failure within a year of their entry, 20% had been hospitalized for heart failure more than 1 year before entry, and 53% had no history of a hospitalization for heart failure.
DAPA-HF was sponsored by AstraZeneca, the company that markets dapagliflozin (Farxiga). Dr. Berg has received research support through his institution from AstraZeneca. Dr. Fonarow has received personal fees from AstraZeneca and from numerous other companies. Dr. Yancy’s spouse works for Abbott Laboratories.
Dapagliflozin’s benefits in patients with heart failure with reduced ejection fraction appeared quickly after treatment began, and patients who had been hospitalized for heart failure within the prior year got the biggest boost from the drug, according to secondary analyses of the more than 4,700-patient DAPA-HF trial.
Dapagliflozin’s significant reduction of the incidence of cardiovascular death or worsening heart failure became apparent in DAPA-HF within 28 days after patients started treatment, by which time those on the study drug had a 49% cut in this combined endpoint, compared with patients on placebo, David D. Berg, MD, and associates said in a recent report published in JAMA Cardiology.
Their analyses also showed that the absolute reduction linked with dapagliflozin treatment for this primary endpoint of the study (which classified worsening heart failure as either hospitalization for heart failure or an urgent visit because of heart failure that required intravenous therapy) was greatest, 10% during 2 years of follow-up, among the roughly one-quarter of enrolled patients who had been hospitalized for heart failure within 12 months of entering the study. Patients previously hospitalized for heart failure more than 12 months before they entered DAPA-HF had a 4% absolute cut in their primary-outcome events during the trial, and those who had never been hospitalized for heart failure had a 2% absolute benefit, compared with placebo, during 2 years of follow-up.
These findings were consistent with the timing of benefits for patients with heart failure with reduced ejection fraction (HFrEF) in recent studies of two other drugs from the same class, the sodium-glucose cotransporter (SGLT) inhibitors, including empagliflozin (Jardiance, which inhibits SGLT-2) in the EMPEROR-Reduced trial, and sotagliflozin (Zynquista, which inhibits both SGLT1 and -2) in the SOLOIST-WHF trial, noted Gregg C. Fonarow, MD, and Clyde W. Yancy, MD, in an editor’s note that accompanied the new report.
The new findings show “the opportunity to expeditiously implement this remarkable class of therapy for HFrEF is now compelling and deserves disruptive efforts to ensure comprehensive treatment and the best patient outcomes,” wrote Dr. Fonarow, a professor of medicine at the University of California, Los Angeles, and Dr. Yancy, a professor of medicine at Northwestern University, Chicago.
But despite these new findings, their exact meaning remains unclear in terms of when to start dapagliflozin (or a different drug from the same class), compared with the other drug classes that have proven highly effective in patients with HFrEF, and exactly how long after hospitalization for heart failure dapagliflozin can safely and effectively begin.
Data needed on starting an SGLT inhibitor soon after hospitalization in patients without diabetes
“DAPA-HF showed that, in patients with or without diabetes, an SGLT2 inhibitor reduced the risk of cardiovascular death or worsening heart failure in patients with stable HFrEF. SOLOIST-WHF looked strictly at patients with diabetes, and showed that a combined SGLT1 and SGLT2 inhibitor could reduce the risk of cardiovascular death or worsening heart failure in patients with recently decompensated heart failure,” Dr. Berg, a cardiologist at Brigham and Women’s Hospital in Boston, noted in an interview. “What we don’t have is a trial focused exclusively on enrolling patients while hospitalized with acute heart failure, irrespective of whether they have diabetes, and testing the immediate clinical efficacy and safety of starting an SGLT2 inhibitor. That is what we are testing with the ongoing DAPA ACT HF-TIMI 68 trial.”
In addition, updated recommendations from the American College of Cardiology on initiating drug therapy in patients newly diagnosed with HFrEF that appeared in early 2021 promoted a sequence that starts most patients on sacubitril/valsartan (Entresto) and a beta-blocker, followed by a diuretic (when needed), a mineralocorticoid receptor agonist, and then an SGLT inhibitor. The recommendations note that starting a patient on all these drug classes could take 3-6 months.
“There are intense debates about the optimal sequence for introducing these therapies, and I don’t think we have solid data to suggest that one sequence is clearly better than another,” noted Dr. Berg. “A one-size-fits-all approach probably doesn’t make sense. For example, each of these therapies has a different set of effects on heart rate and blood pressure, and each has a unique side effect profile, so clinicians will often need to tailor the treatment approach to the patient. And, of course, cost is an important consideration. Although the optimal time to start an SGLT2 inhibitor remains uncertain, the results of our analysis suggest that waiting may result in preventable adverse heart failure events.”
DAPA-HF randomized 4,744 patients with HFrEF and in New York Heart Association functional class II-IV at 410 sites in 20 countries. The incidence of the primary, combined endpoint fell by 26% with dapagliflozin treatment, compared with placebo, during a median 18-month follow-up. Among the study cohort 27% of patients had been hospitalized for heart failure within a year of their entry, 20% had been hospitalized for heart failure more than 1 year before entry, and 53% had no history of a hospitalization for heart failure.
DAPA-HF was sponsored by AstraZeneca, the company that markets dapagliflozin (Farxiga). Dr. Berg has received research support through his institution from AstraZeneca. Dr. Fonarow has received personal fees from AstraZeneca and from numerous other companies. Dr. Yancy’s spouse works for Abbott Laboratories.
Dapagliflozin’s benefits in patients with heart failure with reduced ejection fraction appeared quickly after treatment began, and patients who had been hospitalized for heart failure within the prior year got the biggest boost from the drug, according to secondary analyses of the more than 4,700-patient DAPA-HF trial.
Dapagliflozin’s significant reduction of the incidence of cardiovascular death or worsening heart failure became apparent in DAPA-HF within 28 days after patients started treatment, by which time those on the study drug had a 49% cut in this combined endpoint, compared with patients on placebo, David D. Berg, MD, and associates said in a recent report published in JAMA Cardiology.
Their analyses also showed that the absolute reduction linked with dapagliflozin treatment for this primary endpoint of the study (which classified worsening heart failure as either hospitalization for heart failure or an urgent visit because of heart failure that required intravenous therapy) was greatest, 10% during 2 years of follow-up, among the roughly one-quarter of enrolled patients who had been hospitalized for heart failure within 12 months of entering the study. Patients previously hospitalized for heart failure more than 12 months before they entered DAPA-HF had a 4% absolute cut in their primary-outcome events during the trial, and those who had never been hospitalized for heart failure had a 2% absolute benefit, compared with placebo, during 2 years of follow-up.
These findings were consistent with the timing of benefits for patients with heart failure with reduced ejection fraction (HFrEF) in recent studies of two other drugs from the same class, the sodium-glucose cotransporter (SGLT) inhibitors, including empagliflozin (Jardiance, which inhibits SGLT-2) in the EMPEROR-Reduced trial, and sotagliflozin (Zynquista, which inhibits both SGLT1 and -2) in the SOLOIST-WHF trial, noted Gregg C. Fonarow, MD, and Clyde W. Yancy, MD, in an editor’s note that accompanied the new report.
The new findings show “the opportunity to expeditiously implement this remarkable class of therapy for HFrEF is now compelling and deserves disruptive efforts to ensure comprehensive treatment and the best patient outcomes,” wrote Dr. Fonarow, a professor of medicine at the University of California, Los Angeles, and Dr. Yancy, a professor of medicine at Northwestern University, Chicago.
But despite these new findings, their exact meaning remains unclear in terms of when to start dapagliflozin (or a different drug from the same class), compared with the other drug classes that have proven highly effective in patients with HFrEF, and exactly how long after hospitalization for heart failure dapagliflozin can safely and effectively begin.
Data needed on starting an SGLT inhibitor soon after hospitalization in patients without diabetes
“DAPA-HF showed that, in patients with or without diabetes, an SGLT2 inhibitor reduced the risk of cardiovascular death or worsening heart failure in patients with stable HFrEF. SOLOIST-WHF looked strictly at patients with diabetes, and showed that a combined SGLT1 and SGLT2 inhibitor could reduce the risk of cardiovascular death or worsening heart failure in patients with recently decompensated heart failure,” Dr. Berg, a cardiologist at Brigham and Women’s Hospital in Boston, noted in an interview. “What we don’t have is a trial focused exclusively on enrolling patients while hospitalized with acute heart failure, irrespective of whether they have diabetes, and testing the immediate clinical efficacy and safety of starting an SGLT2 inhibitor. That is what we are testing with the ongoing DAPA ACT HF-TIMI 68 trial.”
In addition, updated recommendations from the American College of Cardiology on initiating drug therapy in patients newly diagnosed with HFrEF that appeared in early 2021 promoted a sequence that starts most patients on sacubitril/valsartan (Entresto) and a beta-blocker, followed by a diuretic (when needed), a mineralocorticoid receptor agonist, and then an SGLT inhibitor. The recommendations note that starting a patient on all these drug classes could take 3-6 months.
“There are intense debates about the optimal sequence for introducing these therapies, and I don’t think we have solid data to suggest that one sequence is clearly better than another,” noted Dr. Berg. “A one-size-fits-all approach probably doesn’t make sense. For example, each of these therapies has a different set of effects on heart rate and blood pressure, and each has a unique side effect profile, so clinicians will often need to tailor the treatment approach to the patient. And, of course, cost is an important consideration. Although the optimal time to start an SGLT2 inhibitor remains uncertain, the results of our analysis suggest that waiting may result in preventable adverse heart failure events.”
DAPA-HF randomized 4,744 patients with HFrEF and in New York Heart Association functional class II-IV at 410 sites in 20 countries. The incidence of the primary, combined endpoint fell by 26% with dapagliflozin treatment, compared with placebo, during a median 18-month follow-up. Among the study cohort 27% of patients had been hospitalized for heart failure within a year of their entry, 20% had been hospitalized for heart failure more than 1 year before entry, and 53% had no history of a hospitalization for heart failure.
DAPA-HF was sponsored by AstraZeneca, the company that markets dapagliflozin (Farxiga). Dr. Berg has received research support through his institution from AstraZeneca. Dr. Fonarow has received personal fees from AstraZeneca and from numerous other companies. Dr. Yancy’s spouse works for Abbott Laboratories.
FROM JAMA CARDIOLOGY
Long-term metformin use linked to fewer ER+ breast cancers
.
Conversely, the results also showed higher rates of ER-negative and triple-negative breast cancer among women with type 2 diabetes who received metformin, although case numbers were small.
“Our conclusion that having type 2 diabetes increases the risk of developing breast cancer but taking metformin may protect against developing ER-positive breast cancer – but not other types of breast cancer – is biologically plausible and supported by our results, even though some [endpoints] are not statistically significant,” senior author Dale P. Sandler, PhD, chief of the epidemiology branch, National Institute of Environmental Health Sciences, Research Triangle Park, N.C., said in an interview.
“Among our findings that are not statistically significant are several that helped us get a better picture of the relationships between type 2 diabetes, metformin treatment, and breast cancer risk,” Dr. Sandler added.
The results were published online Jan. 28 in Annals of Oncology by Yong-Moon Mark Park, MD, PhD, now an epidemiologist at the University of Arkansas for Medical Sciences in Little Rock, and colleagues.
Sara P. Cate, MD, a breast cancer surgeon at Mount Sinai Medical Center in New York, who was not involved with the study, said: “Certainly, metformin helps with weight loss, which is linked with estrogen-driven breast cancers, so this may explain why fewer patients on metformin got this type of breast cancer.”
A tangled web ... with no clear conclusions yet
But in an accompanying editorial, Ana E. Lohmann, MD, PhD, and Pamela J. Goodwin, MD, say that, while this is “a large, well-designed prospective cohort study,” it tells a complicated story.
“The report by Park adds to the growing evidence linking type 2 diabetes and its treatment to breast cancer risk, but definitive conclusions regarding these associations are not yet possible,” they observe.
The “largely negative” results of the new study perhaps in part occurred because the cohort included only 277 women with type 2 diabetes diagnosed with incident breast cancer, note Dr. Lohmann, of London Health Sciences Centre, University of Western Ontario, and Dr. Goodwin, of Mount Sinai Hospital, Toronto.
“Clearly, this is an important area, and additional research is needed to untangle the web of inter-related associations of type 2 diabetes, its treatment, and breast cancer risk,” they write.
Examination of the effects of metformin in studies such as the Canadian Cancer Trial Group MA.32, a phase 3 trial of over 3,500 women with hormone receptor–positive early-stage breast cancer who are being randomized to metformin or placebo for up to 5 years in addition to standard adjuvant therapy, will provide further insights, they observe. The trial is slated to be completed in February 2022.
Study followed women whose sisters had breast cancer
The new data come from the Sister Study, which followed more than 50,000 women without a history of breast cancer who had sisters or half-sisters with a breast cancer diagnosis. The study, run by the NIEHS, enrolled women 35-74 years old from all 50 U.S. states and Puerto Rico in 2003-2009.
The current analysis excluded women with a history of any other type of cancer, missing data about diabetes, or an uncertain breast cancer diagnosis during the study, which left 44,541 available for study. At entry, 7% of the women had type 2 diabetes, and another 5% developed new-onset type 2 diabetes during follow-up.
Among those with diabetes, 61% received treatment with metformin either alone or with other antidiabetic drugs.
During a median follow-up of 8.6 years, 2,678 women received a diagnosis of primary breast cancer, either invasive or ductal carcinoma in situ.
In a series of multivariate analyses that adjusted for numerous potential confounders, the authors found that, overall, no association existed between diabetes and breast cancer incidence, with a hazard ratio of 0.99, compared with women without diabetes.
But, said Dr. Sandler, “there is a strong biological rationale to hypothesize that type 2 diabetes increases the risk for breast cancer, and results from earlier studies support this.”
Association of metformin and breast cancer
Women with type 2 diabetes who received metformin had a 14% lower rate of ER-positive breast cancer, compared with women with diabetes not taking metformin, a nonsignificant association.
Among women taking metformin for at least 10 years, the associated reduction in ER-positive breast cancer, compared with those who did not take it, was 38%, a difference that just missed significance, with a 95% confidence interval of 0.38-1.01.
In contrast, cases of ER-negative and triple-negative breast cancers increased in the women with diabetes taking metformin. The hazard ratio for ER-negative tumors showed a nonsignificant 25% relative increase in women taking metformin and a significant 74% increase in triple-negative cancers.
The editorialists note, however, that “the number of patients who were found to have triple-negative breast cancer was small [so] we cannot draw any practice-changing conclusions from it.”
In conclusion, Dr. Park and colleagues reiterate: “Our analysis is consistent with a potential protective effect of metformin and suggests that long-term use of metformin may reduce breast cancer risk associated with type 2 diabetes.”
The study received no commercial funding. Dr. Sandler, Dr. Park, Dr. Lohmann, Dr. Goodwin, and Dr. Cate have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
.
Conversely, the results also showed higher rates of ER-negative and triple-negative breast cancer among women with type 2 diabetes who received metformin, although case numbers were small.
“Our conclusion that having type 2 diabetes increases the risk of developing breast cancer but taking metformin may protect against developing ER-positive breast cancer – but not other types of breast cancer – is biologically plausible and supported by our results, even though some [endpoints] are not statistically significant,” senior author Dale P. Sandler, PhD, chief of the epidemiology branch, National Institute of Environmental Health Sciences, Research Triangle Park, N.C., said in an interview.
“Among our findings that are not statistically significant are several that helped us get a better picture of the relationships between type 2 diabetes, metformin treatment, and breast cancer risk,” Dr. Sandler added.
The results were published online Jan. 28 in Annals of Oncology by Yong-Moon Mark Park, MD, PhD, now an epidemiologist at the University of Arkansas for Medical Sciences in Little Rock, and colleagues.
Sara P. Cate, MD, a breast cancer surgeon at Mount Sinai Medical Center in New York, who was not involved with the study, said: “Certainly, metformin helps with weight loss, which is linked with estrogen-driven breast cancers, so this may explain why fewer patients on metformin got this type of breast cancer.”
A tangled web ... with no clear conclusions yet
But in an accompanying editorial, Ana E. Lohmann, MD, PhD, and Pamela J. Goodwin, MD, say that, while this is “a large, well-designed prospective cohort study,” it tells a complicated story.
“The report by Park adds to the growing evidence linking type 2 diabetes and its treatment to breast cancer risk, but definitive conclusions regarding these associations are not yet possible,” they observe.
The “largely negative” results of the new study perhaps in part occurred because the cohort included only 277 women with type 2 diabetes diagnosed with incident breast cancer, note Dr. Lohmann, of London Health Sciences Centre, University of Western Ontario, and Dr. Goodwin, of Mount Sinai Hospital, Toronto.
“Clearly, this is an important area, and additional research is needed to untangle the web of inter-related associations of type 2 diabetes, its treatment, and breast cancer risk,” they write.
Examination of the effects of metformin in studies such as the Canadian Cancer Trial Group MA.32, a phase 3 trial of over 3,500 women with hormone receptor–positive early-stage breast cancer who are being randomized to metformin or placebo for up to 5 years in addition to standard adjuvant therapy, will provide further insights, they observe. The trial is slated to be completed in February 2022.
Study followed women whose sisters had breast cancer
The new data come from the Sister Study, which followed more than 50,000 women without a history of breast cancer who had sisters or half-sisters with a breast cancer diagnosis. The study, run by the NIEHS, enrolled women 35-74 years old from all 50 U.S. states and Puerto Rico in 2003-2009.
The current analysis excluded women with a history of any other type of cancer, missing data about diabetes, or an uncertain breast cancer diagnosis during the study, which left 44,541 available for study. At entry, 7% of the women had type 2 diabetes, and another 5% developed new-onset type 2 diabetes during follow-up.
Among those with diabetes, 61% received treatment with metformin either alone or with other antidiabetic drugs.
During a median follow-up of 8.6 years, 2,678 women received a diagnosis of primary breast cancer, either invasive or ductal carcinoma in situ.
In a series of multivariate analyses that adjusted for numerous potential confounders, the authors found that, overall, no association existed between diabetes and breast cancer incidence, with a hazard ratio of 0.99, compared with women without diabetes.
But, said Dr. Sandler, “there is a strong biological rationale to hypothesize that type 2 diabetes increases the risk for breast cancer, and results from earlier studies support this.”
Association of metformin and breast cancer
Women with type 2 diabetes who received metformin had a 14% lower rate of ER-positive breast cancer, compared with women with diabetes not taking metformin, a nonsignificant association.
Among women taking metformin for at least 10 years, the associated reduction in ER-positive breast cancer, compared with those who did not take it, was 38%, a difference that just missed significance, with a 95% confidence interval of 0.38-1.01.
In contrast, cases of ER-negative and triple-negative breast cancers increased in the women with diabetes taking metformin. The hazard ratio for ER-negative tumors showed a nonsignificant 25% relative increase in women taking metformin and a significant 74% increase in triple-negative cancers.
The editorialists note, however, that “the number of patients who were found to have triple-negative breast cancer was small [so] we cannot draw any practice-changing conclusions from it.”
In conclusion, Dr. Park and colleagues reiterate: “Our analysis is consistent with a potential protective effect of metformin and suggests that long-term use of metformin may reduce breast cancer risk associated with type 2 diabetes.”
The study received no commercial funding. Dr. Sandler, Dr. Park, Dr. Lohmann, Dr. Goodwin, and Dr. Cate have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
.
Conversely, the results also showed higher rates of ER-negative and triple-negative breast cancer among women with type 2 diabetes who received metformin, although case numbers were small.
“Our conclusion that having type 2 diabetes increases the risk of developing breast cancer but taking metformin may protect against developing ER-positive breast cancer – but not other types of breast cancer – is biologically plausible and supported by our results, even though some [endpoints] are not statistically significant,” senior author Dale P. Sandler, PhD, chief of the epidemiology branch, National Institute of Environmental Health Sciences, Research Triangle Park, N.C., said in an interview.
“Among our findings that are not statistically significant are several that helped us get a better picture of the relationships between type 2 diabetes, metformin treatment, and breast cancer risk,” Dr. Sandler added.
The results were published online Jan. 28 in Annals of Oncology by Yong-Moon Mark Park, MD, PhD, now an epidemiologist at the University of Arkansas for Medical Sciences in Little Rock, and colleagues.
Sara P. Cate, MD, a breast cancer surgeon at Mount Sinai Medical Center in New York, who was not involved with the study, said: “Certainly, metformin helps with weight loss, which is linked with estrogen-driven breast cancers, so this may explain why fewer patients on metformin got this type of breast cancer.”
A tangled web ... with no clear conclusions yet
But in an accompanying editorial, Ana E. Lohmann, MD, PhD, and Pamela J. Goodwin, MD, say that, while this is “a large, well-designed prospective cohort study,” it tells a complicated story.
“The report by Park adds to the growing evidence linking type 2 diabetes and its treatment to breast cancer risk, but definitive conclusions regarding these associations are not yet possible,” they observe.
The “largely negative” results of the new study perhaps in part occurred because the cohort included only 277 women with type 2 diabetes diagnosed with incident breast cancer, note Dr. Lohmann, of London Health Sciences Centre, University of Western Ontario, and Dr. Goodwin, of Mount Sinai Hospital, Toronto.
“Clearly, this is an important area, and additional research is needed to untangle the web of inter-related associations of type 2 diabetes, its treatment, and breast cancer risk,” they write.
Examination of the effects of metformin in studies such as the Canadian Cancer Trial Group MA.32, a phase 3 trial of over 3,500 women with hormone receptor–positive early-stage breast cancer who are being randomized to metformin or placebo for up to 5 years in addition to standard adjuvant therapy, will provide further insights, they observe. The trial is slated to be completed in February 2022.
Study followed women whose sisters had breast cancer
The new data come from the Sister Study, which followed more than 50,000 women without a history of breast cancer who had sisters or half-sisters with a breast cancer diagnosis. The study, run by the NIEHS, enrolled women 35-74 years old from all 50 U.S. states and Puerto Rico in 2003-2009.
The current analysis excluded women with a history of any other type of cancer, missing data about diabetes, or an uncertain breast cancer diagnosis during the study, which left 44,541 available for study. At entry, 7% of the women had type 2 diabetes, and another 5% developed new-onset type 2 diabetes during follow-up.
Among those with diabetes, 61% received treatment with metformin either alone or with other antidiabetic drugs.
During a median follow-up of 8.6 years, 2,678 women received a diagnosis of primary breast cancer, either invasive or ductal carcinoma in situ.
In a series of multivariate analyses that adjusted for numerous potential confounders, the authors found that, overall, no association existed between diabetes and breast cancer incidence, with a hazard ratio of 0.99, compared with women without diabetes.
But, said Dr. Sandler, “there is a strong biological rationale to hypothesize that type 2 diabetes increases the risk for breast cancer, and results from earlier studies support this.”
Association of metformin and breast cancer
Women with type 2 diabetes who received metformin had a 14% lower rate of ER-positive breast cancer, compared with women with diabetes not taking metformin, a nonsignificant association.
Among women taking metformin for at least 10 years, the associated reduction in ER-positive breast cancer, compared with those who did not take it, was 38%, a difference that just missed significance, with a 95% confidence interval of 0.38-1.01.
In contrast, cases of ER-negative and triple-negative breast cancers increased in the women with diabetes taking metformin. The hazard ratio for ER-negative tumors showed a nonsignificant 25% relative increase in women taking metformin and a significant 74% increase in triple-negative cancers.
The editorialists note, however, that “the number of patients who were found to have triple-negative breast cancer was small [so] we cannot draw any practice-changing conclusions from it.”
In conclusion, Dr. Park and colleagues reiterate: “Our analysis is consistent with a potential protective effect of metformin and suggests that long-term use of metformin may reduce breast cancer risk associated with type 2 diabetes.”
The study received no commercial funding. Dr. Sandler, Dr. Park, Dr. Lohmann, Dr. Goodwin, and Dr. Cate have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Oily fish linked to lower risk of diabetes in largest study to date
People who report regularly eating oily fish had a significantly reduced risk for developing type 2 diabetes in a prospective, observational study of nearly 400,000 UK residents.
The results also show a significant, but weaker, positive link between regular use of fish oil supplements and a drop in the incidence of type 2 diabetes, Qibin Qi, PhD, and colleagues wrote in a report published in Diabetes Care. Their analysis failed to show a significant link between consumption of non-oily fish and type 2 diabetes onset.
The study is notable for being “the largest so far” to examine the link between fish consumption and type 2 diabetes incidence, and the first to establish a clear, significant association between regularly eating oily fish and a drop in the incidence of diabetes, said Dr. Qi, an epidemiologist at Albert Einstein College of Medicine in New York.
“At present, it is prudent to recommend fresh oily fish as a part of a healthy dietary pattern instead of fish oil supplements for diabetes prevention,” said Dr. Qi and coauthors.
The study included just over 392,000 adults without type 2 diabetes or cardiovascular disease at baseline enrolled in the UK Biobank. Median follow-up was just over 10 years, during which 7,262 participants developed diabetes.
Participants who ate either one, or two or more, servings of oily fish weekly each had a significant 22% lower rate of incident type 2 diabetes than that of those who ate no oily fish, after adjustment for multiple confounders. Those who reported regularly taking a fish oil supplement had a significant 9% lower incidence of type 2 diabetes than that of those who didn’t.
Evidence growing to add oily fish to diet to prevent type 2 diabetes
“Many current dietary guidelines recommend consumption of two servings of fish, preferably oily, per week, primarily based on cardiovascular benefits,” Dr. Qi said in an interview.
“No prior statements recommended oily fish for prevention of type 2 diabetes,” he explained, adding: “Our findings support future recommendations, but the evidence is not strong enough to make a [formal] recommendation now. We need evidence from clinical trials.”
Jason Wu, PhD, an epidemiologist at the University of New South Wales in Sydney, Australia, who specializes in this field but was not involved with the current study, said it “is a very well-conducted study, and certainly generates important new evidence supporting the potential benefits of regular consumption of oily fish.”
But he agrees that the evidence remains too preliminary for any official recommendations on eating oily fish for preventing the development of type 2 diabetes, including targeting advice to high-risk subgroups such as those with prediabetes or people who are obese.
Before any groups make recommendations, “we need to thoroughly review all the literature in this space to appraise the overall body of evidence,” Dr. Wu noted in an interview.
Oily fish: Solid evidence for prevention of CVD events
In contrast, the case for including oily fish in the diet to prevent CVD events seems settled. In 2018, a panel assembled by the American Heart Association to address the issue released a statement that concluded: “Current scientific evidence strongly supports the recommendation that seafood be an integral component of a heart-healthy dietary pattern.” It added that “a large body of evidence supports the recommendation to consume nonfried seafood, especially species higher in long-chain n-3 fatty acids, one to two times per week for cardiovascular benefits, including reduced risk of cardiac death, coronary heart disease, and ischemic stroke.”
The statement highlighted that “cold-water oily fish such as salmon, anchovies, herring, mackerel (Atlantic and Pacific), tuna (bluefin and albacore), and sardines have the highest levels” of long-chain n-3 fatty acids, notably eicosapentaenoic acid and docosahexaenoic acid, also collectively known as omega-3 fatty acids.
These fish types were among the oily fishes tallied in the UK Biobank data used by Dr. Qi and colleagues.
The case for fish oil supplements for preventing CVD events is much rockier, as summarized in a 2019 editorial, with some studies reporting no discernible effect while others indicate efficacy.
A second commentary from December 2020 highlighted how results from the REDUCE-IT trial showed clear benefit for preventing CVD using a highly purified form of fish oil, icosapent ethyl (Vascepa, Amarin). However, findings from two other recent reports, the STRENGTH and OMENI studies, failed to show CVD benefits from more conventional fish oil formulations.
Composite CVD and diabetes prevention effects?
The new findings by Dr. Qi and colleagues “highlight the need to specifically test the effect of fish oil supplements on glucose metabolism in people who cannot or choose not to regularly eat oily fish,” said Dr. Wu, a researcher at the George Institute for Global Health in Newtown, Australia.
“If eventually there is really strong evidence that fish, fish oil, or both have independent effects on both CVD and type 2 diabetes” it would be reasonable to integrate both outcomes into a single, composite, efficacy endpoint for the purpose of future studies, he added.
Dr. Qi agreed on both points. “A randomized, controlled trial of fish oil on type 2 diabetes as a primary outcome is needed. Most existing data are based on secondary analyses in the randomized trials for CVD,” he explained.
But, he added, “our results suggest a potential beneficial effect from fish oil supplements,” which implies that these may be “better than nothing” for people who can’t add oily fish to their regular diet.
The means by which fish and fish oil might slow or stop progression to type 2 diabetes remains uncertain.
The mechanisms for preventing both diabetes and CVD events may overlap, Dr. Qi noted, such as anti-inflammatory effects and improved insulin sensitivity, both of which have been observed in animal studies.
Evidence is “still lacking from human studies,” he explained, but if such mechanisms were at play, Dr. Wu said that would “add biologic plausibility” to a possible causal link between oily fish consumption and diabetes prevention.
“But we can’t assume that omega-3 fatty acids alone will have the same effect as oily fish, which obviously contains many other components.”
The study received no commercial funding. Dr. Qi and Dr. Wu have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
People who report regularly eating oily fish had a significantly reduced risk for developing type 2 diabetes in a prospective, observational study of nearly 400,000 UK residents.
The results also show a significant, but weaker, positive link between regular use of fish oil supplements and a drop in the incidence of type 2 diabetes, Qibin Qi, PhD, and colleagues wrote in a report published in Diabetes Care. Their analysis failed to show a significant link between consumption of non-oily fish and type 2 diabetes onset.
The study is notable for being “the largest so far” to examine the link between fish consumption and type 2 diabetes incidence, and the first to establish a clear, significant association between regularly eating oily fish and a drop in the incidence of diabetes, said Dr. Qi, an epidemiologist at Albert Einstein College of Medicine in New York.
“At present, it is prudent to recommend fresh oily fish as a part of a healthy dietary pattern instead of fish oil supplements for diabetes prevention,” said Dr. Qi and coauthors.
The study included just over 392,000 adults without type 2 diabetes or cardiovascular disease at baseline enrolled in the UK Biobank. Median follow-up was just over 10 years, during which 7,262 participants developed diabetes.
Participants who ate either one, or two or more, servings of oily fish weekly each had a significant 22% lower rate of incident type 2 diabetes than that of those who ate no oily fish, after adjustment for multiple confounders. Those who reported regularly taking a fish oil supplement had a significant 9% lower incidence of type 2 diabetes than that of those who didn’t.
Evidence growing to add oily fish to diet to prevent type 2 diabetes
“Many current dietary guidelines recommend consumption of two servings of fish, preferably oily, per week, primarily based on cardiovascular benefits,” Dr. Qi said in an interview.
“No prior statements recommended oily fish for prevention of type 2 diabetes,” he explained, adding: “Our findings support future recommendations, but the evidence is not strong enough to make a [formal] recommendation now. We need evidence from clinical trials.”
Jason Wu, PhD, an epidemiologist at the University of New South Wales in Sydney, Australia, who specializes in this field but was not involved with the current study, said it “is a very well-conducted study, and certainly generates important new evidence supporting the potential benefits of regular consumption of oily fish.”
But he agrees that the evidence remains too preliminary for any official recommendations on eating oily fish for preventing the development of type 2 diabetes, including targeting advice to high-risk subgroups such as those with prediabetes or people who are obese.
Before any groups make recommendations, “we need to thoroughly review all the literature in this space to appraise the overall body of evidence,” Dr. Wu noted in an interview.
Oily fish: Solid evidence for prevention of CVD events
In contrast, the case for including oily fish in the diet to prevent CVD events seems settled. In 2018, a panel assembled by the American Heart Association to address the issue released a statement that concluded: “Current scientific evidence strongly supports the recommendation that seafood be an integral component of a heart-healthy dietary pattern.” It added that “a large body of evidence supports the recommendation to consume nonfried seafood, especially species higher in long-chain n-3 fatty acids, one to two times per week for cardiovascular benefits, including reduced risk of cardiac death, coronary heart disease, and ischemic stroke.”
The statement highlighted that “cold-water oily fish such as salmon, anchovies, herring, mackerel (Atlantic and Pacific), tuna (bluefin and albacore), and sardines have the highest levels” of long-chain n-3 fatty acids, notably eicosapentaenoic acid and docosahexaenoic acid, also collectively known as omega-3 fatty acids.
These fish types were among the oily fishes tallied in the UK Biobank data used by Dr. Qi and colleagues.
The case for fish oil supplements for preventing CVD events is much rockier, as summarized in a 2019 editorial, with some studies reporting no discernible effect while others indicate efficacy.
A second commentary from December 2020 highlighted how results from the REDUCE-IT trial showed clear benefit for preventing CVD using a highly purified form of fish oil, icosapent ethyl (Vascepa, Amarin). However, findings from two other recent reports, the STRENGTH and OMENI studies, failed to show CVD benefits from more conventional fish oil formulations.
Composite CVD and diabetes prevention effects?
The new findings by Dr. Qi and colleagues “highlight the need to specifically test the effect of fish oil supplements on glucose metabolism in people who cannot or choose not to regularly eat oily fish,” said Dr. Wu, a researcher at the George Institute for Global Health in Newtown, Australia.
“If eventually there is really strong evidence that fish, fish oil, or both have independent effects on both CVD and type 2 diabetes” it would be reasonable to integrate both outcomes into a single, composite, efficacy endpoint for the purpose of future studies, he added.
Dr. Qi agreed on both points. “A randomized, controlled trial of fish oil on type 2 diabetes as a primary outcome is needed. Most existing data are based on secondary analyses in the randomized trials for CVD,” he explained.
But, he added, “our results suggest a potential beneficial effect from fish oil supplements,” which implies that these may be “better than nothing” for people who can’t add oily fish to their regular diet.
The means by which fish and fish oil might slow or stop progression to type 2 diabetes remains uncertain.
The mechanisms for preventing both diabetes and CVD events may overlap, Dr. Qi noted, such as anti-inflammatory effects and improved insulin sensitivity, both of which have been observed in animal studies.
Evidence is “still lacking from human studies,” he explained, but if such mechanisms were at play, Dr. Wu said that would “add biologic plausibility” to a possible causal link between oily fish consumption and diabetes prevention.
“But we can’t assume that omega-3 fatty acids alone will have the same effect as oily fish, which obviously contains many other components.”
The study received no commercial funding. Dr. Qi and Dr. Wu have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
People who report regularly eating oily fish had a significantly reduced risk for developing type 2 diabetes in a prospective, observational study of nearly 400,000 UK residents.
The results also show a significant, but weaker, positive link between regular use of fish oil supplements and a drop in the incidence of type 2 diabetes, Qibin Qi, PhD, and colleagues wrote in a report published in Diabetes Care. Their analysis failed to show a significant link between consumption of non-oily fish and type 2 diabetes onset.
The study is notable for being “the largest so far” to examine the link between fish consumption and type 2 diabetes incidence, and the first to establish a clear, significant association between regularly eating oily fish and a drop in the incidence of diabetes, said Dr. Qi, an epidemiologist at Albert Einstein College of Medicine in New York.
“At present, it is prudent to recommend fresh oily fish as a part of a healthy dietary pattern instead of fish oil supplements for diabetes prevention,” said Dr. Qi and coauthors.
The study included just over 392,000 adults without type 2 diabetes or cardiovascular disease at baseline enrolled in the UK Biobank. Median follow-up was just over 10 years, during which 7,262 participants developed diabetes.
Participants who ate either one, or two or more, servings of oily fish weekly each had a significant 22% lower rate of incident type 2 diabetes than that of those who ate no oily fish, after adjustment for multiple confounders. Those who reported regularly taking a fish oil supplement had a significant 9% lower incidence of type 2 diabetes than that of those who didn’t.
Evidence growing to add oily fish to diet to prevent type 2 diabetes
“Many current dietary guidelines recommend consumption of two servings of fish, preferably oily, per week, primarily based on cardiovascular benefits,” Dr. Qi said in an interview.
“No prior statements recommended oily fish for prevention of type 2 diabetes,” he explained, adding: “Our findings support future recommendations, but the evidence is not strong enough to make a [formal] recommendation now. We need evidence from clinical trials.”
Jason Wu, PhD, an epidemiologist at the University of New South Wales in Sydney, Australia, who specializes in this field but was not involved with the current study, said it “is a very well-conducted study, and certainly generates important new evidence supporting the potential benefits of regular consumption of oily fish.”
But he agrees that the evidence remains too preliminary for any official recommendations on eating oily fish for preventing the development of type 2 diabetes, including targeting advice to high-risk subgroups such as those with prediabetes or people who are obese.
Before any groups make recommendations, “we need to thoroughly review all the literature in this space to appraise the overall body of evidence,” Dr. Wu noted in an interview.
Oily fish: Solid evidence for prevention of CVD events
In contrast, the case for including oily fish in the diet to prevent CVD events seems settled. In 2018, a panel assembled by the American Heart Association to address the issue released a statement that concluded: “Current scientific evidence strongly supports the recommendation that seafood be an integral component of a heart-healthy dietary pattern.” It added that “a large body of evidence supports the recommendation to consume nonfried seafood, especially species higher in long-chain n-3 fatty acids, one to two times per week for cardiovascular benefits, including reduced risk of cardiac death, coronary heart disease, and ischemic stroke.”
The statement highlighted that “cold-water oily fish such as salmon, anchovies, herring, mackerel (Atlantic and Pacific), tuna (bluefin and albacore), and sardines have the highest levels” of long-chain n-3 fatty acids, notably eicosapentaenoic acid and docosahexaenoic acid, also collectively known as omega-3 fatty acids.
These fish types were among the oily fishes tallied in the UK Biobank data used by Dr. Qi and colleagues.
The case for fish oil supplements for preventing CVD events is much rockier, as summarized in a 2019 editorial, with some studies reporting no discernible effect while others indicate efficacy.
A second commentary from December 2020 highlighted how results from the REDUCE-IT trial showed clear benefit for preventing CVD using a highly purified form of fish oil, icosapent ethyl (Vascepa, Amarin). However, findings from two other recent reports, the STRENGTH and OMENI studies, failed to show CVD benefits from more conventional fish oil formulations.
Composite CVD and diabetes prevention effects?
The new findings by Dr. Qi and colleagues “highlight the need to specifically test the effect of fish oil supplements on glucose metabolism in people who cannot or choose not to regularly eat oily fish,” said Dr. Wu, a researcher at the George Institute for Global Health in Newtown, Australia.
“If eventually there is really strong evidence that fish, fish oil, or both have independent effects on both CVD and type 2 diabetes” it would be reasonable to integrate both outcomes into a single, composite, efficacy endpoint for the purpose of future studies, he added.
Dr. Qi agreed on both points. “A randomized, controlled trial of fish oil on type 2 diabetes as a primary outcome is needed. Most existing data are based on secondary analyses in the randomized trials for CVD,” he explained.
But, he added, “our results suggest a potential beneficial effect from fish oil supplements,” which implies that these may be “better than nothing” for people who can’t add oily fish to their regular diet.
The means by which fish and fish oil might slow or stop progression to type 2 diabetes remains uncertain.
The mechanisms for preventing both diabetes and CVD events may overlap, Dr. Qi noted, such as anti-inflammatory effects and improved insulin sensitivity, both of which have been observed in animal studies.
Evidence is “still lacking from human studies,” he explained, but if such mechanisms were at play, Dr. Wu said that would “add biologic plausibility” to a possible causal link between oily fish consumption and diabetes prevention.
“But we can’t assume that omega-3 fatty acids alone will have the same effect as oily fish, which obviously contains many other components.”
The study received no commercial funding. Dr. Qi and Dr. Wu have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
PURE: High refined-grain intake boosts death, CVD events
That’s one finding from an assessment of a more than 137,000 people in 21 countries that documented a clear link between a high level of consumption of refined grains and a significantly increased risk for death from any cause or major cardiovascular disease (CVD) event during a median follow-up of 9.5 years.
The results showed that people who reported eating at least 350 g (seven servings) of refined grain daily had a significant 29% increased risk of either death or a major CVD event (MI, stroke, or heart failure), compared with those who consumed less than one serving per day (fewer than 50 g) of refined grain after adjustment for multiple potential confounders, according to a report from the Prospective Urban Rural Epidemiology (PURE) study published in the BMJ on Feb. 3, 2021.
The analysis also showed no significant association between levels of whole grains or white rice in the diet and CVD events. Rice was considered a separate grain in the analysis because nearly two-thirds of the PURE study population reside in Asia, where rice is a staple food.
The findings show that “reduction in the quantity of refined grains and sugar, and improvement in the quality of carbohydrates is essential for better health outcomes, although we do not suggest complete elimination of refined grains,” said Mahshid Dehghan, PhD, lead investigator for this report and a researcher in nutrition epidemiology at the Population Health Research Institute of McMaster University, Hamilton, Ont.
‘Widely applicable’ results from large, diverse study
Although prior evidence had already shown the CVD risk from eating larger amounts of refined grains, “our findings are robust and more widely applicable because our large study recorded over 9,000 deaths and 3,500 major CVD events across a broad range of refined grain intake, and in a variety of different settings and cultures with varying dietary patterns,” Dr. Dehghan said in an interview.
“This is an important paper, with the strength of data from diverse countries. The associations are robust,” commented Dariush Mozaffarian, MD, DrPH, professor and dean of the Friedman School of Nutrition Science and Policy at Tufts University, Boston, who was not involved in the new report.
“The public and the public health community think about added sugar in food as harmful, but starch has gotten a free pass,” he said in an interview. Recently revised U.S. dietary guidelines recommend that refined grains constitute less than half of a person’s carbohydrate consumption, but that limitation remains set too high, Dr. Mozaffarian cautioned. A much safer daily consumption limit would cap refined grains to no more than one serving a day.
The data for the current PURE analysis came from more than 148,000 people aged 35-70 years at entry in 21 geographically and economically diverse countries. Excluding patients with known CVD at baseline left a cohort of 137,130 people.
The results showed no significant association between the quantity of whole grains consumed and the main outcome, nor a link between higher amounts of white rice consumption and the main outcome.
“Our findings suggest that intake of up to 350 g of cooked rice daily may not pose a significant health risk,” said Dr. Dehghan.
Refined grains produce a glucose surge
Dr. Dehghan and associates speculated that possible explanations for their findings are that “varieties of rice such as long-grain rice and especially parboiled white rice may have both a definite glycemic advantage and an overall nutritional advantage over refined wheat products. Also, depending on the culture and the nature of the rice eaten, rice may be displacing less desirable foods.”
In contrast, refined grains undergo “rapid action by digestive enzymes and quick absorption from the small intestines [that] could lead to an increase in postprandial blood glucose concentrations. The rise in glucose concentrations increases the insulin concentrations, which leads to hypoglycemia, lipolysis, and the stimulation of hunger and food intake,” the authors wrote.
“It’s similar to eating sugar, or candy,” noted Dr. Mozaffarian, as refined grain “is 100% glucose.” Whole grains differ by entering the gut packaged in cell structures that slow digestion and avoid delivering sugar in an unnaturally rapid way.
“We are providing new evidence, and we hope that dietary guidelines in North America encourage individuals to lower their refined grain and sugar intake,” Dr. Dehghan said.
PURE has received partial funding with unrestricted grants from several drug companies. Dr. Dehghan had no disclosures. Dr. Mozaffarian has been an adviser to or has received personal fees from several food companies, but had no relevant disclosures.
That’s one finding from an assessment of a more than 137,000 people in 21 countries that documented a clear link between a high level of consumption of refined grains and a significantly increased risk for death from any cause or major cardiovascular disease (CVD) event during a median follow-up of 9.5 years.
The results showed that people who reported eating at least 350 g (seven servings) of refined grain daily had a significant 29% increased risk of either death or a major CVD event (MI, stroke, or heart failure), compared with those who consumed less than one serving per day (fewer than 50 g) of refined grain after adjustment for multiple potential confounders, according to a report from the Prospective Urban Rural Epidemiology (PURE) study published in the BMJ on Feb. 3, 2021.
The analysis also showed no significant association between levels of whole grains or white rice in the diet and CVD events. Rice was considered a separate grain in the analysis because nearly two-thirds of the PURE study population reside in Asia, where rice is a staple food.
The findings show that “reduction in the quantity of refined grains and sugar, and improvement in the quality of carbohydrates is essential for better health outcomes, although we do not suggest complete elimination of refined grains,” said Mahshid Dehghan, PhD, lead investigator for this report and a researcher in nutrition epidemiology at the Population Health Research Institute of McMaster University, Hamilton, Ont.
‘Widely applicable’ results from large, diverse study
Although prior evidence had already shown the CVD risk from eating larger amounts of refined grains, “our findings are robust and more widely applicable because our large study recorded over 9,000 deaths and 3,500 major CVD events across a broad range of refined grain intake, and in a variety of different settings and cultures with varying dietary patterns,” Dr. Dehghan said in an interview.
“This is an important paper, with the strength of data from diverse countries. The associations are robust,” commented Dariush Mozaffarian, MD, DrPH, professor and dean of the Friedman School of Nutrition Science and Policy at Tufts University, Boston, who was not involved in the new report.
“The public and the public health community think about added sugar in food as harmful, but starch has gotten a free pass,” he said in an interview. Recently revised U.S. dietary guidelines recommend that refined grains constitute less than half of a person’s carbohydrate consumption, but that limitation remains set too high, Dr. Mozaffarian cautioned. A much safer daily consumption limit would cap refined grains to no more than one serving a day.
The data for the current PURE analysis came from more than 148,000 people aged 35-70 years at entry in 21 geographically and economically diverse countries. Excluding patients with known CVD at baseline left a cohort of 137,130 people.
The results showed no significant association between the quantity of whole grains consumed and the main outcome, nor a link between higher amounts of white rice consumption and the main outcome.
“Our findings suggest that intake of up to 350 g of cooked rice daily may not pose a significant health risk,” said Dr. Dehghan.
Refined grains produce a glucose surge
Dr. Dehghan and associates speculated that possible explanations for their findings are that “varieties of rice such as long-grain rice and especially parboiled white rice may have both a definite glycemic advantage and an overall nutritional advantage over refined wheat products. Also, depending on the culture and the nature of the rice eaten, rice may be displacing less desirable foods.”
In contrast, refined grains undergo “rapid action by digestive enzymes and quick absorption from the small intestines [that] could lead to an increase in postprandial blood glucose concentrations. The rise in glucose concentrations increases the insulin concentrations, which leads to hypoglycemia, lipolysis, and the stimulation of hunger and food intake,” the authors wrote.
“It’s similar to eating sugar, or candy,” noted Dr. Mozaffarian, as refined grain “is 100% glucose.” Whole grains differ by entering the gut packaged in cell structures that slow digestion and avoid delivering sugar in an unnaturally rapid way.
“We are providing new evidence, and we hope that dietary guidelines in North America encourage individuals to lower their refined grain and sugar intake,” Dr. Dehghan said.
PURE has received partial funding with unrestricted grants from several drug companies. Dr. Dehghan had no disclosures. Dr. Mozaffarian has been an adviser to or has received personal fees from several food companies, but had no relevant disclosures.
That’s one finding from an assessment of a more than 137,000 people in 21 countries that documented a clear link between a high level of consumption of refined grains and a significantly increased risk for death from any cause or major cardiovascular disease (CVD) event during a median follow-up of 9.5 years.
The results showed that people who reported eating at least 350 g (seven servings) of refined grain daily had a significant 29% increased risk of either death or a major CVD event (MI, stroke, or heart failure), compared with those who consumed less than one serving per day (fewer than 50 g) of refined grain after adjustment for multiple potential confounders, according to a report from the Prospective Urban Rural Epidemiology (PURE) study published in the BMJ on Feb. 3, 2021.
The analysis also showed no significant association between levels of whole grains or white rice in the diet and CVD events. Rice was considered a separate grain in the analysis because nearly two-thirds of the PURE study population reside in Asia, where rice is a staple food.
The findings show that “reduction in the quantity of refined grains and sugar, and improvement in the quality of carbohydrates is essential for better health outcomes, although we do not suggest complete elimination of refined grains,” said Mahshid Dehghan, PhD, lead investigator for this report and a researcher in nutrition epidemiology at the Population Health Research Institute of McMaster University, Hamilton, Ont.
‘Widely applicable’ results from large, diverse study
Although prior evidence had already shown the CVD risk from eating larger amounts of refined grains, “our findings are robust and more widely applicable because our large study recorded over 9,000 deaths and 3,500 major CVD events across a broad range of refined grain intake, and in a variety of different settings and cultures with varying dietary patterns,” Dr. Dehghan said in an interview.
“This is an important paper, with the strength of data from diverse countries. The associations are robust,” commented Dariush Mozaffarian, MD, DrPH, professor and dean of the Friedman School of Nutrition Science and Policy at Tufts University, Boston, who was not involved in the new report.
“The public and the public health community think about added sugar in food as harmful, but starch has gotten a free pass,” he said in an interview. Recently revised U.S. dietary guidelines recommend that refined grains constitute less than half of a person’s carbohydrate consumption, but that limitation remains set too high, Dr. Mozaffarian cautioned. A much safer daily consumption limit would cap refined grains to no more than one serving a day.
The data for the current PURE analysis came from more than 148,000 people aged 35-70 years at entry in 21 geographically and economically diverse countries. Excluding patients with known CVD at baseline left a cohort of 137,130 people.
The results showed no significant association between the quantity of whole grains consumed and the main outcome, nor a link between higher amounts of white rice consumption and the main outcome.
“Our findings suggest that intake of up to 350 g of cooked rice daily may not pose a significant health risk,” said Dr. Dehghan.
Refined grains produce a glucose surge
Dr. Dehghan and associates speculated that possible explanations for their findings are that “varieties of rice such as long-grain rice and especially parboiled white rice may have both a definite glycemic advantage and an overall nutritional advantage over refined wheat products. Also, depending on the culture and the nature of the rice eaten, rice may be displacing less desirable foods.”
In contrast, refined grains undergo “rapid action by digestive enzymes and quick absorption from the small intestines [that] could lead to an increase in postprandial blood glucose concentrations. The rise in glucose concentrations increases the insulin concentrations, which leads to hypoglycemia, lipolysis, and the stimulation of hunger and food intake,” the authors wrote.
“It’s similar to eating sugar, or candy,” noted Dr. Mozaffarian, as refined grain “is 100% glucose.” Whole grains differ by entering the gut packaged in cell structures that slow digestion and avoid delivering sugar in an unnaturally rapid way.
“We are providing new evidence, and we hope that dietary guidelines in North America encourage individuals to lower their refined grain and sugar intake,” Dr. Dehghan said.
PURE has received partial funding with unrestricted grants from several drug companies. Dr. Dehghan had no disclosures. Dr. Mozaffarian has been an adviser to or has received personal fees from several food companies, but had no relevant disclosures.
Widespread liver disease missed in patients with T2D
Among these calls is a pending statement from the Endocrine Society, the American Association of Clinical Endocrinologists, the American Gastroenterology Association, and other groups on what the growing appreciation of highly prevalent liver disease in patients with type 2 diabetes (T2D) means for assessing and managing patients. Publication of the statement is expected by spring 2021, said Christos S. Mantzoros, MD, DSc, PhD, chief of endocrinology for the Veterans Affairs Boston Healthcare System and a representative from the Endocrine Society to the statement-writing panel.
This upcoming “Call to Action” from these groups argues for a “need to collaborate across disciplines, and work together on establishing clinical guidelines, and creating new diagnostics and therapeutics,” said Dr. Mantzoros in an interview.
“Over time, it is becoming clearer that management of NAFLD [nonalcoholic fatty liver disease]/NASH [nonalcoholic steatohepatitis] requires a multidisciplinary panel of doctors ranging from primary care practitioners, to endocrinologists, and hepatologists. Given that the nature of the disease crosses scientific discipline boundaries, and that the number of patients is so large (it is estimated that about one in four U.S. adults have NAFLD), not all patients can be treated at the limited number of hepatology centers.
“However, not all stakeholders have fully realized this fact, and no effort had been undertaken so far by any professional society to develop a coordinated approach and clinical care pathway for NAFLD/NASH. The ‘Call to Action’ meeting can be considered as a starting point for such an important effort,” said Dr. Mantzoros, who is also a professor of medicine at Harvard Medical School and director of the human nutrition unit at Beth Israel Deaconess Medical Center, both in Boston.
Dramatic prevalence rates in patients with T2D
Results from two independent epidemiology reports, published in December 2020, documented steatosis (the fatty liver of NAFLD) in 70%-74% of unselected U.S. patients with T2D, advanced liver fibrosis accompanying this disease in 6%-15%, and previously unrecognized cirrhosis in 3%-8%.
One of these reports analyzed 825 patients with T2D included in the National Health and Nutritional Examination Survey of 2017-2018 run by the Centers for Disease Control and Prevention. All these patients, selected to be representative of the overall U.S. adult population with T2D, underwent transient elastography to identify steatosis and fibrosis, the first U.S. National Health Survey to run this type of population-based survey. The results showed an overall steatosis prevalence of 74% with grade 3 steatosis in 58%, advanced liver fibrosis in 15%, and cirrhosis in 8%, reported the team of Italian researchers who analyzed the data .
The second study focused on a single-center series of 561 patients with T2D who also underwent screening by transient elastography during 2018-2020 and had no history of NAFLD or other liver disease, or alcohol abuse. The imaging results showed a NAFLD prevalence of 70%, with 54% of the entire group diagnosed with severe steatosis, severe fibrosis in 6%, and cirrhosis in 3%. Among the 54% of patients with severe steatosis, 30% also had severe liver fibrosis. About 70% of the 561 patients assessed came from either the family medicine or general internal medicine clinics of the University of Florida, Gainesville, with the remaining 30% enrolled from the center’s endocrinology/diabetes outpatient clinic.
Neither report documented a NASH prevalence, which cannot receive definitive diagnosis by imaging alone. “This is the first study of its kind in the U.S. to establish the magnitude of [liver] disease burden in random patients with T2D seeking regular outpatient care,” wrote the University of Florida research team, led by Kenneth Cusi, MD, professor and chief of the university’s division of endocrinology, diabetes, and metabolism. Their finding that patients with T2D and previously unknown to have NAFLD had a 15% prevalence of moderate or advanced liver fibrosis “should trigger a call to action by all clinicians taking care of patients with T2D. Patient and physician awareness of the hepatic and extrahepatic complications of NASH, and reversing current diagnosis and treatment inertia will be the only way to avert the looming epidemic of cirrhosis in patients with diabetes.”
“Endocrinologists don’t ‘see’ NAFLD and NASH” in their patients with T2D “ because they don’t think about it,” Dr. Mantzoros declared.
“Why is NASH underdiagnosed and undertreated? Because many physicians aren’t aware of it,” agreed Dr. Cusi during a talk in December 2020 at the 18th World Congress on Insulin Resistance, Diabetes, and Cardiovascular Disease (WCIRDC). “You never find what you don’t look for.”
“Endocrinologists should do the tests for NASH [in patients with T2D], but we’re all guilty of not doing it enough,” Tracey McLaughlin, MD, an endocrinologist and professor of medicine at Stanford (Calif.) University, commented during the WCIRDC.
These prevalence numbers demand that clinicians suspect liver disease “in any patient with diabetes, especially patients with obesity who are older and have components of metabolic syndrome,” said Dr. Mantzoros. “We need to screen, refer the most advanced cases, and treat the early- and mid-stage cases.”
How to find NASH
Both the American Diabetes Association and the European Association for the Study of Diabetes call for routine screening of patients with T2D, starting with a check of liver enzymes, such as ALT, but no clear consensus exists for the specifics of screening beyond that. Dr. Mantzoros, Dr. Cusi, and other experts agree that the scheme for assessing liver disease in patients with T2D starts with regular monitoring of elevations in liver enzymes including ALT. Next is noninvasive ultrasound assessment of the extent of liver fibrosis inferred from the organ’s stiffness using transient elastography. Another frequently cited initial screening tool is the Fibrosis-4 (FIB-4) score, which incorporates a patient’s age, platelet count, and levels of ALT and a second liver enzyme, AST.
“There is more consensus about FIB-4 and then elastography, but some people use tests other than FIB-4. Unfortunately there is no perfect diagnostic test today. A top priority is to define the best diagnostic test,” said Dr. Mantzoros, who is leading an effort to try to refine screening using artificial intelligence.
“FIB-4 is simple, easy, and well validated,” commented Dr. Cusi during the WCIRDC last December. “FIB-4 and elastography should get you pretty close” to identifying patients with T2D and significant liver disease.
But in a recent editorial, Dr. Cusi agreed on the need for “more reliable tests for the diagnosis of NASH and advanced fibrosis in patients with T2D. Significant work is being done in the field to validate novel and more sophisticated fibrosis biomarkers. Future studies will help us enter a new era of precision medicine where biomarkers will identify and target therapy to those with more active disease at risk for cirrhosis,” he wrote.
“The ultimate goal is to diagnose fibrosis at an early stage to prevent people from developing cirrhosis,” Dr. Cusi said in a recent written statement. “We’re trying to identify these problems before they’re unfixable. Once someone has cirrhosis, there isn’t a whole lot you can do.”
Pioglitazone remains the best-documented treatment
Perhaps some of the inertia in diagnosing NAFLD, NASH, and liver fibrosis in patients with T2D is dissatisfaction with current treatment options, although several proven options exist, notably weight loss and diet, and thiazolidinedione (TZD) pioglitazone. But weight loss and diet pose issues for patient compliance and durability of the intervention, and many clinicians consider pioglitazone flawed by its potential adverse effects.
“When we don’t have an established treatment for something, we tend to not measure it or go after it. That’s been true of liver disease” in patients with T2D, said Yehuda Handelsman, MD, an endocrinologist and diabetes specialist who is medical director of the Metabolic Institute of America in Tarzana, Calif., during the WCIRDC.
Treatment with pioglitazone has resolved NASH in about a third of patients compared with placebo, prevented fibrosis progression, and cut cardiovascular disease events, noted Dr. Cusi during the WCIRDC.
“Pioglitazone is used in only 8% of patients with T2D, or less, but we need to use it more often because of its proven efficacy in patients with T2D and NASH” said Dr. Mantzoros. “The problem is that pioglitazone has side effects, including weight gain and fluid retention, that makes it less attractive unless one thinks about the diagnosis of NASH.”
Others highlight that the adverse effects of pioglitazone have been either misunderstood, or can be effectively minimized with careful dosing.
“The data with the TZDs are much stronger than the data from anything else. TZDs have gotten a bad name because they also work in the kidney and enhance fluid reabsorption. We use modest dosages of pioglitazone, 15 mg or 30 mg a day, to avoid excess fluid retention,” Ralph A. DeFronzo, MD, chief of the diabetes division and professor of medicine at the University of Texas Health Science Center, San Antonio, said during the WCIRDC. “The best drug for NASH is pioglitazone. No other drug beats it” based on current data, Dr. DeFronzo asserted.
Other strategies include the potential to pair pioglitazone with other interventions that can blunt a weight-gain effect. One intriguing combination would combine pioglitazone with a GLP-1 receptor agonist, a drug class that can produce significant weight loss. Results from a phase 2 study showed promise for semaglutide (Rybelsus) in treating patients with NASH.
Getting the name right
Another factor that may be keeping NAFLD and NASH from achieving a higher profile for patients with T2D are those names, which focus on what the diseases are not – nonalcoholic – rather than what they are.
A series of recent publications in both the endocrinology and hepatology literature have called for renaming these disorders either “metabolic (dysfunction)–associated fatty liver disease (MALFD)”, or “dysmetabolism-associated fatty liver disease (DALFD)”.
“The names NAFLD and NASH indicate absence of alcohol as a cause, but the disease is also characterized by the absence of other causes, such as autoimmune disorders or hepatitis. The names were coined when we did not know much about these diseases. We now know that it is dysmetabolism that causes these conditions, and so we need to adopt a new, more accurate name,” explained Dr. Mantzoros, who has published support for a name change.
While many agree, some have raised concerns as to whether a name change now is premature. A group of hepatologists recently published a rebuttal to an immediate name change , saying that, “although we are in agreement that metabolic fatty liver disease may more accurately and positively reflect the relevant risk factors better than the age-old term nonalcoholic fatty liver disease, the term still leaves a great deal of ambiguity. A name change will be appropriate when informed by a new understanding of the molecular basis of the disease entity, insights that fundamentally change risk stratification, or other important aspects of the disease. We may be on the cusp of this, but we are not there yet.”
Dr. Mantzoros agreed, but for somewhat different reasons.
“We need to be careful and deliberate, because there is a significant body of knowledge and a lot of data from clinical trials collected using the old definitions. We need to find an appropriate time frame for a [name] transition. We need to find a nice and robust way to productively bridge the old to the new,” he said. “We also need new diagnostic criteria, and new therapies. A new name and definition will facilitate progress.”
Dr. Mantzoros been a shareholder of and consultant to Coherus and Pangea, he has been a consultant to AstraZeneca, Eisai, Genfit, Intercept, Novo Nordisk, P.E.S., and Regeneron, and has received travel support from the Metabolic Institute of America and the California Walnut Commission. Dr. Cusi has been a consultant to and has received research funding from numerous drug companies. Dr. McLaughlin is a consultant to January AI. Dr. Handelsman has been a consultant to numerous drug companies. Dr. DeFronzo received research grants from AstraZeneca, Janssen, and Merck; he has been an adviser to AstraZeneca, Boehringer Ingelheim, Intarcia, Janssen, and Novo Nordisk; and he has been a speaker on behalf of AstraZeneca and Novo Nordisk.
Among these calls is a pending statement from the Endocrine Society, the American Association of Clinical Endocrinologists, the American Gastroenterology Association, and other groups on what the growing appreciation of highly prevalent liver disease in patients with type 2 diabetes (T2D) means for assessing and managing patients. Publication of the statement is expected by spring 2021, said Christos S. Mantzoros, MD, DSc, PhD, chief of endocrinology for the Veterans Affairs Boston Healthcare System and a representative from the Endocrine Society to the statement-writing panel.
This upcoming “Call to Action” from these groups argues for a “need to collaborate across disciplines, and work together on establishing clinical guidelines, and creating new diagnostics and therapeutics,” said Dr. Mantzoros in an interview.
“Over time, it is becoming clearer that management of NAFLD [nonalcoholic fatty liver disease]/NASH [nonalcoholic steatohepatitis] requires a multidisciplinary panel of doctors ranging from primary care practitioners, to endocrinologists, and hepatologists. Given that the nature of the disease crosses scientific discipline boundaries, and that the number of patients is so large (it is estimated that about one in four U.S. adults have NAFLD), not all patients can be treated at the limited number of hepatology centers.
“However, not all stakeholders have fully realized this fact, and no effort had been undertaken so far by any professional society to develop a coordinated approach and clinical care pathway for NAFLD/NASH. The ‘Call to Action’ meeting can be considered as a starting point for such an important effort,” said Dr. Mantzoros, who is also a professor of medicine at Harvard Medical School and director of the human nutrition unit at Beth Israel Deaconess Medical Center, both in Boston.
Dramatic prevalence rates in patients with T2D
Results from two independent epidemiology reports, published in December 2020, documented steatosis (the fatty liver of NAFLD) in 70%-74% of unselected U.S. patients with T2D, advanced liver fibrosis accompanying this disease in 6%-15%, and previously unrecognized cirrhosis in 3%-8%.
One of these reports analyzed 825 patients with T2D included in the National Health and Nutritional Examination Survey of 2017-2018 run by the Centers for Disease Control and Prevention. All these patients, selected to be representative of the overall U.S. adult population with T2D, underwent transient elastography to identify steatosis and fibrosis, the first U.S. National Health Survey to run this type of population-based survey. The results showed an overall steatosis prevalence of 74% with grade 3 steatosis in 58%, advanced liver fibrosis in 15%, and cirrhosis in 8%, reported the team of Italian researchers who analyzed the data .
The second study focused on a single-center series of 561 patients with T2D who also underwent screening by transient elastography during 2018-2020 and had no history of NAFLD or other liver disease, or alcohol abuse. The imaging results showed a NAFLD prevalence of 70%, with 54% of the entire group diagnosed with severe steatosis, severe fibrosis in 6%, and cirrhosis in 3%. Among the 54% of patients with severe steatosis, 30% also had severe liver fibrosis. About 70% of the 561 patients assessed came from either the family medicine or general internal medicine clinics of the University of Florida, Gainesville, with the remaining 30% enrolled from the center’s endocrinology/diabetes outpatient clinic.
Neither report documented a NASH prevalence, which cannot receive definitive diagnosis by imaging alone. “This is the first study of its kind in the U.S. to establish the magnitude of [liver] disease burden in random patients with T2D seeking regular outpatient care,” wrote the University of Florida research team, led by Kenneth Cusi, MD, professor and chief of the university’s division of endocrinology, diabetes, and metabolism. Their finding that patients with T2D and previously unknown to have NAFLD had a 15% prevalence of moderate or advanced liver fibrosis “should trigger a call to action by all clinicians taking care of patients with T2D. Patient and physician awareness of the hepatic and extrahepatic complications of NASH, and reversing current diagnosis and treatment inertia will be the only way to avert the looming epidemic of cirrhosis in patients with diabetes.”
“Endocrinologists don’t ‘see’ NAFLD and NASH” in their patients with T2D “ because they don’t think about it,” Dr. Mantzoros declared.
“Why is NASH underdiagnosed and undertreated? Because many physicians aren’t aware of it,” agreed Dr. Cusi during a talk in December 2020 at the 18th World Congress on Insulin Resistance, Diabetes, and Cardiovascular Disease (WCIRDC). “You never find what you don’t look for.”
“Endocrinologists should do the tests for NASH [in patients with T2D], but we’re all guilty of not doing it enough,” Tracey McLaughlin, MD, an endocrinologist and professor of medicine at Stanford (Calif.) University, commented during the WCIRDC.
These prevalence numbers demand that clinicians suspect liver disease “in any patient with diabetes, especially patients with obesity who are older and have components of metabolic syndrome,” said Dr. Mantzoros. “We need to screen, refer the most advanced cases, and treat the early- and mid-stage cases.”
How to find NASH
Both the American Diabetes Association and the European Association for the Study of Diabetes call for routine screening of patients with T2D, starting with a check of liver enzymes, such as ALT, but no clear consensus exists for the specifics of screening beyond that. Dr. Mantzoros, Dr. Cusi, and other experts agree that the scheme for assessing liver disease in patients with T2D starts with regular monitoring of elevations in liver enzymes including ALT. Next is noninvasive ultrasound assessment of the extent of liver fibrosis inferred from the organ’s stiffness using transient elastography. Another frequently cited initial screening tool is the Fibrosis-4 (FIB-4) score, which incorporates a patient’s age, platelet count, and levels of ALT and a second liver enzyme, AST.
“There is more consensus about FIB-4 and then elastography, but some people use tests other than FIB-4. Unfortunately there is no perfect diagnostic test today. A top priority is to define the best diagnostic test,” said Dr. Mantzoros, who is leading an effort to try to refine screening using artificial intelligence.
“FIB-4 is simple, easy, and well validated,” commented Dr. Cusi during the WCIRDC last December. “FIB-4 and elastography should get you pretty close” to identifying patients with T2D and significant liver disease.
But in a recent editorial, Dr. Cusi agreed on the need for “more reliable tests for the diagnosis of NASH and advanced fibrosis in patients with T2D. Significant work is being done in the field to validate novel and more sophisticated fibrosis biomarkers. Future studies will help us enter a new era of precision medicine where biomarkers will identify and target therapy to those with more active disease at risk for cirrhosis,” he wrote.
“The ultimate goal is to diagnose fibrosis at an early stage to prevent people from developing cirrhosis,” Dr. Cusi said in a recent written statement. “We’re trying to identify these problems before they’re unfixable. Once someone has cirrhosis, there isn’t a whole lot you can do.”
Pioglitazone remains the best-documented treatment
Perhaps some of the inertia in diagnosing NAFLD, NASH, and liver fibrosis in patients with T2D is dissatisfaction with current treatment options, although several proven options exist, notably weight loss and diet, and thiazolidinedione (TZD) pioglitazone. But weight loss and diet pose issues for patient compliance and durability of the intervention, and many clinicians consider pioglitazone flawed by its potential adverse effects.
“When we don’t have an established treatment for something, we tend to not measure it or go after it. That’s been true of liver disease” in patients with T2D, said Yehuda Handelsman, MD, an endocrinologist and diabetes specialist who is medical director of the Metabolic Institute of America in Tarzana, Calif., during the WCIRDC.
Treatment with pioglitazone has resolved NASH in about a third of patients compared with placebo, prevented fibrosis progression, and cut cardiovascular disease events, noted Dr. Cusi during the WCIRDC.
“Pioglitazone is used in only 8% of patients with T2D, or less, but we need to use it more often because of its proven efficacy in patients with T2D and NASH” said Dr. Mantzoros. “The problem is that pioglitazone has side effects, including weight gain and fluid retention, that makes it less attractive unless one thinks about the diagnosis of NASH.”
Others highlight that the adverse effects of pioglitazone have been either misunderstood, or can be effectively minimized with careful dosing.
“The data with the TZDs are much stronger than the data from anything else. TZDs have gotten a bad name because they also work in the kidney and enhance fluid reabsorption. We use modest dosages of pioglitazone, 15 mg or 30 mg a day, to avoid excess fluid retention,” Ralph A. DeFronzo, MD, chief of the diabetes division and professor of medicine at the University of Texas Health Science Center, San Antonio, said during the WCIRDC. “The best drug for NASH is pioglitazone. No other drug beats it” based on current data, Dr. DeFronzo asserted.
Other strategies include the potential to pair pioglitazone with other interventions that can blunt a weight-gain effect. One intriguing combination would combine pioglitazone with a GLP-1 receptor agonist, a drug class that can produce significant weight loss. Results from a phase 2 study showed promise for semaglutide (Rybelsus) in treating patients with NASH.
Getting the name right
Another factor that may be keeping NAFLD and NASH from achieving a higher profile for patients with T2D are those names, which focus on what the diseases are not – nonalcoholic – rather than what they are.
A series of recent publications in both the endocrinology and hepatology literature have called for renaming these disorders either “metabolic (dysfunction)–associated fatty liver disease (MALFD)”, or “dysmetabolism-associated fatty liver disease (DALFD)”.
“The names NAFLD and NASH indicate absence of alcohol as a cause, but the disease is also characterized by the absence of other causes, such as autoimmune disorders or hepatitis. The names were coined when we did not know much about these diseases. We now know that it is dysmetabolism that causes these conditions, and so we need to adopt a new, more accurate name,” explained Dr. Mantzoros, who has published support for a name change.
While many agree, some have raised concerns as to whether a name change now is premature. A group of hepatologists recently published a rebuttal to an immediate name change , saying that, “although we are in agreement that metabolic fatty liver disease may more accurately and positively reflect the relevant risk factors better than the age-old term nonalcoholic fatty liver disease, the term still leaves a great deal of ambiguity. A name change will be appropriate when informed by a new understanding of the molecular basis of the disease entity, insights that fundamentally change risk stratification, or other important aspects of the disease. We may be on the cusp of this, but we are not there yet.”
Dr. Mantzoros agreed, but for somewhat different reasons.
“We need to be careful and deliberate, because there is a significant body of knowledge and a lot of data from clinical trials collected using the old definitions. We need to find an appropriate time frame for a [name] transition. We need to find a nice and robust way to productively bridge the old to the new,” he said. “We also need new diagnostic criteria, and new therapies. A new name and definition will facilitate progress.”
Dr. Mantzoros been a shareholder of and consultant to Coherus and Pangea, he has been a consultant to AstraZeneca, Eisai, Genfit, Intercept, Novo Nordisk, P.E.S., and Regeneron, and has received travel support from the Metabolic Institute of America and the California Walnut Commission. Dr. Cusi has been a consultant to and has received research funding from numerous drug companies. Dr. McLaughlin is a consultant to January AI. Dr. Handelsman has been a consultant to numerous drug companies. Dr. DeFronzo received research grants from AstraZeneca, Janssen, and Merck; he has been an adviser to AstraZeneca, Boehringer Ingelheim, Intarcia, Janssen, and Novo Nordisk; and he has been a speaker on behalf of AstraZeneca and Novo Nordisk.
Among these calls is a pending statement from the Endocrine Society, the American Association of Clinical Endocrinologists, the American Gastroenterology Association, and other groups on what the growing appreciation of highly prevalent liver disease in patients with type 2 diabetes (T2D) means for assessing and managing patients. Publication of the statement is expected by spring 2021, said Christos S. Mantzoros, MD, DSc, PhD, chief of endocrinology for the Veterans Affairs Boston Healthcare System and a representative from the Endocrine Society to the statement-writing panel.
This upcoming “Call to Action” from these groups argues for a “need to collaborate across disciplines, and work together on establishing clinical guidelines, and creating new diagnostics and therapeutics,” said Dr. Mantzoros in an interview.
“Over time, it is becoming clearer that management of NAFLD [nonalcoholic fatty liver disease]/NASH [nonalcoholic steatohepatitis] requires a multidisciplinary panel of doctors ranging from primary care practitioners, to endocrinologists, and hepatologists. Given that the nature of the disease crosses scientific discipline boundaries, and that the number of patients is so large (it is estimated that about one in four U.S. adults have NAFLD), not all patients can be treated at the limited number of hepatology centers.
“However, not all stakeholders have fully realized this fact, and no effort had been undertaken so far by any professional society to develop a coordinated approach and clinical care pathway for NAFLD/NASH. The ‘Call to Action’ meeting can be considered as a starting point for such an important effort,” said Dr. Mantzoros, who is also a professor of medicine at Harvard Medical School and director of the human nutrition unit at Beth Israel Deaconess Medical Center, both in Boston.
Dramatic prevalence rates in patients with T2D
Results from two independent epidemiology reports, published in December 2020, documented steatosis (the fatty liver of NAFLD) in 70%-74% of unselected U.S. patients with T2D, advanced liver fibrosis accompanying this disease in 6%-15%, and previously unrecognized cirrhosis in 3%-8%.
One of these reports analyzed 825 patients with T2D included in the National Health and Nutritional Examination Survey of 2017-2018 run by the Centers for Disease Control and Prevention. All these patients, selected to be representative of the overall U.S. adult population with T2D, underwent transient elastography to identify steatosis and fibrosis, the first U.S. National Health Survey to run this type of population-based survey. The results showed an overall steatosis prevalence of 74% with grade 3 steatosis in 58%, advanced liver fibrosis in 15%, and cirrhosis in 8%, reported the team of Italian researchers who analyzed the data .
The second study focused on a single-center series of 561 patients with T2D who also underwent screening by transient elastography during 2018-2020 and had no history of NAFLD or other liver disease, or alcohol abuse. The imaging results showed a NAFLD prevalence of 70%, with 54% of the entire group diagnosed with severe steatosis, severe fibrosis in 6%, and cirrhosis in 3%. Among the 54% of patients with severe steatosis, 30% also had severe liver fibrosis. About 70% of the 561 patients assessed came from either the family medicine or general internal medicine clinics of the University of Florida, Gainesville, with the remaining 30% enrolled from the center’s endocrinology/diabetes outpatient clinic.
Neither report documented a NASH prevalence, which cannot receive definitive diagnosis by imaging alone. “This is the first study of its kind in the U.S. to establish the magnitude of [liver] disease burden in random patients with T2D seeking regular outpatient care,” wrote the University of Florida research team, led by Kenneth Cusi, MD, professor and chief of the university’s division of endocrinology, diabetes, and metabolism. Their finding that patients with T2D and previously unknown to have NAFLD had a 15% prevalence of moderate or advanced liver fibrosis “should trigger a call to action by all clinicians taking care of patients with T2D. Patient and physician awareness of the hepatic and extrahepatic complications of NASH, and reversing current diagnosis and treatment inertia will be the only way to avert the looming epidemic of cirrhosis in patients with diabetes.”
“Endocrinologists don’t ‘see’ NAFLD and NASH” in their patients with T2D “ because they don’t think about it,” Dr. Mantzoros declared.
“Why is NASH underdiagnosed and undertreated? Because many physicians aren’t aware of it,” agreed Dr. Cusi during a talk in December 2020 at the 18th World Congress on Insulin Resistance, Diabetes, and Cardiovascular Disease (WCIRDC). “You never find what you don’t look for.”
“Endocrinologists should do the tests for NASH [in patients with T2D], but we’re all guilty of not doing it enough,” Tracey McLaughlin, MD, an endocrinologist and professor of medicine at Stanford (Calif.) University, commented during the WCIRDC.
These prevalence numbers demand that clinicians suspect liver disease “in any patient with diabetes, especially patients with obesity who are older and have components of metabolic syndrome,” said Dr. Mantzoros. “We need to screen, refer the most advanced cases, and treat the early- and mid-stage cases.”
How to find NASH
Both the American Diabetes Association and the European Association for the Study of Diabetes call for routine screening of patients with T2D, starting with a check of liver enzymes, such as ALT, but no clear consensus exists for the specifics of screening beyond that. Dr. Mantzoros, Dr. Cusi, and other experts agree that the scheme for assessing liver disease in patients with T2D starts with regular monitoring of elevations in liver enzymes including ALT. Next is noninvasive ultrasound assessment of the extent of liver fibrosis inferred from the organ’s stiffness using transient elastography. Another frequently cited initial screening tool is the Fibrosis-4 (FIB-4) score, which incorporates a patient’s age, platelet count, and levels of ALT and a second liver enzyme, AST.
“There is more consensus about FIB-4 and then elastography, but some people use tests other than FIB-4. Unfortunately there is no perfect diagnostic test today. A top priority is to define the best diagnostic test,” said Dr. Mantzoros, who is leading an effort to try to refine screening using artificial intelligence.
“FIB-4 is simple, easy, and well validated,” commented Dr. Cusi during the WCIRDC last December. “FIB-4 and elastography should get you pretty close” to identifying patients with T2D and significant liver disease.
But in a recent editorial, Dr. Cusi agreed on the need for “more reliable tests for the diagnosis of NASH and advanced fibrosis in patients with T2D. Significant work is being done in the field to validate novel and more sophisticated fibrosis biomarkers. Future studies will help us enter a new era of precision medicine where biomarkers will identify and target therapy to those with more active disease at risk for cirrhosis,” he wrote.
“The ultimate goal is to diagnose fibrosis at an early stage to prevent people from developing cirrhosis,” Dr. Cusi said in a recent written statement. “We’re trying to identify these problems before they’re unfixable. Once someone has cirrhosis, there isn’t a whole lot you can do.”
Pioglitazone remains the best-documented treatment
Perhaps some of the inertia in diagnosing NAFLD, NASH, and liver fibrosis in patients with T2D is dissatisfaction with current treatment options, although several proven options exist, notably weight loss and diet, and thiazolidinedione (TZD) pioglitazone. But weight loss and diet pose issues for patient compliance and durability of the intervention, and many clinicians consider pioglitazone flawed by its potential adverse effects.
“When we don’t have an established treatment for something, we tend to not measure it or go after it. That’s been true of liver disease” in patients with T2D, said Yehuda Handelsman, MD, an endocrinologist and diabetes specialist who is medical director of the Metabolic Institute of America in Tarzana, Calif., during the WCIRDC.
Treatment with pioglitazone has resolved NASH in about a third of patients compared with placebo, prevented fibrosis progression, and cut cardiovascular disease events, noted Dr. Cusi during the WCIRDC.
“Pioglitazone is used in only 8% of patients with T2D, or less, but we need to use it more often because of its proven efficacy in patients with T2D and NASH” said Dr. Mantzoros. “The problem is that pioglitazone has side effects, including weight gain and fluid retention, that makes it less attractive unless one thinks about the diagnosis of NASH.”
Others highlight that the adverse effects of pioglitazone have been either misunderstood, or can be effectively minimized with careful dosing.
“The data with the TZDs are much stronger than the data from anything else. TZDs have gotten a bad name because they also work in the kidney and enhance fluid reabsorption. We use modest dosages of pioglitazone, 15 mg or 30 mg a day, to avoid excess fluid retention,” Ralph A. DeFronzo, MD, chief of the diabetes division and professor of medicine at the University of Texas Health Science Center, San Antonio, said during the WCIRDC. “The best drug for NASH is pioglitazone. No other drug beats it” based on current data, Dr. DeFronzo asserted.
Other strategies include the potential to pair pioglitazone with other interventions that can blunt a weight-gain effect. One intriguing combination would combine pioglitazone with a GLP-1 receptor agonist, a drug class that can produce significant weight loss. Results from a phase 2 study showed promise for semaglutide (Rybelsus) in treating patients with NASH.
Getting the name right
Another factor that may be keeping NAFLD and NASH from achieving a higher profile for patients with T2D are those names, which focus on what the diseases are not – nonalcoholic – rather than what they are.
A series of recent publications in both the endocrinology and hepatology literature have called for renaming these disorders either “metabolic (dysfunction)–associated fatty liver disease (MALFD)”, or “dysmetabolism-associated fatty liver disease (DALFD)”.
“The names NAFLD and NASH indicate absence of alcohol as a cause, but the disease is also characterized by the absence of other causes, such as autoimmune disorders or hepatitis. The names were coined when we did not know much about these diseases. We now know that it is dysmetabolism that causes these conditions, and so we need to adopt a new, more accurate name,” explained Dr. Mantzoros, who has published support for a name change.
While many agree, some have raised concerns as to whether a name change now is premature. A group of hepatologists recently published a rebuttal to an immediate name change , saying that, “although we are in agreement that metabolic fatty liver disease may more accurately and positively reflect the relevant risk factors better than the age-old term nonalcoholic fatty liver disease, the term still leaves a great deal of ambiguity. A name change will be appropriate when informed by a new understanding of the molecular basis of the disease entity, insights that fundamentally change risk stratification, or other important aspects of the disease. We may be on the cusp of this, but we are not there yet.”
Dr. Mantzoros agreed, but for somewhat different reasons.
“We need to be careful and deliberate, because there is a significant body of knowledge and a lot of data from clinical trials collected using the old definitions. We need to find an appropriate time frame for a [name] transition. We need to find a nice and robust way to productively bridge the old to the new,” he said. “We also need new diagnostic criteria, and new therapies. A new name and definition will facilitate progress.”
Dr. Mantzoros been a shareholder of and consultant to Coherus and Pangea, he has been a consultant to AstraZeneca, Eisai, Genfit, Intercept, Novo Nordisk, P.E.S., and Regeneron, and has received travel support from the Metabolic Institute of America and the California Walnut Commission. Dr. Cusi has been a consultant to and has received research funding from numerous drug companies. Dr. McLaughlin is a consultant to January AI. Dr. Handelsman has been a consultant to numerous drug companies. Dr. DeFronzo received research grants from AstraZeneca, Janssen, and Merck; he has been an adviser to AstraZeneca, Boehringer Ingelheim, Intarcia, Janssen, and Novo Nordisk; and he has been a speaker on behalf of AstraZeneca and Novo Nordisk.
Cardiometabolic Center Alliance promotes multiorgan, integrated T2D treatment
A one-stop shop approach to managing the spectrum of complications in patients with type 2 diabetes with a coordinated, multidisciplinary team of clinicians has taken root in at least two U.S. medical centers, and their efforts have now joined to take this concept national through the Cardiometabolic Center Alliance, which hopes to have at least 20 such centers running by the end of 2022.
In patients with type 2 diabetes (T2D), “multiple organs are affected by the same disease process,” notably the heart, kidneys, vasculature, and liver, but the care these patients often receive today is “fragmented, and typically without good coordination,” explained Mikhail N. Kosiborod, MD, a cardiologist and codirector of the Saint Luke’s Michael & Marlys Haverty Cardiometabolic Center of Excellence in Kansas City, Mo.
“We need to depart from the outdated idea that each medical specialty focuses on an organ system. It’s one patient with one disease that affects multiple organs and needs comprehensive, multidisciplinary care,” he said.
Historically, “we’ve looked to primary care physicians to ‘conduct the orchestra’ for complex, multispecialty care” for patients with T2D, but a recent “avalanche” of new treatments with new data and recommendations has made coordination by a single, generalist physician essentially impossible. “It isn’t realistic” to expect a single primary care physician to coordinate all the care a patient with T2D now needs to receive, said Dr. Kosiborod, who is also a professor of medicine at the University of Missouri–Kansas City. Plus, “patients can get lost” when they try to navigate on their own among several physicians, possibly in disparate locations, and without fully understanding what each physician is responsible for managing.
Application of recommended treatments ‘lagging’
“The data are there, and the recommendations are there for T2D and cardiovascular disease, heart failure, and diabetic kidney disease, but the problem has been implementation,” said Dr. Kosiborod. “Application in practice is lagging way behind the recommendations.” That led him and his associates to devise a “new model of care for patients with T2D,” the cardiometabolic center (CMC), as a status quo alternative.
The CMC paradigm is that patients with T2D, especially those with existing cardiovascular or chronic kidney disease or at high risk for these complications, undergo assessment and treatment at one site from a multidisciplinary staff of physicians and allied caregivers including nurse practitioners, nurse coordinators, pharmacists, dieticians, and diabetes educators who are cross-trained for managing both T2D and cardiovascular diseases.
The Cardiometabolic Center Alliance builds on the idea that this care model is defined by a set of detailed treatment protocols and processes of care that other sites can adopt to boost the number of patients aided by this approach, to gather data from a larger patient pool in a dedicated registry to better document the program’s impact, and to form a quality-improvement network that can collectively improve performance.
“It’s absolutely replicable,” maintained Dr. Kosiborod, who is also executive director of the Cardiometabolic Center Alliance. “We’ve codified all of the care and medications into an impressive package. We now have something that works, and many other centers are interested in building programs like this. By establishing a base of well-defined protocols and operating procedures we can train a cadre of allied professionals who can effectively implement the program across wider populations of patients, while using the brick and mortar center to manage more complex patients,” he added.
“We’re not taking patients” from primary care physicians, Dr. Kosiborod stressed. “We’re helping generalists give better care. They already have their hands full. We’re here to help physicians do better.”
He cited a recent study of 1,735 patients with atherosclerotic cardiovascular disease and diabetes (96% with T2D) enrolled in a registry at 119 U.S. sites during 2016-2018 that found less than 7% were on the full range of guideline-directed medical therapy that they qualified for based on existing treatment guidelines. “This is not acceptable,” Dr. Kosiborod declared.
“It’s so obvious that this needs to be a combined approach. It’s very difficult to have one provider take care of all of the T2D complications. There needs to be a new approach, and [the Cardiometabolic Center program at Saint Luke’s] has done a great job getting their initiative underway to take a more global approach,” commented Ralph A. DeFronzo, MD, chief of the diabetes division and professor of medicine at the University of Texas Health Science Center, San Antonio.
Early results show improved metrics
The Saint Luke’s Haverty CMC launched in 2019, and data from its first 129 patients with at least one follow-up visit documented early efficacy for the program, as reported at the American Heart Association’s Quality of Care and Outcome’s Research meeting, held virtually on May 15 and 16, 2020.
That analysis from Dr. Kosiborod and associates compared various short-term metrics among their CMC patients against a control cohort of 387 similar patients with T2D who also received care in the Saint Luke’s Health System during 2019 but outside of the CMC. This observational study involved no patient randomization, but the researchers used propensity scoring to match the control patients with those managed in the CMC by several demographic and clinical parameters.
During follow-up that was generally less than 6 months, patients managed in the CMC averaged 12 pounds of weight loss, a 0.5% reduction in their average hemoglobin A1c, a mean 4.6–mm Hg cut in their systolic blood pressure, an average drop in their LDL cholesterol of 11.4 mg/dL, and among those receiving insulin the daily, average insulin dose fell by a relative 43%, compared with baseline. Among the controls, averages for these five parameters were weight loss of 2 pounds, a cut in A1c of 0.2%, a systolic blood pressure reduction of 0.6 mm Hg, a drop in LDL cholesterol of 4.9 mg/dL, and a relative rise in insulin dose of 6%. All of these between group differences were statistically significant except for LDL cholesterol.
Additional analysis of the medications that patients in the CMC and control group received also showed striking differences. Combined prescriptions for all components of guideline-directed medical therapy went to 41% of the CMC patients, compared with 2% of the controls, a statistically significant difference. Contributing to this difference were significantly increased rates of prescriptions for ACE inhibitors and statins.
The CMC staff also started 57% of their patients on a SGLT2 inhibitor and 90% on a GLP-1 receptor agonist (GLP-1 RA), compared with rates of 18% and 13%, respectively, among controls. Both of these between-group differences were also significant, and they highlighted the willingness and success of the CMC clinicians to put a large number of their patients on agents from both of these beneficial drug classes. This is a notable change from usual recent practice that limits most patients who actually receive these medications to a drug from just one of these two classes, often because of real or perceived limits on insurance coverage.
The data from these initial patients in the Saint Luke’s CMC show that the program was “very successful; it looks very promising,” said Dr. Kosiborod. The results show “transformational improvement in the quality of care.” Subsequent to this initial cohort from 2019, the Saint Luke’s CMC has seen “hundreds” of additional patients with T2D.
The Cardiometabolic Center Alliance gets started
The second member of the Cardiometabolic Center Alliance is a program run by the University Hospitals system based in Cleveland that had begun earlier in 2020. The University Hospitals’ Center for Integrated and Novel Approaches in Vascular-Metabolic Disease (CINEMA) uses a comprehensive, multidisciplinary-care model developed independently of but very similar to the Saint Luke’s CMC. By the end of 2020, the CINEMA program had managed about 150 patients, said Sanjay Rajagopalan, MD, director of CINEMA and a professor of medicine at Case Western Reserve University, Cleveland.
“Our outcomes have been quite similar” to what the Saint Luke’s program reported, he said. “We had better use of guideline-directed therapies, more weight loss, and better control of metabolic parameters.” The CINEMA program entered the Cardiometabolic Center Alliance as a “key strategic partner,” which means it will have a role in shaping the alliance going forward. One issue the alliance faces is how to leverage its growth to improve management of patients with T2D who do not have access to a CMC.
The CMCs “are not meant for every patient with T2D, but for those with high risk for cardiovascular complications who require extra attention,” Dr. Rajagopalan said in an interview. Both he and Dr. Kosiborod acknowledged that, even if 200 CMCs were to eventually open, and even if each center averaged 5,000 managed patients, those 1 million patients would be a small fraction of the total number of U.S. patients with T2D.
“Having these centers will produce a ripple effect. The protocols will percolate to primary care physicians,” Dr. Rajagopalan predicted. Once that happens, “not all patients will need to go to a cardiometabolic center.” In addition, leveraging established protocols via nurse coordinators and virtual care could bring this model to many more patients, Dr. Kosiborod noted.
By the end of 2020, a total of three additional U.S. centers had joined Saint Luke’s and University Hospitals in the alliance, but Dr. Kosiborod said that none of the three had yet been officially announced. The alliance has also started a national cardiometabolic registry, which will be “instrumental for its mission to track, benchmark, and improve quality of care and outcomes; enable mechanisms for “learning health care systems”; and can be used to answer important research questions,” Dr. Kosiborod said.
Combined SGLT2 inhibitor and GLP-1 RA treatment takes off
A key element of the more aggressive, risk-driven management emphasized in the CMC approach is frequent use of combined treatment with an SGLT2 inhibitor and a GLP-1 RA. Both classes of glucose-lowering drugs have well-documented, risk-reducing benefits, notably reduced atherosclerotic cardiovascular events and weight loss produced by the GLP1-RAs, and cuts in heart failure onset and hospitalizations and slowing of chronic kidney disease progression by the SGLT2 inhibitors.
Until now, medical society recommendations as well as opinion leaders have approached these two drug classes with a presumption that physicians would usually prescribe patients an agent from only one of these two classes, largely because the high cost of agents in both classes, all still under patent, often means coverage limits by insurers. Physicians at both the Saint Luke’s and University Hospitals programs have been more proactive, and successful, in prescribing agents from both classes to their high-risk patients with T2D.
“We use combination treatment quite a bit,” said Dr. Kosiborod. “It’s very sensible to use both. Their mechanisms of action are different and likely don’t overlap, so it’s reasonable to presume their activity is complimentary.” But he acknowledged that this has not yet been formally studied for cardiovascular or renal outcomes. Study results have documented complimentary effects between the two classes for weight loss, blood pressure reduction, and to some extent A1c reduction. A key reason for more frequent combined treatment with an SGLT2 inhibitor and GLP-1 RA is increased focus on the ability of both drug classes to lower risk in patients with T2D and high cardiovascular-disease risk, rather than prescribing decisions driven largely by trying to further reduce a patient’s A1c.
Although insurance coverage is not a given, the Saint Luke’s CMC has had good results using patient-assistance programs run by various drug companies. Some patients have received their medications free of charge or with modest copays, depending on their income and insurance coverage. At Saint Luke’s, “many” patients with T2D have been able to get free medications through assistance programs, he said. And for patients with health insurance, getting coverage for an agent from each class “is easier now than it was 3-4 years ago.”
Dr. Kosiborod has been a consultant to several companies, and has received research grants from AstraZeneca and Boehringer Ingelheim. Dr. DeFronzo received research grants from Astra Zeneca, Janssen, and Merck; he has been an adviser to AstraZeneca, Boehringer Ingelheim, Intarcia, Janssen, and Novo Nordisk; and he has been a speaker on behalf of AstraZeneca and Novo Nordisk. Dr. Rajagopalan has been a consultant to Novo Nordisk and Takeda.
A one-stop shop approach to managing the spectrum of complications in patients with type 2 diabetes with a coordinated, multidisciplinary team of clinicians has taken root in at least two U.S. medical centers, and their efforts have now joined to take this concept national through the Cardiometabolic Center Alliance, which hopes to have at least 20 such centers running by the end of 2022.
In patients with type 2 diabetes (T2D), “multiple organs are affected by the same disease process,” notably the heart, kidneys, vasculature, and liver, but the care these patients often receive today is “fragmented, and typically without good coordination,” explained Mikhail N. Kosiborod, MD, a cardiologist and codirector of the Saint Luke’s Michael & Marlys Haverty Cardiometabolic Center of Excellence in Kansas City, Mo.
“We need to depart from the outdated idea that each medical specialty focuses on an organ system. It’s one patient with one disease that affects multiple organs and needs comprehensive, multidisciplinary care,” he said.
Historically, “we’ve looked to primary care physicians to ‘conduct the orchestra’ for complex, multispecialty care” for patients with T2D, but a recent “avalanche” of new treatments with new data and recommendations has made coordination by a single, generalist physician essentially impossible. “It isn’t realistic” to expect a single primary care physician to coordinate all the care a patient with T2D now needs to receive, said Dr. Kosiborod, who is also a professor of medicine at the University of Missouri–Kansas City. Plus, “patients can get lost” when they try to navigate on their own among several physicians, possibly in disparate locations, and without fully understanding what each physician is responsible for managing.
Application of recommended treatments ‘lagging’
“The data are there, and the recommendations are there for T2D and cardiovascular disease, heart failure, and diabetic kidney disease, but the problem has been implementation,” said Dr. Kosiborod. “Application in practice is lagging way behind the recommendations.” That led him and his associates to devise a “new model of care for patients with T2D,” the cardiometabolic center (CMC), as a status quo alternative.
The CMC paradigm is that patients with T2D, especially those with existing cardiovascular or chronic kidney disease or at high risk for these complications, undergo assessment and treatment at one site from a multidisciplinary staff of physicians and allied caregivers including nurse practitioners, nurse coordinators, pharmacists, dieticians, and diabetes educators who are cross-trained for managing both T2D and cardiovascular diseases.
The Cardiometabolic Center Alliance builds on the idea that this care model is defined by a set of detailed treatment protocols and processes of care that other sites can adopt to boost the number of patients aided by this approach, to gather data from a larger patient pool in a dedicated registry to better document the program’s impact, and to form a quality-improvement network that can collectively improve performance.
“It’s absolutely replicable,” maintained Dr. Kosiborod, who is also executive director of the Cardiometabolic Center Alliance. “We’ve codified all of the care and medications into an impressive package. We now have something that works, and many other centers are interested in building programs like this. By establishing a base of well-defined protocols and operating procedures we can train a cadre of allied professionals who can effectively implement the program across wider populations of patients, while using the brick and mortar center to manage more complex patients,” he added.
“We’re not taking patients” from primary care physicians, Dr. Kosiborod stressed. “We’re helping generalists give better care. They already have their hands full. We’re here to help physicians do better.”
He cited a recent study of 1,735 patients with atherosclerotic cardiovascular disease and diabetes (96% with T2D) enrolled in a registry at 119 U.S. sites during 2016-2018 that found less than 7% were on the full range of guideline-directed medical therapy that they qualified for based on existing treatment guidelines. “This is not acceptable,” Dr. Kosiborod declared.
“It’s so obvious that this needs to be a combined approach. It’s very difficult to have one provider take care of all of the T2D complications. There needs to be a new approach, and [the Cardiometabolic Center program at Saint Luke’s] has done a great job getting their initiative underway to take a more global approach,” commented Ralph A. DeFronzo, MD, chief of the diabetes division and professor of medicine at the University of Texas Health Science Center, San Antonio.
Early results show improved metrics
The Saint Luke’s Haverty CMC launched in 2019, and data from its first 129 patients with at least one follow-up visit documented early efficacy for the program, as reported at the American Heart Association’s Quality of Care and Outcome’s Research meeting, held virtually on May 15 and 16, 2020.
That analysis from Dr. Kosiborod and associates compared various short-term metrics among their CMC patients against a control cohort of 387 similar patients with T2D who also received care in the Saint Luke’s Health System during 2019 but outside of the CMC. This observational study involved no patient randomization, but the researchers used propensity scoring to match the control patients with those managed in the CMC by several demographic and clinical parameters.
During follow-up that was generally less than 6 months, patients managed in the CMC averaged 12 pounds of weight loss, a 0.5% reduction in their average hemoglobin A1c, a mean 4.6–mm Hg cut in their systolic blood pressure, an average drop in their LDL cholesterol of 11.4 mg/dL, and among those receiving insulin the daily, average insulin dose fell by a relative 43%, compared with baseline. Among the controls, averages for these five parameters were weight loss of 2 pounds, a cut in A1c of 0.2%, a systolic blood pressure reduction of 0.6 mm Hg, a drop in LDL cholesterol of 4.9 mg/dL, and a relative rise in insulin dose of 6%. All of these between group differences were statistically significant except for LDL cholesterol.
Additional analysis of the medications that patients in the CMC and control group received also showed striking differences. Combined prescriptions for all components of guideline-directed medical therapy went to 41% of the CMC patients, compared with 2% of the controls, a statistically significant difference. Contributing to this difference were significantly increased rates of prescriptions for ACE inhibitors and statins.
The CMC staff also started 57% of their patients on a SGLT2 inhibitor and 90% on a GLP-1 receptor agonist (GLP-1 RA), compared with rates of 18% and 13%, respectively, among controls. Both of these between-group differences were also significant, and they highlighted the willingness and success of the CMC clinicians to put a large number of their patients on agents from both of these beneficial drug classes. This is a notable change from usual recent practice that limits most patients who actually receive these medications to a drug from just one of these two classes, often because of real or perceived limits on insurance coverage.
The data from these initial patients in the Saint Luke’s CMC show that the program was “very successful; it looks very promising,” said Dr. Kosiborod. The results show “transformational improvement in the quality of care.” Subsequent to this initial cohort from 2019, the Saint Luke’s CMC has seen “hundreds” of additional patients with T2D.
The Cardiometabolic Center Alliance gets started
The second member of the Cardiometabolic Center Alliance is a program run by the University Hospitals system based in Cleveland that had begun earlier in 2020. The University Hospitals’ Center for Integrated and Novel Approaches in Vascular-Metabolic Disease (CINEMA) uses a comprehensive, multidisciplinary-care model developed independently of but very similar to the Saint Luke’s CMC. By the end of 2020, the CINEMA program had managed about 150 patients, said Sanjay Rajagopalan, MD, director of CINEMA and a professor of medicine at Case Western Reserve University, Cleveland.
“Our outcomes have been quite similar” to what the Saint Luke’s program reported, he said. “We had better use of guideline-directed therapies, more weight loss, and better control of metabolic parameters.” The CINEMA program entered the Cardiometabolic Center Alliance as a “key strategic partner,” which means it will have a role in shaping the alliance going forward. One issue the alliance faces is how to leverage its growth to improve management of patients with T2D who do not have access to a CMC.
The CMCs “are not meant for every patient with T2D, but for those with high risk for cardiovascular complications who require extra attention,” Dr. Rajagopalan said in an interview. Both he and Dr. Kosiborod acknowledged that, even if 200 CMCs were to eventually open, and even if each center averaged 5,000 managed patients, those 1 million patients would be a small fraction of the total number of U.S. patients with T2D.
“Having these centers will produce a ripple effect. The protocols will percolate to primary care physicians,” Dr. Rajagopalan predicted. Once that happens, “not all patients will need to go to a cardiometabolic center.” In addition, leveraging established protocols via nurse coordinators and virtual care could bring this model to many more patients, Dr. Kosiborod noted.
By the end of 2020, a total of three additional U.S. centers had joined Saint Luke’s and University Hospitals in the alliance, but Dr. Kosiborod said that none of the three had yet been officially announced. The alliance has also started a national cardiometabolic registry, which will be “instrumental for its mission to track, benchmark, and improve quality of care and outcomes; enable mechanisms for “learning health care systems”; and can be used to answer important research questions,” Dr. Kosiborod said.
Combined SGLT2 inhibitor and GLP-1 RA treatment takes off
A key element of the more aggressive, risk-driven management emphasized in the CMC approach is frequent use of combined treatment with an SGLT2 inhibitor and a GLP-1 RA. Both classes of glucose-lowering drugs have well-documented, risk-reducing benefits, notably reduced atherosclerotic cardiovascular events and weight loss produced by the GLP1-RAs, and cuts in heart failure onset and hospitalizations and slowing of chronic kidney disease progression by the SGLT2 inhibitors.
Until now, medical society recommendations as well as opinion leaders have approached these two drug classes with a presumption that physicians would usually prescribe patients an agent from only one of these two classes, largely because the high cost of agents in both classes, all still under patent, often means coverage limits by insurers. Physicians at both the Saint Luke’s and University Hospitals programs have been more proactive, and successful, in prescribing agents from both classes to their high-risk patients with T2D.
“We use combination treatment quite a bit,” said Dr. Kosiborod. “It’s very sensible to use both. Their mechanisms of action are different and likely don’t overlap, so it’s reasonable to presume their activity is complimentary.” But he acknowledged that this has not yet been formally studied for cardiovascular or renal outcomes. Study results have documented complimentary effects between the two classes for weight loss, blood pressure reduction, and to some extent A1c reduction. A key reason for more frequent combined treatment with an SGLT2 inhibitor and GLP-1 RA is increased focus on the ability of both drug classes to lower risk in patients with T2D and high cardiovascular-disease risk, rather than prescribing decisions driven largely by trying to further reduce a patient’s A1c.
Although insurance coverage is not a given, the Saint Luke’s CMC has had good results using patient-assistance programs run by various drug companies. Some patients have received their medications free of charge or with modest copays, depending on their income and insurance coverage. At Saint Luke’s, “many” patients with T2D have been able to get free medications through assistance programs, he said. And for patients with health insurance, getting coverage for an agent from each class “is easier now than it was 3-4 years ago.”
Dr. Kosiborod has been a consultant to several companies, and has received research grants from AstraZeneca and Boehringer Ingelheim. Dr. DeFronzo received research grants from Astra Zeneca, Janssen, and Merck; he has been an adviser to AstraZeneca, Boehringer Ingelheim, Intarcia, Janssen, and Novo Nordisk; and he has been a speaker on behalf of AstraZeneca and Novo Nordisk. Dr. Rajagopalan has been a consultant to Novo Nordisk and Takeda.
A one-stop shop approach to managing the spectrum of complications in patients with type 2 diabetes with a coordinated, multidisciplinary team of clinicians has taken root in at least two U.S. medical centers, and their efforts have now joined to take this concept national through the Cardiometabolic Center Alliance, which hopes to have at least 20 such centers running by the end of 2022.
In patients with type 2 diabetes (T2D), “multiple organs are affected by the same disease process,” notably the heart, kidneys, vasculature, and liver, but the care these patients often receive today is “fragmented, and typically without good coordination,” explained Mikhail N. Kosiborod, MD, a cardiologist and codirector of the Saint Luke’s Michael & Marlys Haverty Cardiometabolic Center of Excellence in Kansas City, Mo.
“We need to depart from the outdated idea that each medical specialty focuses on an organ system. It’s one patient with one disease that affects multiple organs and needs comprehensive, multidisciplinary care,” he said.
Historically, “we’ve looked to primary care physicians to ‘conduct the orchestra’ for complex, multispecialty care” for patients with T2D, but a recent “avalanche” of new treatments with new data and recommendations has made coordination by a single, generalist physician essentially impossible. “It isn’t realistic” to expect a single primary care physician to coordinate all the care a patient with T2D now needs to receive, said Dr. Kosiborod, who is also a professor of medicine at the University of Missouri–Kansas City. Plus, “patients can get lost” when they try to navigate on their own among several physicians, possibly in disparate locations, and without fully understanding what each physician is responsible for managing.
Application of recommended treatments ‘lagging’
“The data are there, and the recommendations are there for T2D and cardiovascular disease, heart failure, and diabetic kidney disease, but the problem has been implementation,” said Dr. Kosiborod. “Application in practice is lagging way behind the recommendations.” That led him and his associates to devise a “new model of care for patients with T2D,” the cardiometabolic center (CMC), as a status quo alternative.
The CMC paradigm is that patients with T2D, especially those with existing cardiovascular or chronic kidney disease or at high risk for these complications, undergo assessment and treatment at one site from a multidisciplinary staff of physicians and allied caregivers including nurse practitioners, nurse coordinators, pharmacists, dieticians, and diabetes educators who are cross-trained for managing both T2D and cardiovascular diseases.
The Cardiometabolic Center Alliance builds on the idea that this care model is defined by a set of detailed treatment protocols and processes of care that other sites can adopt to boost the number of patients aided by this approach, to gather data from a larger patient pool in a dedicated registry to better document the program’s impact, and to form a quality-improvement network that can collectively improve performance.
“It’s absolutely replicable,” maintained Dr. Kosiborod, who is also executive director of the Cardiometabolic Center Alliance. “We’ve codified all of the care and medications into an impressive package. We now have something that works, and many other centers are interested in building programs like this. By establishing a base of well-defined protocols and operating procedures we can train a cadre of allied professionals who can effectively implement the program across wider populations of patients, while using the brick and mortar center to manage more complex patients,” he added.
“We’re not taking patients” from primary care physicians, Dr. Kosiborod stressed. “We’re helping generalists give better care. They already have their hands full. We’re here to help physicians do better.”
He cited a recent study of 1,735 patients with atherosclerotic cardiovascular disease and diabetes (96% with T2D) enrolled in a registry at 119 U.S. sites during 2016-2018 that found less than 7% were on the full range of guideline-directed medical therapy that they qualified for based on existing treatment guidelines. “This is not acceptable,” Dr. Kosiborod declared.
“It’s so obvious that this needs to be a combined approach. It’s very difficult to have one provider take care of all of the T2D complications. There needs to be a new approach, and [the Cardiometabolic Center program at Saint Luke’s] has done a great job getting their initiative underway to take a more global approach,” commented Ralph A. DeFronzo, MD, chief of the diabetes division and professor of medicine at the University of Texas Health Science Center, San Antonio.
Early results show improved metrics
The Saint Luke’s Haverty CMC launched in 2019, and data from its first 129 patients with at least one follow-up visit documented early efficacy for the program, as reported at the American Heart Association’s Quality of Care and Outcome’s Research meeting, held virtually on May 15 and 16, 2020.
That analysis from Dr. Kosiborod and associates compared various short-term metrics among their CMC patients against a control cohort of 387 similar patients with T2D who also received care in the Saint Luke’s Health System during 2019 but outside of the CMC. This observational study involved no patient randomization, but the researchers used propensity scoring to match the control patients with those managed in the CMC by several demographic and clinical parameters.
During follow-up that was generally less than 6 months, patients managed in the CMC averaged 12 pounds of weight loss, a 0.5% reduction in their average hemoglobin A1c, a mean 4.6–mm Hg cut in their systolic blood pressure, an average drop in their LDL cholesterol of 11.4 mg/dL, and among those receiving insulin the daily, average insulin dose fell by a relative 43%, compared with baseline. Among the controls, averages for these five parameters were weight loss of 2 pounds, a cut in A1c of 0.2%, a systolic blood pressure reduction of 0.6 mm Hg, a drop in LDL cholesterol of 4.9 mg/dL, and a relative rise in insulin dose of 6%. All of these between group differences were statistically significant except for LDL cholesterol.
Additional analysis of the medications that patients in the CMC and control group received also showed striking differences. Combined prescriptions for all components of guideline-directed medical therapy went to 41% of the CMC patients, compared with 2% of the controls, a statistically significant difference. Contributing to this difference were significantly increased rates of prescriptions for ACE inhibitors and statins.
The CMC staff also started 57% of their patients on a SGLT2 inhibitor and 90% on a GLP-1 receptor agonist (GLP-1 RA), compared with rates of 18% and 13%, respectively, among controls. Both of these between-group differences were also significant, and they highlighted the willingness and success of the CMC clinicians to put a large number of their patients on agents from both of these beneficial drug classes. This is a notable change from usual recent practice that limits most patients who actually receive these medications to a drug from just one of these two classes, often because of real or perceived limits on insurance coverage.
The data from these initial patients in the Saint Luke’s CMC show that the program was “very successful; it looks very promising,” said Dr. Kosiborod. The results show “transformational improvement in the quality of care.” Subsequent to this initial cohort from 2019, the Saint Luke’s CMC has seen “hundreds” of additional patients with T2D.
The Cardiometabolic Center Alliance gets started
The second member of the Cardiometabolic Center Alliance is a program run by the University Hospitals system based in Cleveland that had begun earlier in 2020. The University Hospitals’ Center for Integrated and Novel Approaches in Vascular-Metabolic Disease (CINEMA) uses a comprehensive, multidisciplinary-care model developed independently of but very similar to the Saint Luke’s CMC. By the end of 2020, the CINEMA program had managed about 150 patients, said Sanjay Rajagopalan, MD, director of CINEMA and a professor of medicine at Case Western Reserve University, Cleveland.
“Our outcomes have been quite similar” to what the Saint Luke’s program reported, he said. “We had better use of guideline-directed therapies, more weight loss, and better control of metabolic parameters.” The CINEMA program entered the Cardiometabolic Center Alliance as a “key strategic partner,” which means it will have a role in shaping the alliance going forward. One issue the alliance faces is how to leverage its growth to improve management of patients with T2D who do not have access to a CMC.
The CMCs “are not meant for every patient with T2D, but for those with high risk for cardiovascular complications who require extra attention,” Dr. Rajagopalan said in an interview. Both he and Dr. Kosiborod acknowledged that, even if 200 CMCs were to eventually open, and even if each center averaged 5,000 managed patients, those 1 million patients would be a small fraction of the total number of U.S. patients with T2D.
“Having these centers will produce a ripple effect. The protocols will percolate to primary care physicians,” Dr. Rajagopalan predicted. Once that happens, “not all patients will need to go to a cardiometabolic center.” In addition, leveraging established protocols via nurse coordinators and virtual care could bring this model to many more patients, Dr. Kosiborod noted.
By the end of 2020, a total of three additional U.S. centers had joined Saint Luke’s and University Hospitals in the alliance, but Dr. Kosiborod said that none of the three had yet been officially announced. The alliance has also started a national cardiometabolic registry, which will be “instrumental for its mission to track, benchmark, and improve quality of care and outcomes; enable mechanisms for “learning health care systems”; and can be used to answer important research questions,” Dr. Kosiborod said.
Combined SGLT2 inhibitor and GLP-1 RA treatment takes off
A key element of the more aggressive, risk-driven management emphasized in the CMC approach is frequent use of combined treatment with an SGLT2 inhibitor and a GLP-1 RA. Both classes of glucose-lowering drugs have well-documented, risk-reducing benefits, notably reduced atherosclerotic cardiovascular events and weight loss produced by the GLP1-RAs, and cuts in heart failure onset and hospitalizations and slowing of chronic kidney disease progression by the SGLT2 inhibitors.
Until now, medical society recommendations as well as opinion leaders have approached these two drug classes with a presumption that physicians would usually prescribe patients an agent from only one of these two classes, largely because the high cost of agents in both classes, all still under patent, often means coverage limits by insurers. Physicians at both the Saint Luke’s and University Hospitals programs have been more proactive, and successful, in prescribing agents from both classes to their high-risk patients with T2D.
“We use combination treatment quite a bit,” said Dr. Kosiborod. “It’s very sensible to use both. Their mechanisms of action are different and likely don’t overlap, so it’s reasonable to presume their activity is complimentary.” But he acknowledged that this has not yet been formally studied for cardiovascular or renal outcomes. Study results have documented complimentary effects between the two classes for weight loss, blood pressure reduction, and to some extent A1c reduction. A key reason for more frequent combined treatment with an SGLT2 inhibitor and GLP-1 RA is increased focus on the ability of both drug classes to lower risk in patients with T2D and high cardiovascular-disease risk, rather than prescribing decisions driven largely by trying to further reduce a patient’s A1c.
Although insurance coverage is not a given, the Saint Luke’s CMC has had good results using patient-assistance programs run by various drug companies. Some patients have received their medications free of charge or with modest copays, depending on their income and insurance coverage. At Saint Luke’s, “many” patients with T2D have been able to get free medications through assistance programs, he said. And for patients with health insurance, getting coverage for an agent from each class “is easier now than it was 3-4 years ago.”
Dr. Kosiborod has been a consultant to several companies, and has received research grants from AstraZeneca and Boehringer Ingelheim. Dr. DeFronzo received research grants from Astra Zeneca, Janssen, and Merck; he has been an adviser to AstraZeneca, Boehringer Ingelheim, Intarcia, Janssen, and Novo Nordisk; and he has been a speaker on behalf of AstraZeneca and Novo Nordisk. Dr. Rajagopalan has been a consultant to Novo Nordisk and Takeda.
Sotagliflozin’s trial data receives FDA welcome for NDA filing
The Food and Drug Administration has determined that data collected on the dual SGLT1/2 inhibitor sotagliflozin (Zynquista) for treating patients with type 2 diabetes in the SOLOIST and SCORED pivotal trials can help support a New Drug Application (NDA) submission, according to a statement released on Jan. 14 by Lexicon Pharmaceuticals, the company developing this drug. Lexicon concurrently said that it hopes to potentially file this NDA later in 2021.
The statement said the FDA’s decision related to an NDA for “an indication to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent visits for heart failure in adult patients with type 2 diabetes with either worsening heart failure or additional risk factors for heart failure.”
Results from SOLOIST and SCORED, first reported in November 2020 at the American Heart Association scientific sessions, showed statistically significant benefits for their respective primary endpoints.
The findings also demonstrated several novel benefits from the first advanced clinical trials of an SGLT inhibitor that blocks both the SGLT2 protein in kidneys as well as the SGLT1 protein, which resides primarily in the gastrointestinal system and is the main route for glucose out of the gut.
In both SOLOIST and SCORED, patient outcomes on sotagliflozin tracked the benefits and adverse effects previously seen with several SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin), but in addition showed several unprecedented benefits: An ability to lower hemoglobin A1c in patients with severely depressed renal function, safe initiation in patients recently hospitalized for heart failure, the first prospective data to show improvements in patients with heart failure with preserved ejection fraction, and a higher level of protection against MIs and strokes than the SGLT2 inhibitors.
The FDA’s willingness to consider data from both trials in an NDA was not a given, as the primary endpoints for both trials underwent tweaking while they were underway to compensate for an unexpectedly early end to patient enrollment and follow-up caused by changes in drug company sponsorship and challenges introduced by the COVID-19 pandemic.
In 2019, the FDA denied the NDA for sotagliflozin as a treatment for patients with type 1 diabetes, but this indication received approval in Europe.
SOLOIST and SCORED were sponsored initially by Sanofi, and more recently by Lexicon.
The Food and Drug Administration has determined that data collected on the dual SGLT1/2 inhibitor sotagliflozin (Zynquista) for treating patients with type 2 diabetes in the SOLOIST and SCORED pivotal trials can help support a New Drug Application (NDA) submission, according to a statement released on Jan. 14 by Lexicon Pharmaceuticals, the company developing this drug. Lexicon concurrently said that it hopes to potentially file this NDA later in 2021.
The statement said the FDA’s decision related to an NDA for “an indication to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent visits for heart failure in adult patients with type 2 diabetes with either worsening heart failure or additional risk factors for heart failure.”
Results from SOLOIST and SCORED, first reported in November 2020 at the American Heart Association scientific sessions, showed statistically significant benefits for their respective primary endpoints.
The findings also demonstrated several novel benefits from the first advanced clinical trials of an SGLT inhibitor that blocks both the SGLT2 protein in kidneys as well as the SGLT1 protein, which resides primarily in the gastrointestinal system and is the main route for glucose out of the gut.
In both SOLOIST and SCORED, patient outcomes on sotagliflozin tracked the benefits and adverse effects previously seen with several SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin), but in addition showed several unprecedented benefits: An ability to lower hemoglobin A1c in patients with severely depressed renal function, safe initiation in patients recently hospitalized for heart failure, the first prospective data to show improvements in patients with heart failure with preserved ejection fraction, and a higher level of protection against MIs and strokes than the SGLT2 inhibitors.
The FDA’s willingness to consider data from both trials in an NDA was not a given, as the primary endpoints for both trials underwent tweaking while they were underway to compensate for an unexpectedly early end to patient enrollment and follow-up caused by changes in drug company sponsorship and challenges introduced by the COVID-19 pandemic.
In 2019, the FDA denied the NDA for sotagliflozin as a treatment for patients with type 1 diabetes, but this indication received approval in Europe.
SOLOIST and SCORED were sponsored initially by Sanofi, and more recently by Lexicon.
The Food and Drug Administration has determined that data collected on the dual SGLT1/2 inhibitor sotagliflozin (Zynquista) for treating patients with type 2 diabetes in the SOLOIST and SCORED pivotal trials can help support a New Drug Application (NDA) submission, according to a statement released on Jan. 14 by Lexicon Pharmaceuticals, the company developing this drug. Lexicon concurrently said that it hopes to potentially file this NDA later in 2021.
The statement said the FDA’s decision related to an NDA for “an indication to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent visits for heart failure in adult patients with type 2 diabetes with either worsening heart failure or additional risk factors for heart failure.”
Results from SOLOIST and SCORED, first reported in November 2020 at the American Heart Association scientific sessions, showed statistically significant benefits for their respective primary endpoints.
The findings also demonstrated several novel benefits from the first advanced clinical trials of an SGLT inhibitor that blocks both the SGLT2 protein in kidneys as well as the SGLT1 protein, which resides primarily in the gastrointestinal system and is the main route for glucose out of the gut.
In both SOLOIST and SCORED, patient outcomes on sotagliflozin tracked the benefits and adverse effects previously seen with several SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin), but in addition showed several unprecedented benefits: An ability to lower hemoglobin A1c in patients with severely depressed renal function, safe initiation in patients recently hospitalized for heart failure, the first prospective data to show improvements in patients with heart failure with preserved ejection fraction, and a higher level of protection against MIs and strokes than the SGLT2 inhibitors.
The FDA’s willingness to consider data from both trials in an NDA was not a given, as the primary endpoints for both trials underwent tweaking while they were underway to compensate for an unexpectedly early end to patient enrollment and follow-up caused by changes in drug company sponsorship and challenges introduced by the COVID-19 pandemic.
In 2019, the FDA denied the NDA for sotagliflozin as a treatment for patients with type 1 diabetes, but this indication received approval in Europe.
SOLOIST and SCORED were sponsored initially by Sanofi, and more recently by Lexicon.
Far too few with treatment-resistant hypertension get hormone test
despite guidelines that call for such an approach, according to findings from the first reported large-scale, multicenter study of PA testing practices.
Researchers ran a retrospective review of PA testing among 269,010 patients who met the definition as having treatment-resistant hypertension and were managed at any one of 130 Veterans Health Administration (VHA) medical centers from 2000 to 2017.
The results showed that, despite the fact that primary aldosteronism is highly prevalent among patients with treatment-resistant hypertension, only 4,277 (1.6%) underwent assessment for PA during a median of 3.3 years’ follow-up after they first met the defining criteria, Jordana B. Cohen, MD, and her associates reported in a study published in Annals of Internal Medicine on December 28.
“Testing rates also did not change meaningfully over nearly 2 decades ... despite an increasing number of guidelines recommending testing for primary aldosteronism in this population,” including the most recent recommendations from the Endocrine Society, issued in 2016, noted Dr. Cohen, a nephrologist and hypertension researcher at the University of Pennsylvania in Philadelphia, and colleagues.
Most patients in the study (almost 90%) were seen by a primary care practitioner (PCP).
The small percentage of patients seen by a nephrologist or endocrinologist were more than twice as likely to be tested for PA than those seen by a PCP or cardiologist.
Those clinicians who did order a test for PA were much more likely to treat patients with the appropriate medication, a mineralocorticoid receptor antagonist (MRA). In addition, therapy was started sooner, the researchers found.
“Our results corroborate” earlier reports from smaller health systems and suggest that dramatic underuse of PA assessment “is an issue across the US,” Dr. Cohen said in an interview.
The VHA experience “is very representative of what we think goes on across U.S. practice” and contrasts with the VHA’s reputation for “doing a pretty good job managing hypertension” in general, she noted.
Missed diagnosis, missed treatment
Dr. Cohen believes a number of factors likely help drive the abysmally low rate of PA testing they observed in the VHA system. She believes rates of PA testing are low elsewhere as well.
First, optimal hypertension management “is often taken for granted” but is challenging in busy primary care practices, so many of patients likely fall through the cracks, she said.
Dr. Cohen cited efforts at her institution, as well as by the VHA system, to better employ electronic health records to flag patients with treatment-resistant hypertension – defined as patients whose systolic or diastolic blood pressure remains at or above 140/90 mm Hg on at least two successive measurements at least a month apart while the patient is undergoing treatment with three conventional antihypertensive drugs – and to guide clinicians to order the right tests and treatments for these patients.
Many care providers mistakenly “see treatment-resistant hypertension as a disease of noncompliance,” although it is much more often the result of a missed diagnosis and inadequate intervention, she explained.
Physicians in denial; side effects of MRAs may deter prescribing
A second big cause of low PA testing rates is that doctors make the mistake of thinking a PA test result won’t change how they manage these patients.
The established treatment for most patients with treatment-resistant hypertension as well as PA is adding an MRA, either spironolactone or eplerenone (Inspra).
Many providers cling to the belief that they will start an MRA in these patients without first determining their PA status, says Dr. Cohen, but the data she and her colleagues collected show the opposite.
Overall, about 13% of all patients in the study began treatment with an MRA during follow-up. The likelihood of starting treatment with this drug class was fourfold higher among the patients tested for PA compared with those who were not tested.
PA testing also hastened the start of MRA use by more than a year, compared with untested patients.
“Providers think they prescribe an MRA” to treatment-resistant patients, “but it’s part of their denial. They are not using the evidence-based treatments [spironolactone or eplerenone], perhaps because of concerns about MRA side effects, although those have been pretty well overcome during the past 20 years,” she observed.
Dr. Cohen says gynecomastia is one adverse effect that gives pause to VHA clinicians who see a heavily male patient population. “It’s probably the biggest concern and why PA testing and MRA use is low” in the VHA system, she said.
“You can use a lower dosage of spironolactone, and the incidence is less common with eplerenone,” although using eplerenone does not completely eliminate all gynecomastia cases, she noted.
At the University of Pennsylvania hospitals, men often start on spironolactone first because it retains a significant price advantage, even though eplerenone is now generic, but “if there is a hint of gynecomastia, we quickly switch to eplerenone, which is usually well tolerated,” she explained.
And while eplerenone has a reputation of being less effective than spironolactone, “I’ve prescribed a lot of eplerenone and have had good results,” Dr. Cohen said. “Even if the blood pressure lowering is not as great compared with spironolactone, it still blunts the toxic effects of aldosterone on target organs.”
Hyperkalemia is the other big concern about spironolactone and eplerenone. Both agents cause it at roughly the same rate, although the rate is lower in patients without chronic kidney disease.
A new, nonsteroidal MRA, finerenone, caused substantially less hyperkalemia in a recent phase 3 trial, FIDELIO-DKD, and as a nonsteroidal MRA, it does not cause gynecomastia. Finerenone has promise as a potentially safer option for treating PA and treatment-resistant hypertension, noted Cohen, but so far, no advanced clinical trials have been launched to examine its efficacy for these indications.
PA testing allows a surgical option
A third reason to test patients with treatment-resistant hypertension for PA is that jumping straight to MRA treatment denies the patient assessment for a unilateral adrenal adenoma as the cause of excess aldosterone.
When unilateral adenomas exist, patients are candidates for adrenalectomy. Despite the potential advantage this gives patients to eliminate the cause of their PA without the need for additional drug treatment, some clinicians don’t see this as a compelling rationale to test for PA because they have a bias against surgery or have seen too many cases in which surgery failed to produce full hypertension resolution.
“It’s all about setting expectations appropriately” for the impact of this surgery, Dr. Cohen said.
“Adrenalectomy is not a cure; it just gets rid of the source of excess aldosterone.” But in patients with long-standing PA and hypertension, this is often not enough to completely resolve entrenched cardiovascular pathology.
PCPs, cardiologists in rural locations least likely to order PA testing
Of the 269,010 patients analyzed by Dr. Cohen and her coauthors, the average age was 65 years; 96% were men; half were obese; and 40% had diabetes. The researchers excluded patients who had already been tested for PA, as well as those who were already receiving treatment with an MRA.
For 88% of the patients, the main physician overseeing care was a PCP. A cardiologist was the main physician for 10%; a nephrologist, for 1%; and an endocrinologist, for fewer than 1%.
The rate of testing for PA varied across the 130 VHA centers that contributed data, ranging from 0% to 6%. The testing data showed that endocrinologists were most likely to order PA testing, doing it 2.48-fold more often than PCPs. Nephrologists were roughly twice as likely to order PA testing than PCPs, and cardiologists ordered testing at about the same rate as PCPs.
Patients managed at VHA centers in rural locations were nearly half as likely to undergo testing as patients managed at nonrural centers. The number of patients with treatment-resistant hypertension seen by a physician or at a center had no significant relationship to PA testing frequency.
The study received no commercial funding. Dr. Cohen has disclosed no relevant financial relationships.
A version of this story first appeared on Medscape.com.
despite guidelines that call for such an approach, according to findings from the first reported large-scale, multicenter study of PA testing practices.
Researchers ran a retrospective review of PA testing among 269,010 patients who met the definition as having treatment-resistant hypertension and were managed at any one of 130 Veterans Health Administration (VHA) medical centers from 2000 to 2017.
The results showed that, despite the fact that primary aldosteronism is highly prevalent among patients with treatment-resistant hypertension, only 4,277 (1.6%) underwent assessment for PA during a median of 3.3 years’ follow-up after they first met the defining criteria, Jordana B. Cohen, MD, and her associates reported in a study published in Annals of Internal Medicine on December 28.
“Testing rates also did not change meaningfully over nearly 2 decades ... despite an increasing number of guidelines recommending testing for primary aldosteronism in this population,” including the most recent recommendations from the Endocrine Society, issued in 2016, noted Dr. Cohen, a nephrologist and hypertension researcher at the University of Pennsylvania in Philadelphia, and colleagues.
Most patients in the study (almost 90%) were seen by a primary care practitioner (PCP).
The small percentage of patients seen by a nephrologist or endocrinologist were more than twice as likely to be tested for PA than those seen by a PCP or cardiologist.
Those clinicians who did order a test for PA were much more likely to treat patients with the appropriate medication, a mineralocorticoid receptor antagonist (MRA). In addition, therapy was started sooner, the researchers found.
“Our results corroborate” earlier reports from smaller health systems and suggest that dramatic underuse of PA assessment “is an issue across the US,” Dr. Cohen said in an interview.
The VHA experience “is very representative of what we think goes on across U.S. practice” and contrasts with the VHA’s reputation for “doing a pretty good job managing hypertension” in general, she noted.
Missed diagnosis, missed treatment
Dr. Cohen believes a number of factors likely help drive the abysmally low rate of PA testing they observed in the VHA system. She believes rates of PA testing are low elsewhere as well.
First, optimal hypertension management “is often taken for granted” but is challenging in busy primary care practices, so many of patients likely fall through the cracks, she said.
Dr. Cohen cited efforts at her institution, as well as by the VHA system, to better employ electronic health records to flag patients with treatment-resistant hypertension – defined as patients whose systolic or diastolic blood pressure remains at or above 140/90 mm Hg on at least two successive measurements at least a month apart while the patient is undergoing treatment with three conventional antihypertensive drugs – and to guide clinicians to order the right tests and treatments for these patients.
Many care providers mistakenly “see treatment-resistant hypertension as a disease of noncompliance,” although it is much more often the result of a missed diagnosis and inadequate intervention, she explained.
Physicians in denial; side effects of MRAs may deter prescribing
A second big cause of low PA testing rates is that doctors make the mistake of thinking a PA test result won’t change how they manage these patients.
The established treatment for most patients with treatment-resistant hypertension as well as PA is adding an MRA, either spironolactone or eplerenone (Inspra).
Many providers cling to the belief that they will start an MRA in these patients without first determining their PA status, says Dr. Cohen, but the data she and her colleagues collected show the opposite.
Overall, about 13% of all patients in the study began treatment with an MRA during follow-up. The likelihood of starting treatment with this drug class was fourfold higher among the patients tested for PA compared with those who were not tested.
PA testing also hastened the start of MRA use by more than a year, compared with untested patients.
“Providers think they prescribe an MRA” to treatment-resistant patients, “but it’s part of their denial. They are not using the evidence-based treatments [spironolactone or eplerenone], perhaps because of concerns about MRA side effects, although those have been pretty well overcome during the past 20 years,” she observed.
Dr. Cohen says gynecomastia is one adverse effect that gives pause to VHA clinicians who see a heavily male patient population. “It’s probably the biggest concern and why PA testing and MRA use is low” in the VHA system, she said.
“You can use a lower dosage of spironolactone, and the incidence is less common with eplerenone,” although using eplerenone does not completely eliminate all gynecomastia cases, she noted.
At the University of Pennsylvania hospitals, men often start on spironolactone first because it retains a significant price advantage, even though eplerenone is now generic, but “if there is a hint of gynecomastia, we quickly switch to eplerenone, which is usually well tolerated,” she explained.
And while eplerenone has a reputation of being less effective than spironolactone, “I’ve prescribed a lot of eplerenone and have had good results,” Dr. Cohen said. “Even if the blood pressure lowering is not as great compared with spironolactone, it still blunts the toxic effects of aldosterone on target organs.”
Hyperkalemia is the other big concern about spironolactone and eplerenone. Both agents cause it at roughly the same rate, although the rate is lower in patients without chronic kidney disease.
A new, nonsteroidal MRA, finerenone, caused substantially less hyperkalemia in a recent phase 3 trial, FIDELIO-DKD, and as a nonsteroidal MRA, it does not cause gynecomastia. Finerenone has promise as a potentially safer option for treating PA and treatment-resistant hypertension, noted Cohen, but so far, no advanced clinical trials have been launched to examine its efficacy for these indications.
PA testing allows a surgical option
A third reason to test patients with treatment-resistant hypertension for PA is that jumping straight to MRA treatment denies the patient assessment for a unilateral adrenal adenoma as the cause of excess aldosterone.
When unilateral adenomas exist, patients are candidates for adrenalectomy. Despite the potential advantage this gives patients to eliminate the cause of their PA without the need for additional drug treatment, some clinicians don’t see this as a compelling rationale to test for PA because they have a bias against surgery or have seen too many cases in which surgery failed to produce full hypertension resolution.
“It’s all about setting expectations appropriately” for the impact of this surgery, Dr. Cohen said.
“Adrenalectomy is not a cure; it just gets rid of the source of excess aldosterone.” But in patients with long-standing PA and hypertension, this is often not enough to completely resolve entrenched cardiovascular pathology.
PCPs, cardiologists in rural locations least likely to order PA testing
Of the 269,010 patients analyzed by Dr. Cohen and her coauthors, the average age was 65 years; 96% were men; half were obese; and 40% had diabetes. The researchers excluded patients who had already been tested for PA, as well as those who were already receiving treatment with an MRA.
For 88% of the patients, the main physician overseeing care was a PCP. A cardiologist was the main physician for 10%; a nephrologist, for 1%; and an endocrinologist, for fewer than 1%.
The rate of testing for PA varied across the 130 VHA centers that contributed data, ranging from 0% to 6%. The testing data showed that endocrinologists were most likely to order PA testing, doing it 2.48-fold more often than PCPs. Nephrologists were roughly twice as likely to order PA testing than PCPs, and cardiologists ordered testing at about the same rate as PCPs.
Patients managed at VHA centers in rural locations were nearly half as likely to undergo testing as patients managed at nonrural centers. The number of patients with treatment-resistant hypertension seen by a physician or at a center had no significant relationship to PA testing frequency.
The study received no commercial funding. Dr. Cohen has disclosed no relevant financial relationships.
A version of this story first appeared on Medscape.com.
despite guidelines that call for such an approach, according to findings from the first reported large-scale, multicenter study of PA testing practices.
Researchers ran a retrospective review of PA testing among 269,010 patients who met the definition as having treatment-resistant hypertension and were managed at any one of 130 Veterans Health Administration (VHA) medical centers from 2000 to 2017.
The results showed that, despite the fact that primary aldosteronism is highly prevalent among patients with treatment-resistant hypertension, only 4,277 (1.6%) underwent assessment for PA during a median of 3.3 years’ follow-up after they first met the defining criteria, Jordana B. Cohen, MD, and her associates reported in a study published in Annals of Internal Medicine on December 28.
“Testing rates also did not change meaningfully over nearly 2 decades ... despite an increasing number of guidelines recommending testing for primary aldosteronism in this population,” including the most recent recommendations from the Endocrine Society, issued in 2016, noted Dr. Cohen, a nephrologist and hypertension researcher at the University of Pennsylvania in Philadelphia, and colleagues.
Most patients in the study (almost 90%) were seen by a primary care practitioner (PCP).
The small percentage of patients seen by a nephrologist or endocrinologist were more than twice as likely to be tested for PA than those seen by a PCP or cardiologist.
Those clinicians who did order a test for PA were much more likely to treat patients with the appropriate medication, a mineralocorticoid receptor antagonist (MRA). In addition, therapy was started sooner, the researchers found.
“Our results corroborate” earlier reports from smaller health systems and suggest that dramatic underuse of PA assessment “is an issue across the US,” Dr. Cohen said in an interview.
The VHA experience “is very representative of what we think goes on across U.S. practice” and contrasts with the VHA’s reputation for “doing a pretty good job managing hypertension” in general, she noted.
Missed diagnosis, missed treatment
Dr. Cohen believes a number of factors likely help drive the abysmally low rate of PA testing they observed in the VHA system. She believes rates of PA testing are low elsewhere as well.
First, optimal hypertension management “is often taken for granted” but is challenging in busy primary care practices, so many of patients likely fall through the cracks, she said.
Dr. Cohen cited efforts at her institution, as well as by the VHA system, to better employ electronic health records to flag patients with treatment-resistant hypertension – defined as patients whose systolic or diastolic blood pressure remains at or above 140/90 mm Hg on at least two successive measurements at least a month apart while the patient is undergoing treatment with three conventional antihypertensive drugs – and to guide clinicians to order the right tests and treatments for these patients.
Many care providers mistakenly “see treatment-resistant hypertension as a disease of noncompliance,” although it is much more often the result of a missed diagnosis and inadequate intervention, she explained.
Physicians in denial; side effects of MRAs may deter prescribing
A second big cause of low PA testing rates is that doctors make the mistake of thinking a PA test result won’t change how they manage these patients.
The established treatment for most patients with treatment-resistant hypertension as well as PA is adding an MRA, either spironolactone or eplerenone (Inspra).
Many providers cling to the belief that they will start an MRA in these patients without first determining their PA status, says Dr. Cohen, but the data she and her colleagues collected show the opposite.
Overall, about 13% of all patients in the study began treatment with an MRA during follow-up. The likelihood of starting treatment with this drug class was fourfold higher among the patients tested for PA compared with those who were not tested.
PA testing also hastened the start of MRA use by more than a year, compared with untested patients.
“Providers think they prescribe an MRA” to treatment-resistant patients, “but it’s part of their denial. They are not using the evidence-based treatments [spironolactone or eplerenone], perhaps because of concerns about MRA side effects, although those have been pretty well overcome during the past 20 years,” she observed.
Dr. Cohen says gynecomastia is one adverse effect that gives pause to VHA clinicians who see a heavily male patient population. “It’s probably the biggest concern and why PA testing and MRA use is low” in the VHA system, she said.
“You can use a lower dosage of spironolactone, and the incidence is less common with eplerenone,” although using eplerenone does not completely eliminate all gynecomastia cases, she noted.
At the University of Pennsylvania hospitals, men often start on spironolactone first because it retains a significant price advantage, even though eplerenone is now generic, but “if there is a hint of gynecomastia, we quickly switch to eplerenone, which is usually well tolerated,” she explained.
And while eplerenone has a reputation of being less effective than spironolactone, “I’ve prescribed a lot of eplerenone and have had good results,” Dr. Cohen said. “Even if the blood pressure lowering is not as great compared with spironolactone, it still blunts the toxic effects of aldosterone on target organs.”
Hyperkalemia is the other big concern about spironolactone and eplerenone. Both agents cause it at roughly the same rate, although the rate is lower in patients without chronic kidney disease.
A new, nonsteroidal MRA, finerenone, caused substantially less hyperkalemia in a recent phase 3 trial, FIDELIO-DKD, and as a nonsteroidal MRA, it does not cause gynecomastia. Finerenone has promise as a potentially safer option for treating PA and treatment-resistant hypertension, noted Cohen, but so far, no advanced clinical trials have been launched to examine its efficacy for these indications.
PA testing allows a surgical option
A third reason to test patients with treatment-resistant hypertension for PA is that jumping straight to MRA treatment denies the patient assessment for a unilateral adrenal adenoma as the cause of excess aldosterone.
When unilateral adenomas exist, patients are candidates for adrenalectomy. Despite the potential advantage this gives patients to eliminate the cause of their PA without the need for additional drug treatment, some clinicians don’t see this as a compelling rationale to test for PA because they have a bias against surgery or have seen too many cases in which surgery failed to produce full hypertension resolution.
“It’s all about setting expectations appropriately” for the impact of this surgery, Dr. Cohen said.
“Adrenalectomy is not a cure; it just gets rid of the source of excess aldosterone.” But in patients with long-standing PA and hypertension, this is often not enough to completely resolve entrenched cardiovascular pathology.
PCPs, cardiologists in rural locations least likely to order PA testing
Of the 269,010 patients analyzed by Dr. Cohen and her coauthors, the average age was 65 years; 96% were men; half were obese; and 40% had diabetes. The researchers excluded patients who had already been tested for PA, as well as those who were already receiving treatment with an MRA.
For 88% of the patients, the main physician overseeing care was a PCP. A cardiologist was the main physician for 10%; a nephrologist, for 1%; and an endocrinologist, for fewer than 1%.
The rate of testing for PA varied across the 130 VHA centers that contributed data, ranging from 0% to 6%. The testing data showed that endocrinologists were most likely to order PA testing, doing it 2.48-fold more often than PCPs. Nephrologists were roughly twice as likely to order PA testing than PCPs, and cardiologists ordered testing at about the same rate as PCPs.
Patients managed at VHA centers in rural locations were nearly half as likely to undergo testing as patients managed at nonrural centers. The number of patients with treatment-resistant hypertension seen by a physician or at a center had no significant relationship to PA testing frequency.
The study received no commercial funding. Dr. Cohen has disclosed no relevant financial relationships.
A version of this story first appeared on Medscape.com.
Twincretin ‘impressive’: Topline data from phase 3 trial in diabetes
Tirzepatide, a novel subcutaneously injected drug that acts via two related but separate pathways of glucose control, produced strikingly positive effects in top-line results from the phase 3, placebo-controlled study SURPASS-1 in 478 adults with type 2 diabetes, according to a Dec. 9 press release from the manufacturer, Lilly.
The tirzepatide molecule exerts agonist effects at both the glucose-dependent insulinotropic polypeptide (GIP) receptor and the glucagon-like peptide-1 (GLP-1) receptor, and has been called a “twincretin” for its activity encompassing two different incretins. Phase 2 trial results caused excitement, with one physician calling the data “unbelievable” when reported in 2018.
SURPASS-1 enrolled patients who were very early in the course of their disease, had on average relatively mild elevation in glucose levels, and few metabolic comorbidities. They took one of three doses of the agent (5, 10, or 15 mg) as monotherapy or placebo for 40 weeks.
Julio Rosenstock, MD, said in the Lilly statement: “The study took a bold approach in assessing A1c targets. Not only did nearly 90% of all participants taking tirzepatide meet the standard A1c goal of less than 7%, more than half taking the highest dose also achieved an A1c less than 5.7%, the level seen in people without diabetes.”
Dr. Rosenstock is principal investigator of SURPASS-1 and director of the Dallas Diabetes Research Center in Texas.
The discontinuation rate in the high-dose group was 21.5% compared with less than 10% in the two lower-dose cohorts. Lilly said most of the dropouts “were due to the pandemic and family or work reasons.” The dropout rate in the placebo group was 14.8%.
These data were not included in the efficacy analysis, however, which “muddied” the analysis somewhat, one pharma analyst told BioPharma Dive.
Commenting on the new trial data, Ildiko Lingvay, MD, said in an interview: “I am very impressed with these results,” which are “unprecedented for any glucose-lowering medication that has ever been tested.”
Dr. Lingvay, of the department of internal medicine/endocrinology, and medical director, office of clinical trials management at UT Southwestern Medical Center, Dallas, was not involved in the study.
She added that the weight loss seen with tirzepatide “is equally impressive with greater than 10% of body weight loss above placebo achieved within 40 weeks of treatment and without any directed weight loss efforts.”
If the agent is eventually approved, “I am enthusiastic about the prospect of having another very powerful tool to address both diabetes and obesity,” she added.
The full results of SURPASS-1 will be presented at the American Diabetes Association 81st Scientific Sessions and published in a peer-reviewed journal in 2021.
SURPASS-1 is one of eight phase 3 studies of the drug, including five registration studies and one large 12,500-patient cardiovascular outcomes trial.
Tirzepatide patients lost up to 20 lb, side effect profile ‘reassuring’
In the study, patients had been recently diagnosed with type 2 diabetes (average duration, 4.8 years) and 54% were treatment-naive. Average baseline hemoglobin A1c was 7.9% and mean weight was 85.9 kg (189 pounds).
Patients started on a subcutaneous injectable dose of tirzepatide of 2.5 mg per week, which was titrated up to the final dose – 5, 10, or 15 mg – in 2.5-mg increments given as monotherapy for 40 weeks and compared with placebo.
Treatment with tirzepatide resulted in average reductions in A1c from baseline that ranged from 1.87% to 2.07%, depending on the dose, and were all significant compared with an increase of 0.4% with placebo.
The percentage of patients whose A1c fell to normal levels (less than 5.7%) ranged from 30.5% to 51.7%, compared with 0.9% among controls, and again, was significant for all doses.
Patients treated with tirzepatide also lost weight. Average weight reductions after 40 weeks were significant and ranged from 7.0 to 9.5 kg (15-21 pounds) compared with an average loss of 0.7 kg (1.5 pounds) among patients who received placebo.
The most common adverse events were gastrointestinal-related and mild to moderate in severity, and usually occurred during dose escalation.
Dr. Lingvay said the safety data reported are “reassuring, with side effects in the anticipated range and comparable with other medications in the GLP-1 agonist class.”
And no hypoglycemic (level 2, < 54 mg/dL) events were reported, “which is impressive considering the overall glucose level achieved,” she noted.
“I am eagerly awaiting the results of the other studies within the SURPASS program and hope those will confirm these initial findings and provide additional safety and efficacy information in a wider range of patients with type 2 diabetes,” she concluded.
Dr. Lingvay has reported receiving research funding, advisory/consulting fees, and/or other support from Novo Nordisk, Eli Lilly, Sanofi, AstraZeneca, Boehringer Ingelheim, Janssen, Intercept, Intarcia, Target Pharma, Merck, Pfizer, Novartis, GI Dynamics, Mylan, MannKind, Valeritas, Bayer, and Zealand Pharma.
A version of this article originally appeared on Medscape.com.
Tirzepatide, a novel subcutaneously injected drug that acts via two related but separate pathways of glucose control, produced strikingly positive effects in top-line results from the phase 3, placebo-controlled study SURPASS-1 in 478 adults with type 2 diabetes, according to a Dec. 9 press release from the manufacturer, Lilly.
The tirzepatide molecule exerts agonist effects at both the glucose-dependent insulinotropic polypeptide (GIP) receptor and the glucagon-like peptide-1 (GLP-1) receptor, and has been called a “twincretin” for its activity encompassing two different incretins. Phase 2 trial results caused excitement, with one physician calling the data “unbelievable” when reported in 2018.
SURPASS-1 enrolled patients who were very early in the course of their disease, had on average relatively mild elevation in glucose levels, and few metabolic comorbidities. They took one of three doses of the agent (5, 10, or 15 mg) as monotherapy or placebo for 40 weeks.
Julio Rosenstock, MD, said in the Lilly statement: “The study took a bold approach in assessing A1c targets. Not only did nearly 90% of all participants taking tirzepatide meet the standard A1c goal of less than 7%, more than half taking the highest dose also achieved an A1c less than 5.7%, the level seen in people without diabetes.”
Dr. Rosenstock is principal investigator of SURPASS-1 and director of the Dallas Diabetes Research Center in Texas.
The discontinuation rate in the high-dose group was 21.5% compared with less than 10% in the two lower-dose cohorts. Lilly said most of the dropouts “were due to the pandemic and family or work reasons.” The dropout rate in the placebo group was 14.8%.
These data were not included in the efficacy analysis, however, which “muddied” the analysis somewhat, one pharma analyst told BioPharma Dive.
Commenting on the new trial data, Ildiko Lingvay, MD, said in an interview: “I am very impressed with these results,” which are “unprecedented for any glucose-lowering medication that has ever been tested.”
Dr. Lingvay, of the department of internal medicine/endocrinology, and medical director, office of clinical trials management at UT Southwestern Medical Center, Dallas, was not involved in the study.
She added that the weight loss seen with tirzepatide “is equally impressive with greater than 10% of body weight loss above placebo achieved within 40 weeks of treatment and without any directed weight loss efforts.”
If the agent is eventually approved, “I am enthusiastic about the prospect of having another very powerful tool to address both diabetes and obesity,” she added.
The full results of SURPASS-1 will be presented at the American Diabetes Association 81st Scientific Sessions and published in a peer-reviewed journal in 2021.
SURPASS-1 is one of eight phase 3 studies of the drug, including five registration studies and one large 12,500-patient cardiovascular outcomes trial.
Tirzepatide patients lost up to 20 lb, side effect profile ‘reassuring’
In the study, patients had been recently diagnosed with type 2 diabetes (average duration, 4.8 years) and 54% were treatment-naive. Average baseline hemoglobin A1c was 7.9% and mean weight was 85.9 kg (189 pounds).
Patients started on a subcutaneous injectable dose of tirzepatide of 2.5 mg per week, which was titrated up to the final dose – 5, 10, or 15 mg – in 2.5-mg increments given as monotherapy for 40 weeks and compared with placebo.
Treatment with tirzepatide resulted in average reductions in A1c from baseline that ranged from 1.87% to 2.07%, depending on the dose, and were all significant compared with an increase of 0.4% with placebo.
The percentage of patients whose A1c fell to normal levels (less than 5.7%) ranged from 30.5% to 51.7%, compared with 0.9% among controls, and again, was significant for all doses.
Patients treated with tirzepatide also lost weight. Average weight reductions after 40 weeks were significant and ranged from 7.0 to 9.5 kg (15-21 pounds) compared with an average loss of 0.7 kg (1.5 pounds) among patients who received placebo.
The most common adverse events were gastrointestinal-related and mild to moderate in severity, and usually occurred during dose escalation.
Dr. Lingvay said the safety data reported are “reassuring, with side effects in the anticipated range and comparable with other medications in the GLP-1 agonist class.”
And no hypoglycemic (level 2, < 54 mg/dL) events were reported, “which is impressive considering the overall glucose level achieved,” she noted.
“I am eagerly awaiting the results of the other studies within the SURPASS program and hope those will confirm these initial findings and provide additional safety and efficacy information in a wider range of patients with type 2 diabetes,” she concluded.
Dr. Lingvay has reported receiving research funding, advisory/consulting fees, and/or other support from Novo Nordisk, Eli Lilly, Sanofi, AstraZeneca, Boehringer Ingelheim, Janssen, Intercept, Intarcia, Target Pharma, Merck, Pfizer, Novartis, GI Dynamics, Mylan, MannKind, Valeritas, Bayer, and Zealand Pharma.
A version of this article originally appeared on Medscape.com.
Tirzepatide, a novel subcutaneously injected drug that acts via two related but separate pathways of glucose control, produced strikingly positive effects in top-line results from the phase 3, placebo-controlled study SURPASS-1 in 478 adults with type 2 diabetes, according to a Dec. 9 press release from the manufacturer, Lilly.
The tirzepatide molecule exerts agonist effects at both the glucose-dependent insulinotropic polypeptide (GIP) receptor and the glucagon-like peptide-1 (GLP-1) receptor, and has been called a “twincretin” for its activity encompassing two different incretins. Phase 2 trial results caused excitement, with one physician calling the data “unbelievable” when reported in 2018.
SURPASS-1 enrolled patients who were very early in the course of their disease, had on average relatively mild elevation in glucose levels, and few metabolic comorbidities. They took one of three doses of the agent (5, 10, or 15 mg) as monotherapy or placebo for 40 weeks.
Julio Rosenstock, MD, said in the Lilly statement: “The study took a bold approach in assessing A1c targets. Not only did nearly 90% of all participants taking tirzepatide meet the standard A1c goal of less than 7%, more than half taking the highest dose also achieved an A1c less than 5.7%, the level seen in people without diabetes.”
Dr. Rosenstock is principal investigator of SURPASS-1 and director of the Dallas Diabetes Research Center in Texas.
The discontinuation rate in the high-dose group was 21.5% compared with less than 10% in the two lower-dose cohorts. Lilly said most of the dropouts “were due to the pandemic and family or work reasons.” The dropout rate in the placebo group was 14.8%.
These data were not included in the efficacy analysis, however, which “muddied” the analysis somewhat, one pharma analyst told BioPharma Dive.
Commenting on the new trial data, Ildiko Lingvay, MD, said in an interview: “I am very impressed with these results,” which are “unprecedented for any glucose-lowering medication that has ever been tested.”
Dr. Lingvay, of the department of internal medicine/endocrinology, and medical director, office of clinical trials management at UT Southwestern Medical Center, Dallas, was not involved in the study.
She added that the weight loss seen with tirzepatide “is equally impressive with greater than 10% of body weight loss above placebo achieved within 40 weeks of treatment and without any directed weight loss efforts.”
If the agent is eventually approved, “I am enthusiastic about the prospect of having another very powerful tool to address both diabetes and obesity,” she added.
The full results of SURPASS-1 will be presented at the American Diabetes Association 81st Scientific Sessions and published in a peer-reviewed journal in 2021.
SURPASS-1 is one of eight phase 3 studies of the drug, including five registration studies and one large 12,500-patient cardiovascular outcomes trial.
Tirzepatide patients lost up to 20 lb, side effect profile ‘reassuring’
In the study, patients had been recently diagnosed with type 2 diabetes (average duration, 4.8 years) and 54% were treatment-naive. Average baseline hemoglobin A1c was 7.9% and mean weight was 85.9 kg (189 pounds).
Patients started on a subcutaneous injectable dose of tirzepatide of 2.5 mg per week, which was titrated up to the final dose – 5, 10, or 15 mg – in 2.5-mg increments given as monotherapy for 40 weeks and compared with placebo.
Treatment with tirzepatide resulted in average reductions in A1c from baseline that ranged from 1.87% to 2.07%, depending on the dose, and were all significant compared with an increase of 0.4% with placebo.
The percentage of patients whose A1c fell to normal levels (less than 5.7%) ranged from 30.5% to 51.7%, compared with 0.9% among controls, and again, was significant for all doses.
Patients treated with tirzepatide also lost weight. Average weight reductions after 40 weeks were significant and ranged from 7.0 to 9.5 kg (15-21 pounds) compared with an average loss of 0.7 kg (1.5 pounds) among patients who received placebo.
The most common adverse events were gastrointestinal-related and mild to moderate in severity, and usually occurred during dose escalation.
Dr. Lingvay said the safety data reported are “reassuring, with side effects in the anticipated range and comparable with other medications in the GLP-1 agonist class.”
And no hypoglycemic (level 2, < 54 mg/dL) events were reported, “which is impressive considering the overall glucose level achieved,” she noted.
“I am eagerly awaiting the results of the other studies within the SURPASS program and hope those will confirm these initial findings and provide additional safety and efficacy information in a wider range of patients with type 2 diabetes,” she concluded.
Dr. Lingvay has reported receiving research funding, advisory/consulting fees, and/or other support from Novo Nordisk, Eli Lilly, Sanofi, AstraZeneca, Boehringer Ingelheim, Janssen, Intercept, Intarcia, Target Pharma, Merck, Pfizer, Novartis, GI Dynamics, Mylan, MannKind, Valeritas, Bayer, and Zealand Pharma.
A version of this article originally appeared on Medscape.com.
FDA approves liraglutide for adolescents with obesity
The Food and Drug Administration’s new indication for liraglutide (Saxenda) for weight loss in adolescents with obesity, announced on Dec. 4, received welcome as a milestone for advancing a field that’s seen no new drug options since 2003 and boosted by 50% the list of agents indicated for weight loss in this age group.
But liraglutide’s track record in adolescents in the key study published earlier in 2020 left some experts unconvinced that liraglutide’s modest effects would have much impact on blunting the expanding cohort of teens who are obese.
“Until now, we’ve had phentermine and orlistat with FDA approval” for adolescents with obesity, and phentermine’s label specifies only patients older than 16 years. “It’s important that the FDA deemed liraglutide’s benefits greater than its risks for adolescents,” said Aaron S. Kelly, PhD, leader of the 82-week, multicenter, randomized study of liraglutide in 251 adolescents with obesity that directly led to the FDA’s action.
“We have results from a strong, published randomized trial, and the green light from the FDA, and that should give clinicians reassurance and confidence to use liraglutide clinically,” said Dr. Kelly, professor of pediatrics and codirector of the Center for Pediatric Obesity Medicine at the University of Minnesota in Minneapolis.
An ‘unimpressive’ drop in BMI
Sonia Caprio, MD, had a more skeptical take on liraglutide’s role with its new indication: “Approval of higher-dose liraglutide is an improvement that reflects a willingness to accept adolescent obesity as a disease that needs treatment with pharmacological agents. However, the study, published in New England Journal of Medicine, was not impressive in terms of weight loss, and more importantly liraglutide was not associated with any significant changes in metabolic markers” such as insulin resistance, high-sensitivity C-reactive protein, lipoproteins and triglycerides, and hemoglobin A1c.
The observed average 5% drop in body mass index seen after a year on liraglutide treatment, compared with baseline and relative to no average change from baseline in the placebo arm, was “totally insufficient, and will not diminish any of the metabolic complications in youth with obesity,” commented Dr. Caprio, an endocrinologist and professor of pediatrics at Yale University in New Haven, Conn.
Results from the study led by Dr. Kelly also showed that liraglutide for 56 weeks cut BMI by 5% in 43% of patients, and by 10% in 26%, compared with respective rates of 19% and 8% among those in the placebo-control arm. He took a more expansive view of the potential benefits from weight loss of the caliber demonstrated by liraglutide in the study.
“In general, we wait too long with obesity in children; the earlier the intervention the better. A 3% or 4% reduction in BMI at 12 or 13 years old can pay big dividends down the road” when a typical adolescent trajectory of steadily rising weight can be flattened, he said in an interview.
Bariatric and metabolic surgery, although highly effective and usually safe, is seen by many clinicians, patients, and families as an “intervention of last resort,” and its very low level of uptake in adolescents bears witness to that reputation. It also creates an important niche for safe and effective drugs to fill as an adjunct to lifestyle changes, which are often ineffective when used by themselves. Liraglutide’s main mechanism for weight loss is depressing hunger, Dr. Kelly noted.
Existing meds have limitations
The existing medical treatments, orlistat and phentermine, both have significant drawbacks that limit their use. Orlistat (Xenical, Alli), FDA approved for adolescents 12-16 years old since 2003, limits intestinal fat absorption and as a result often produces unwanted GI effects. Phentermine’s approval for older adolescents dates from 1959 and has a weak evidence base, its label limits it to “short-term” use that’s generally taken to mean a maximum of 12 weeks. And, as a stimulant, phentermine has often been regarded as potentially dangerous, although Dr. Kelly noted that stimulants are well-accepted treatments for other disorders in children and adolescents.
“The earlier we treat obesity in youth, the better, given that it tends to track into adulthood,” agreed Dr. Caprio. “However, it remains to be seen whether weight reduction with a pharmacological agent is going to help prevent the intractable trajectories of weight and its complications. So far, it looks like surgery may be more efficacious,” she said in an interview.
Another drawback for the near future with liraglutide will likely be its cost for many patients, more than $10,000/year at full retail prices for the weight-loss formulation, given that insurers have had a poor record of covering the drug for this indication in adults, both Dr. Caprio and Dr. Kelly noted.
Compliance with liraglutide is also important. Dr. Kelly’s study followed patients for their first 26 weeks off treatment after 56 weeks on the drug, and showed that on average weights rebounded to virtually baseline levels by 6 months after treatment stopped.
Obesity treatment lasts a lifetime
“Obesity is a chronic disease, that requires chronic treatment, just like hypertension,” Dr. Kelly stressed, and cited the rebound seen in his study when liraglutide stopped as further proof of that concept. “All obesity treatment is lifelong,” he maintained.
He highlighted the importance of clinicians discussing with adolescent patients and their families the prospect of potentially remaining on liraglutide treatment for years to maintain weight loss. His experience with the randomized study convinced him that many adolescents with obesity are amenable to daily subcutaneous injection using the pen device that liraglutide comes in, but he acknowledged that some teens find this off-putting.
For the near term, Dr. Kelly foresaw liraglutide treatment of adolescents as something that will mostly be administered to patients who seek care at centers that specialize in obesity management. “I’ll think we’ll eventually see it move to more primary care settings, but that will be down the road.”
The study of liraglutide in adolescents was sponsored by Novo Nordisk, the company that markets liraglutide (Saxenda). Dr. Kelly has been a consultant to Novo Nordisk and also to Orexigen Therapeutics, Vivus, and WW, and he has received research funding from AstraZeneca. Dr. Caprio had no disclosures.
The Food and Drug Administration’s new indication for liraglutide (Saxenda) for weight loss in adolescents with obesity, announced on Dec. 4, received welcome as a milestone for advancing a field that’s seen no new drug options since 2003 and boosted by 50% the list of agents indicated for weight loss in this age group.
But liraglutide’s track record in adolescents in the key study published earlier in 2020 left some experts unconvinced that liraglutide’s modest effects would have much impact on blunting the expanding cohort of teens who are obese.
“Until now, we’ve had phentermine and orlistat with FDA approval” for adolescents with obesity, and phentermine’s label specifies only patients older than 16 years. “It’s important that the FDA deemed liraglutide’s benefits greater than its risks for adolescents,” said Aaron S. Kelly, PhD, leader of the 82-week, multicenter, randomized study of liraglutide in 251 adolescents with obesity that directly led to the FDA’s action.
“We have results from a strong, published randomized trial, and the green light from the FDA, and that should give clinicians reassurance and confidence to use liraglutide clinically,” said Dr. Kelly, professor of pediatrics and codirector of the Center for Pediatric Obesity Medicine at the University of Minnesota in Minneapolis.
An ‘unimpressive’ drop in BMI
Sonia Caprio, MD, had a more skeptical take on liraglutide’s role with its new indication: “Approval of higher-dose liraglutide is an improvement that reflects a willingness to accept adolescent obesity as a disease that needs treatment with pharmacological agents. However, the study, published in New England Journal of Medicine, was not impressive in terms of weight loss, and more importantly liraglutide was not associated with any significant changes in metabolic markers” such as insulin resistance, high-sensitivity C-reactive protein, lipoproteins and triglycerides, and hemoglobin A1c.
The observed average 5% drop in body mass index seen after a year on liraglutide treatment, compared with baseline and relative to no average change from baseline in the placebo arm, was “totally insufficient, and will not diminish any of the metabolic complications in youth with obesity,” commented Dr. Caprio, an endocrinologist and professor of pediatrics at Yale University in New Haven, Conn.
Results from the study led by Dr. Kelly also showed that liraglutide for 56 weeks cut BMI by 5% in 43% of patients, and by 10% in 26%, compared with respective rates of 19% and 8% among those in the placebo-control arm. He took a more expansive view of the potential benefits from weight loss of the caliber demonstrated by liraglutide in the study.
“In general, we wait too long with obesity in children; the earlier the intervention the better. A 3% or 4% reduction in BMI at 12 or 13 years old can pay big dividends down the road” when a typical adolescent trajectory of steadily rising weight can be flattened, he said in an interview.
Bariatric and metabolic surgery, although highly effective and usually safe, is seen by many clinicians, patients, and families as an “intervention of last resort,” and its very low level of uptake in adolescents bears witness to that reputation. It also creates an important niche for safe and effective drugs to fill as an adjunct to lifestyle changes, which are often ineffective when used by themselves. Liraglutide’s main mechanism for weight loss is depressing hunger, Dr. Kelly noted.
Existing meds have limitations
The existing medical treatments, orlistat and phentermine, both have significant drawbacks that limit their use. Orlistat (Xenical, Alli), FDA approved for adolescents 12-16 years old since 2003, limits intestinal fat absorption and as a result often produces unwanted GI effects. Phentermine’s approval for older adolescents dates from 1959 and has a weak evidence base, its label limits it to “short-term” use that’s generally taken to mean a maximum of 12 weeks. And, as a stimulant, phentermine has often been regarded as potentially dangerous, although Dr. Kelly noted that stimulants are well-accepted treatments for other disorders in children and adolescents.
“The earlier we treat obesity in youth, the better, given that it tends to track into adulthood,” agreed Dr. Caprio. “However, it remains to be seen whether weight reduction with a pharmacological agent is going to help prevent the intractable trajectories of weight and its complications. So far, it looks like surgery may be more efficacious,” she said in an interview.
Another drawback for the near future with liraglutide will likely be its cost for many patients, more than $10,000/year at full retail prices for the weight-loss formulation, given that insurers have had a poor record of covering the drug for this indication in adults, both Dr. Caprio and Dr. Kelly noted.
Compliance with liraglutide is also important. Dr. Kelly’s study followed patients for their first 26 weeks off treatment after 56 weeks on the drug, and showed that on average weights rebounded to virtually baseline levels by 6 months after treatment stopped.
Obesity treatment lasts a lifetime
“Obesity is a chronic disease, that requires chronic treatment, just like hypertension,” Dr. Kelly stressed, and cited the rebound seen in his study when liraglutide stopped as further proof of that concept. “All obesity treatment is lifelong,” he maintained.
He highlighted the importance of clinicians discussing with adolescent patients and their families the prospect of potentially remaining on liraglutide treatment for years to maintain weight loss. His experience with the randomized study convinced him that many adolescents with obesity are amenable to daily subcutaneous injection using the pen device that liraglutide comes in, but he acknowledged that some teens find this off-putting.
For the near term, Dr. Kelly foresaw liraglutide treatment of adolescents as something that will mostly be administered to patients who seek care at centers that specialize in obesity management. “I’ll think we’ll eventually see it move to more primary care settings, but that will be down the road.”
The study of liraglutide in adolescents was sponsored by Novo Nordisk, the company that markets liraglutide (Saxenda). Dr. Kelly has been a consultant to Novo Nordisk and also to Orexigen Therapeutics, Vivus, and WW, and he has received research funding from AstraZeneca. Dr. Caprio had no disclosures.
The Food and Drug Administration’s new indication for liraglutide (Saxenda) for weight loss in adolescents with obesity, announced on Dec. 4, received welcome as a milestone for advancing a field that’s seen no new drug options since 2003 and boosted by 50% the list of agents indicated for weight loss in this age group.
But liraglutide’s track record in adolescents in the key study published earlier in 2020 left some experts unconvinced that liraglutide’s modest effects would have much impact on blunting the expanding cohort of teens who are obese.
“Until now, we’ve had phentermine and orlistat with FDA approval” for adolescents with obesity, and phentermine’s label specifies only patients older than 16 years. “It’s important that the FDA deemed liraglutide’s benefits greater than its risks for adolescents,” said Aaron S. Kelly, PhD, leader of the 82-week, multicenter, randomized study of liraglutide in 251 adolescents with obesity that directly led to the FDA’s action.
“We have results from a strong, published randomized trial, and the green light from the FDA, and that should give clinicians reassurance and confidence to use liraglutide clinically,” said Dr. Kelly, professor of pediatrics and codirector of the Center for Pediatric Obesity Medicine at the University of Minnesota in Minneapolis.
An ‘unimpressive’ drop in BMI
Sonia Caprio, MD, had a more skeptical take on liraglutide’s role with its new indication: “Approval of higher-dose liraglutide is an improvement that reflects a willingness to accept adolescent obesity as a disease that needs treatment with pharmacological agents. However, the study, published in New England Journal of Medicine, was not impressive in terms of weight loss, and more importantly liraglutide was not associated with any significant changes in metabolic markers” such as insulin resistance, high-sensitivity C-reactive protein, lipoproteins and triglycerides, and hemoglobin A1c.
The observed average 5% drop in body mass index seen after a year on liraglutide treatment, compared with baseline and relative to no average change from baseline in the placebo arm, was “totally insufficient, and will not diminish any of the metabolic complications in youth with obesity,” commented Dr. Caprio, an endocrinologist and professor of pediatrics at Yale University in New Haven, Conn.
Results from the study led by Dr. Kelly also showed that liraglutide for 56 weeks cut BMI by 5% in 43% of patients, and by 10% in 26%, compared with respective rates of 19% and 8% among those in the placebo-control arm. He took a more expansive view of the potential benefits from weight loss of the caliber demonstrated by liraglutide in the study.
“In general, we wait too long with obesity in children; the earlier the intervention the better. A 3% or 4% reduction in BMI at 12 or 13 years old can pay big dividends down the road” when a typical adolescent trajectory of steadily rising weight can be flattened, he said in an interview.
Bariatric and metabolic surgery, although highly effective and usually safe, is seen by many clinicians, patients, and families as an “intervention of last resort,” and its very low level of uptake in adolescents bears witness to that reputation. It also creates an important niche for safe and effective drugs to fill as an adjunct to lifestyle changes, which are often ineffective when used by themselves. Liraglutide’s main mechanism for weight loss is depressing hunger, Dr. Kelly noted.
Existing meds have limitations
The existing medical treatments, orlistat and phentermine, both have significant drawbacks that limit their use. Orlistat (Xenical, Alli), FDA approved for adolescents 12-16 years old since 2003, limits intestinal fat absorption and as a result often produces unwanted GI effects. Phentermine’s approval for older adolescents dates from 1959 and has a weak evidence base, its label limits it to “short-term” use that’s generally taken to mean a maximum of 12 weeks. And, as a stimulant, phentermine has often been regarded as potentially dangerous, although Dr. Kelly noted that stimulants are well-accepted treatments for other disorders in children and adolescents.
“The earlier we treat obesity in youth, the better, given that it tends to track into adulthood,” agreed Dr. Caprio. “However, it remains to be seen whether weight reduction with a pharmacological agent is going to help prevent the intractable trajectories of weight and its complications. So far, it looks like surgery may be more efficacious,” she said in an interview.
Another drawback for the near future with liraglutide will likely be its cost for many patients, more than $10,000/year at full retail prices for the weight-loss formulation, given that insurers have had a poor record of covering the drug for this indication in adults, both Dr. Caprio and Dr. Kelly noted.
Compliance with liraglutide is also important. Dr. Kelly’s study followed patients for their first 26 weeks off treatment after 56 weeks on the drug, and showed that on average weights rebounded to virtually baseline levels by 6 months after treatment stopped.
Obesity treatment lasts a lifetime
“Obesity is a chronic disease, that requires chronic treatment, just like hypertension,” Dr. Kelly stressed, and cited the rebound seen in his study when liraglutide stopped as further proof of that concept. “All obesity treatment is lifelong,” he maintained.
He highlighted the importance of clinicians discussing with adolescent patients and their families the prospect of potentially remaining on liraglutide treatment for years to maintain weight loss. His experience with the randomized study convinced him that many adolescents with obesity are amenable to daily subcutaneous injection using the pen device that liraglutide comes in, but he acknowledged that some teens find this off-putting.
For the near term, Dr. Kelly foresaw liraglutide treatment of adolescents as something that will mostly be administered to patients who seek care at centers that specialize in obesity management. “I’ll think we’ll eventually see it move to more primary care settings, but that will be down the road.”
The study of liraglutide in adolescents was sponsored by Novo Nordisk, the company that markets liraglutide (Saxenda). Dr. Kelly has been a consultant to Novo Nordisk and also to Orexigen Therapeutics, Vivus, and WW, and he has received research funding from AstraZeneca. Dr. Caprio had no disclosures.
