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Torrent Pharmaceuticals expands losartan recall
Torrent Pharmaceuticals is expanding its recall of losartan potassium tablets from 2 lots to 12 lots, according to a Safety Alert from the Food and Drug Administration.
The recall was based on the discovery of N-nitrosodiethylamine (NDEA) above recommended levels in seven 100-mg lots of losartan, four 50-mg lots, and one 25-mg lot. NDEA is a naturally occurring substance that has been classified as a probable human carcinogen by the International Agency for Research on Cancer. Torrent Pharmaceuticals has not reported any adverse events related to the recall.
Losartan currently is indicated to treat hypertension, hypertensive patients with left ventricular hypertrophy, and nephropathy in type 2 diabetic patients. Patients who are taking losartan should continue to do so, as stopping treatment without an alternative could represent a greater health risk.
“Patients should contact their pharmacist or physician who can advise them about an alternative treatment prior to returning their medication,” the FDA said in the press release.
Find the full press release on the FDA website.
Torrent Pharmaceuticals is expanding its recall of losartan potassium tablets from 2 lots to 12 lots, according to a Safety Alert from the Food and Drug Administration.
The recall was based on the discovery of N-nitrosodiethylamine (NDEA) above recommended levels in seven 100-mg lots of losartan, four 50-mg lots, and one 25-mg lot. NDEA is a naturally occurring substance that has been classified as a probable human carcinogen by the International Agency for Research on Cancer. Torrent Pharmaceuticals has not reported any adverse events related to the recall.
Losartan currently is indicated to treat hypertension, hypertensive patients with left ventricular hypertrophy, and nephropathy in type 2 diabetic patients. Patients who are taking losartan should continue to do so, as stopping treatment without an alternative could represent a greater health risk.
“Patients should contact their pharmacist or physician who can advise them about an alternative treatment prior to returning their medication,” the FDA said in the press release.
Find the full press release on the FDA website.
Torrent Pharmaceuticals is expanding its recall of losartan potassium tablets from 2 lots to 12 lots, according to a Safety Alert from the Food and Drug Administration.
The recall was based on the discovery of N-nitrosodiethylamine (NDEA) above recommended levels in seven 100-mg lots of losartan, four 50-mg lots, and one 25-mg lot. NDEA is a naturally occurring substance that has been classified as a probable human carcinogen by the International Agency for Research on Cancer. Torrent Pharmaceuticals has not reported any adverse events related to the recall.
Losartan currently is indicated to treat hypertension, hypertensive patients with left ventricular hypertrophy, and nephropathy in type 2 diabetic patients. Patients who are taking losartan should continue to do so, as stopping treatment without an alternative could represent a greater health risk.
“Patients should contact their pharmacist or physician who can advise them about an alternative treatment prior to returning their medication,” the FDA said in the press release.
Find the full press release on the FDA website.
Postprandial glucose responses to identical meals vary from person to person
LOS ANGELES – .
“The reason we got interested in nutrition in general is for its important role in health and disease, but also because, reading the literature on nutrition in general, it seemed that the science was relatively poor,” Eran Segal, PhD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “As a testament, you can see how frequently dietary recommendations for the public are changed. For example, 30 years ago, the cover of Time magazine said that eating cholesterol in the diet is very bad for you. Fifteen years later, Time magazine said that some cholesterol is actually good for you. There are other questions, like should you be eating dairy products? I think it shows that we have a poor understanding of what healthy nutrition is for human individuals. That’s why we wanted to start a study which would collect the right amount and the right kind of data to try to answer the question of what is a healthy diet for human individuals.”
In what is believed to be the first study of its kind, Dr. Segal, professor of computer science and applied mathematics at the Weizmann Institute of Science in Rehovot, Israel, and his associates recruited 1,000 individuals and asked them to wear a continuous glucose monitor (CGM) for 1 week (Cell 2015;163[5]:1079-94). For the study, known as The Personalized Nutrition Project, participants were asked to log everything they ate into a mobile app the researchers developed. “They would select a meal from a database of 10,000 foods,” Dr. Segal explained. “Each meal has full nutritional value so at the end of the study, we had about 50,000 meals that we had measurements of postprandial glucose response to, coupled with full nutritional values.” They also collected a comprehensive profile of individuals, which included body measurements, blood tests, medical background, food frequency questionnaires, and a measurement of the microbiome by both 16S rRNA sequencing and shotgun metagenomics.
For the first part of the study, researchers supplied a breakfast to all participants: either bread, bread with butter, glucose, or fructose, in each case 50 g of available carbohydrates. “The participants were asked to consume these the morning after the night fast,” Dr. Segal said. “This allowed us to compare how the same individual responds to eating the exact same food versus how different individuals respond to eating the same food.” The researchers found that, when the same person ate the same meal on 2 different days, the glucose response was highly reproducible. In contrast, different people had widely different postmeal glucose responses to identical meals. “Some individuals responded most highly to glucose; others responded most highly to bread,” Dr. Segal said. “There was about 10% of individuals who responded to bread and butter, compared to the other test foods. These results mean that any universal diet is going to have limited efficacy in its ability to balance blood glucose levels, because some foods will spike glucose levels in one person but not in another person. It also means that the concepts we’ve been using like the glycemic index are also going to have limited efficacy.”
Next, the researchers aimed to determine what factors influence the variability in people’s responses to the same food. “We found many different correlations between the various blood markers and physical measurements that we obtained, but what was most novel was the variability in postmeal glucose response across people associated with microbiota composition and function,” Dr. Segal said. From this, he and his colleagues developed a machine-learning algorithm that integrates blood parameters, dietary habits, anthropometrics, physical activity, and gut microbiota. Using this algorithm, the prediction accuracy of personalized glucose responses achieved an r value of 0.68, which explains about 50% of the variability. For the final component of the study, the researchers randomized 26 participants to one of five dietary arms and followed for 1 week by continuous glucose monitoring. They were able to demonstrate that personally tailored diets lower the postprandial glucose response.
As a follow-up to this work, Dr. Segal and his associates enrolled 200 people with an hemoglobin A1c between 5.7% and 6.5% into the Personalized Nutrition Project for Prediabetes (PNP3) study, which investigates whether personalized diet intervention will improve postprandial blood glucose levels and other metabolic health factors in individuals with prediabetes, compared with the standard Mediterranean-style low-fat diet (NCT03222791). Participants were randomized to 6 months of standard of care following Dietary Guidelines for Americans 2015-2020, Eighth Edition, or to an algorithm diet. Primary outcomes are reduction in average glucose levels and evaluation of the total daily time of plasma glucose levels were below 140 mg/dL. Participants wore the continuous glucose monitor for the entire 6 months of intervention. “I don’t think this was ever done before,” he said. “We’re also looking at secondary metabolic endpoints and exploratory endpoints such as changes in the microbiome. We’re asking people to log everything they eat for the entire 6 months of intervention. It gives us a lot of power in terms assessing compliance. It’s an immense amount of data.”
Evaluation of the data are not yet complete, but interim results are promising. For example, he discussed results from one study participant on the algorithm diet. “Across 1 month, this person was able to entirely reduce the peaks in glucose levels and dramatic reductions in the time above 140 mg/dL in the 6-month treatment period,” said Dr. Segal, who is one of the study’s principal investigators. He disclosed that he is a paid consultant to DayTwo.
LOS ANGELES – .
“The reason we got interested in nutrition in general is for its important role in health and disease, but also because, reading the literature on nutrition in general, it seemed that the science was relatively poor,” Eran Segal, PhD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “As a testament, you can see how frequently dietary recommendations for the public are changed. For example, 30 years ago, the cover of Time magazine said that eating cholesterol in the diet is very bad for you. Fifteen years later, Time magazine said that some cholesterol is actually good for you. There are other questions, like should you be eating dairy products? I think it shows that we have a poor understanding of what healthy nutrition is for human individuals. That’s why we wanted to start a study which would collect the right amount and the right kind of data to try to answer the question of what is a healthy diet for human individuals.”
In what is believed to be the first study of its kind, Dr. Segal, professor of computer science and applied mathematics at the Weizmann Institute of Science in Rehovot, Israel, and his associates recruited 1,000 individuals and asked them to wear a continuous glucose monitor (CGM) for 1 week (Cell 2015;163[5]:1079-94). For the study, known as The Personalized Nutrition Project, participants were asked to log everything they ate into a mobile app the researchers developed. “They would select a meal from a database of 10,000 foods,” Dr. Segal explained. “Each meal has full nutritional value so at the end of the study, we had about 50,000 meals that we had measurements of postprandial glucose response to, coupled with full nutritional values.” They also collected a comprehensive profile of individuals, which included body measurements, blood tests, medical background, food frequency questionnaires, and a measurement of the microbiome by both 16S rRNA sequencing and shotgun metagenomics.
For the first part of the study, researchers supplied a breakfast to all participants: either bread, bread with butter, glucose, or fructose, in each case 50 g of available carbohydrates. “The participants were asked to consume these the morning after the night fast,” Dr. Segal said. “This allowed us to compare how the same individual responds to eating the exact same food versus how different individuals respond to eating the same food.” The researchers found that, when the same person ate the same meal on 2 different days, the glucose response was highly reproducible. In contrast, different people had widely different postmeal glucose responses to identical meals. “Some individuals responded most highly to glucose; others responded most highly to bread,” Dr. Segal said. “There was about 10% of individuals who responded to bread and butter, compared to the other test foods. These results mean that any universal diet is going to have limited efficacy in its ability to balance blood glucose levels, because some foods will spike glucose levels in one person but not in another person. It also means that the concepts we’ve been using like the glycemic index are also going to have limited efficacy.”
Next, the researchers aimed to determine what factors influence the variability in people’s responses to the same food. “We found many different correlations between the various blood markers and physical measurements that we obtained, but what was most novel was the variability in postmeal glucose response across people associated with microbiota composition and function,” Dr. Segal said. From this, he and his colleagues developed a machine-learning algorithm that integrates blood parameters, dietary habits, anthropometrics, physical activity, and gut microbiota. Using this algorithm, the prediction accuracy of personalized glucose responses achieved an r value of 0.68, which explains about 50% of the variability. For the final component of the study, the researchers randomized 26 participants to one of five dietary arms and followed for 1 week by continuous glucose monitoring. They were able to demonstrate that personally tailored diets lower the postprandial glucose response.
As a follow-up to this work, Dr. Segal and his associates enrolled 200 people with an hemoglobin A1c between 5.7% and 6.5% into the Personalized Nutrition Project for Prediabetes (PNP3) study, which investigates whether personalized diet intervention will improve postprandial blood glucose levels and other metabolic health factors in individuals with prediabetes, compared with the standard Mediterranean-style low-fat diet (NCT03222791). Participants were randomized to 6 months of standard of care following Dietary Guidelines for Americans 2015-2020, Eighth Edition, or to an algorithm diet. Primary outcomes are reduction in average glucose levels and evaluation of the total daily time of plasma glucose levels were below 140 mg/dL. Participants wore the continuous glucose monitor for the entire 6 months of intervention. “I don’t think this was ever done before,” he said. “We’re also looking at secondary metabolic endpoints and exploratory endpoints such as changes in the microbiome. We’re asking people to log everything they eat for the entire 6 months of intervention. It gives us a lot of power in terms assessing compliance. It’s an immense amount of data.”
Evaluation of the data are not yet complete, but interim results are promising. For example, he discussed results from one study participant on the algorithm diet. “Across 1 month, this person was able to entirely reduce the peaks in glucose levels and dramatic reductions in the time above 140 mg/dL in the 6-month treatment period,” said Dr. Segal, who is one of the study’s principal investigators. He disclosed that he is a paid consultant to DayTwo.
LOS ANGELES – .
“The reason we got interested in nutrition in general is for its important role in health and disease, but also because, reading the literature on nutrition in general, it seemed that the science was relatively poor,” Eran Segal, PhD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “As a testament, you can see how frequently dietary recommendations for the public are changed. For example, 30 years ago, the cover of Time magazine said that eating cholesterol in the diet is very bad for you. Fifteen years later, Time magazine said that some cholesterol is actually good for you. There are other questions, like should you be eating dairy products? I think it shows that we have a poor understanding of what healthy nutrition is for human individuals. That’s why we wanted to start a study which would collect the right amount and the right kind of data to try to answer the question of what is a healthy diet for human individuals.”
In what is believed to be the first study of its kind, Dr. Segal, professor of computer science and applied mathematics at the Weizmann Institute of Science in Rehovot, Israel, and his associates recruited 1,000 individuals and asked them to wear a continuous glucose monitor (CGM) for 1 week (Cell 2015;163[5]:1079-94). For the study, known as The Personalized Nutrition Project, participants were asked to log everything they ate into a mobile app the researchers developed. “They would select a meal from a database of 10,000 foods,” Dr. Segal explained. “Each meal has full nutritional value so at the end of the study, we had about 50,000 meals that we had measurements of postprandial glucose response to, coupled with full nutritional values.” They also collected a comprehensive profile of individuals, which included body measurements, blood tests, medical background, food frequency questionnaires, and a measurement of the microbiome by both 16S rRNA sequencing and shotgun metagenomics.
For the first part of the study, researchers supplied a breakfast to all participants: either bread, bread with butter, glucose, or fructose, in each case 50 g of available carbohydrates. “The participants were asked to consume these the morning after the night fast,” Dr. Segal said. “This allowed us to compare how the same individual responds to eating the exact same food versus how different individuals respond to eating the same food.” The researchers found that, when the same person ate the same meal on 2 different days, the glucose response was highly reproducible. In contrast, different people had widely different postmeal glucose responses to identical meals. “Some individuals responded most highly to glucose; others responded most highly to bread,” Dr. Segal said. “There was about 10% of individuals who responded to bread and butter, compared to the other test foods. These results mean that any universal diet is going to have limited efficacy in its ability to balance blood glucose levels, because some foods will spike glucose levels in one person but not in another person. It also means that the concepts we’ve been using like the glycemic index are also going to have limited efficacy.”
Next, the researchers aimed to determine what factors influence the variability in people’s responses to the same food. “We found many different correlations between the various blood markers and physical measurements that we obtained, but what was most novel was the variability in postmeal glucose response across people associated with microbiota composition and function,” Dr. Segal said. From this, he and his colleagues developed a machine-learning algorithm that integrates blood parameters, dietary habits, anthropometrics, physical activity, and gut microbiota. Using this algorithm, the prediction accuracy of personalized glucose responses achieved an r value of 0.68, which explains about 50% of the variability. For the final component of the study, the researchers randomized 26 participants to one of five dietary arms and followed for 1 week by continuous glucose monitoring. They were able to demonstrate that personally tailored diets lower the postprandial glucose response.
As a follow-up to this work, Dr. Segal and his associates enrolled 200 people with an hemoglobin A1c between 5.7% and 6.5% into the Personalized Nutrition Project for Prediabetes (PNP3) study, which investigates whether personalized diet intervention will improve postprandial blood glucose levels and other metabolic health factors in individuals with prediabetes, compared with the standard Mediterranean-style low-fat diet (NCT03222791). Participants were randomized to 6 months of standard of care following Dietary Guidelines for Americans 2015-2020, Eighth Edition, or to an algorithm diet. Primary outcomes are reduction in average glucose levels and evaluation of the total daily time of plasma glucose levels were below 140 mg/dL. Participants wore the continuous glucose monitor for the entire 6 months of intervention. “I don’t think this was ever done before,” he said. “We’re also looking at secondary metabolic endpoints and exploratory endpoints such as changes in the microbiome. We’re asking people to log everything they eat for the entire 6 months of intervention. It gives us a lot of power in terms assessing compliance. It’s an immense amount of data.”
Evaluation of the data are not yet complete, but interim results are promising. For example, he discussed results from one study participant on the algorithm diet. “Across 1 month, this person was able to entirely reduce the peaks in glucose levels and dramatic reductions in the time above 140 mg/dL in the 6-month treatment period,” said Dr. Segal, who is one of the study’s principal investigators. He disclosed that he is a paid consultant to DayTwo.
EXPERT ANALYSIS FROM WCIRDC 2018
Researchers exploring ways to mitigate aging’s impact on diabetes
LOS ANGELES – When Derek LeRoith, MD, PhD, was a medical student, he remembers professors telling him that human tissue response to aging diminishes over time, and that individuals can develop insulin resistance purely from aging.
“Whether that was right or wrong I don’t know, but certainly it seems to be one of the major issues that leads to the increase in diabetes, with all of its associated aspects such as dyslipidemia and hypertension,” he said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease.
According to Dr. LeRoith, professor of medicine and director of research in the division of endocrinology at Icahn School of Medicine at Mount Sinai, New York, studies have demonstrated that the elderly have worse glucose tolerance, compared with younger adults. One such analysis found that the insulin secretion index and disposition index are lower in the elderly, compared with their younger patients (Diabetes 2003;52[7]:1738-48). “But it’s not just the insulin resistance per se,” he said. “It’s also a defect of the beta cell. .”
Another major issue for aging patients is the impact of diabetes on cognitive decline and the formation of Alzheimer’s disease. “There’s a suggestion that the brain has insulin resistance and that this may also affect cognitive decline and Alzheimer’s,” Dr. LeRoith said. “But there are other aspects: insulin insufficiency, hyperglycemia, and, of course ... hypoglycemia. There is a debate as to what the major causes are. Is it amyloid beta accumulation, or is it vascular damage?”
In collaboration with Israeli researchers, Dr. LeRoith and his associates have been evaluating patients that belong to the Maccabi Health System in Tel Aviv, which has a diabetes registry with complete hemoglobin A1c measurements since 1998. One study of 897 registry participants found a strong association between worse diabetes control and worse cognition (Am J Geriatr Psych 2014;22:1055-9). Specifically, an interaction of duration of type 2 diabetes with HbA1c was associated with executive functioning (P = .006), semantic categorization (P = .019), attention/working memory (P = .011), and overall cognition (P = .006), such that the associations between duration of type 2 diabetes and cognitive impairment increased as HbA1c levels increased – but not for episodic memory (P = .984).
In a separate analysis of patients from the same registry, Dr. LeRoith and his colleagues evaluated the relationships of long-term trajectories of glycemic control with cognitive performance in cognitively normal elderly with type 2 diabetes (PLoS ONE 9[6]:e97384 doi: 10.1371/journal.pone.0097384). They found that subjects with stable HbA1c over time had the lowest HbA1c at study entry and performed best on cognitive measures, “suggesting that the trajectile of HbA1c over 10 or 12 years can really influence the cognitive ability in these patients,” he said.
Another, unrelated study found that insulin in combination with other diabetes medication is associated with less Alzheimer’s neuropathology (Neurology 2008;71:750-7), while an Alzheimer’s mouse model from Dr. LeRoith and his colleagues demonstrated that high dietary advanced glycation end products are associated with poorer spatial learning and accelerated amyloid beta deposition (Aging Cell 2016;15:309-16). “From that study we conclude that high dietary advance glycation end (AGE) products may be neurotoxic and that a diet low in AGEs may decrease dementia risk, particularly in diabetic elderly who are at increased risk and have higher levels of AGEs,” he said.
Potential ways to mitigate some of aging’s effects on the course of diabetes include caloric restriction, exercise, and taking metformin, Dr. LeRoith said. “There is a correlation between fitness and cognitive function, so the implication for clinical practice in individuals with diabetes is to encourage them to engage in physical activity on most days of the week,” he said. “It’s also known that depression makes the diabetes worse and depression makes cognitive function worse. It’s been suggested that if you have patients who are depressed, you should treat them with antidepressants if necessary, because this may help with their cognitive function.”
Meanwhile, an ongoing trial first announced in 2016 known as Targeting Aging with Metformin (TAME) is exploring the effects of metformin in helping to delay the aging process (Cell Metab 2016;23[6]:1060-5). Early support exists that metformin may delay cognitive decline and Alzheimer’s, even in non–type 2 diabetes. “An intended consequence of this effort is to create a paradigm for evaluation of pharmacologic approaches to delay aging,” the researchers wrote in an article describing the project, which is funded by the National Institute on Aging. “The randomized, controlled clinical trial we have proposed, if successful, could profoundly change the approach to aging and its diseases and affect health care delivery and costs.”
Dr. LeRoith reported having no financial disclosures.
LOS ANGELES – When Derek LeRoith, MD, PhD, was a medical student, he remembers professors telling him that human tissue response to aging diminishes over time, and that individuals can develop insulin resistance purely from aging.
“Whether that was right or wrong I don’t know, but certainly it seems to be one of the major issues that leads to the increase in diabetes, with all of its associated aspects such as dyslipidemia and hypertension,” he said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease.
According to Dr. LeRoith, professor of medicine and director of research in the division of endocrinology at Icahn School of Medicine at Mount Sinai, New York, studies have demonstrated that the elderly have worse glucose tolerance, compared with younger adults. One such analysis found that the insulin secretion index and disposition index are lower in the elderly, compared with their younger patients (Diabetes 2003;52[7]:1738-48). “But it’s not just the insulin resistance per se,” he said. “It’s also a defect of the beta cell. .”
Another major issue for aging patients is the impact of diabetes on cognitive decline and the formation of Alzheimer’s disease. “There’s a suggestion that the brain has insulin resistance and that this may also affect cognitive decline and Alzheimer’s,” Dr. LeRoith said. “But there are other aspects: insulin insufficiency, hyperglycemia, and, of course ... hypoglycemia. There is a debate as to what the major causes are. Is it amyloid beta accumulation, or is it vascular damage?”
In collaboration with Israeli researchers, Dr. LeRoith and his associates have been evaluating patients that belong to the Maccabi Health System in Tel Aviv, which has a diabetes registry with complete hemoglobin A1c measurements since 1998. One study of 897 registry participants found a strong association between worse diabetes control and worse cognition (Am J Geriatr Psych 2014;22:1055-9). Specifically, an interaction of duration of type 2 diabetes with HbA1c was associated with executive functioning (P = .006), semantic categorization (P = .019), attention/working memory (P = .011), and overall cognition (P = .006), such that the associations between duration of type 2 diabetes and cognitive impairment increased as HbA1c levels increased – but not for episodic memory (P = .984).
In a separate analysis of patients from the same registry, Dr. LeRoith and his colleagues evaluated the relationships of long-term trajectories of glycemic control with cognitive performance in cognitively normal elderly with type 2 diabetes (PLoS ONE 9[6]:e97384 doi: 10.1371/journal.pone.0097384). They found that subjects with stable HbA1c over time had the lowest HbA1c at study entry and performed best on cognitive measures, “suggesting that the trajectile of HbA1c over 10 or 12 years can really influence the cognitive ability in these patients,” he said.
Another, unrelated study found that insulin in combination with other diabetes medication is associated with less Alzheimer’s neuropathology (Neurology 2008;71:750-7), while an Alzheimer’s mouse model from Dr. LeRoith and his colleagues demonstrated that high dietary advanced glycation end products are associated with poorer spatial learning and accelerated amyloid beta deposition (Aging Cell 2016;15:309-16). “From that study we conclude that high dietary advance glycation end (AGE) products may be neurotoxic and that a diet low in AGEs may decrease dementia risk, particularly in diabetic elderly who are at increased risk and have higher levels of AGEs,” he said.
Potential ways to mitigate some of aging’s effects on the course of diabetes include caloric restriction, exercise, and taking metformin, Dr. LeRoith said. “There is a correlation between fitness and cognitive function, so the implication for clinical practice in individuals with diabetes is to encourage them to engage in physical activity on most days of the week,” he said. “It’s also known that depression makes the diabetes worse and depression makes cognitive function worse. It’s been suggested that if you have patients who are depressed, you should treat them with antidepressants if necessary, because this may help with their cognitive function.”
Meanwhile, an ongoing trial first announced in 2016 known as Targeting Aging with Metformin (TAME) is exploring the effects of metformin in helping to delay the aging process (Cell Metab 2016;23[6]:1060-5). Early support exists that metformin may delay cognitive decline and Alzheimer’s, even in non–type 2 diabetes. “An intended consequence of this effort is to create a paradigm for evaluation of pharmacologic approaches to delay aging,” the researchers wrote in an article describing the project, which is funded by the National Institute on Aging. “The randomized, controlled clinical trial we have proposed, if successful, could profoundly change the approach to aging and its diseases and affect health care delivery and costs.”
Dr. LeRoith reported having no financial disclosures.
LOS ANGELES – When Derek LeRoith, MD, PhD, was a medical student, he remembers professors telling him that human tissue response to aging diminishes over time, and that individuals can develop insulin resistance purely from aging.
“Whether that was right or wrong I don’t know, but certainly it seems to be one of the major issues that leads to the increase in diabetes, with all of its associated aspects such as dyslipidemia and hypertension,” he said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease.
According to Dr. LeRoith, professor of medicine and director of research in the division of endocrinology at Icahn School of Medicine at Mount Sinai, New York, studies have demonstrated that the elderly have worse glucose tolerance, compared with younger adults. One such analysis found that the insulin secretion index and disposition index are lower in the elderly, compared with their younger patients (Diabetes 2003;52[7]:1738-48). “But it’s not just the insulin resistance per se,” he said. “It’s also a defect of the beta cell. .”
Another major issue for aging patients is the impact of diabetes on cognitive decline and the formation of Alzheimer’s disease. “There’s a suggestion that the brain has insulin resistance and that this may also affect cognitive decline and Alzheimer’s,” Dr. LeRoith said. “But there are other aspects: insulin insufficiency, hyperglycemia, and, of course ... hypoglycemia. There is a debate as to what the major causes are. Is it amyloid beta accumulation, or is it vascular damage?”
In collaboration with Israeli researchers, Dr. LeRoith and his associates have been evaluating patients that belong to the Maccabi Health System in Tel Aviv, which has a diabetes registry with complete hemoglobin A1c measurements since 1998. One study of 897 registry participants found a strong association between worse diabetes control and worse cognition (Am J Geriatr Psych 2014;22:1055-9). Specifically, an interaction of duration of type 2 diabetes with HbA1c was associated with executive functioning (P = .006), semantic categorization (P = .019), attention/working memory (P = .011), and overall cognition (P = .006), such that the associations between duration of type 2 diabetes and cognitive impairment increased as HbA1c levels increased – but not for episodic memory (P = .984).
In a separate analysis of patients from the same registry, Dr. LeRoith and his colleagues evaluated the relationships of long-term trajectories of glycemic control with cognitive performance in cognitively normal elderly with type 2 diabetes (PLoS ONE 9[6]:e97384 doi: 10.1371/journal.pone.0097384). They found that subjects with stable HbA1c over time had the lowest HbA1c at study entry and performed best on cognitive measures, “suggesting that the trajectile of HbA1c over 10 or 12 years can really influence the cognitive ability in these patients,” he said.
Another, unrelated study found that insulin in combination with other diabetes medication is associated with less Alzheimer’s neuropathology (Neurology 2008;71:750-7), while an Alzheimer’s mouse model from Dr. LeRoith and his colleagues demonstrated that high dietary advanced glycation end products are associated with poorer spatial learning and accelerated amyloid beta deposition (Aging Cell 2016;15:309-16). “From that study we conclude that high dietary advance glycation end (AGE) products may be neurotoxic and that a diet low in AGEs may decrease dementia risk, particularly in diabetic elderly who are at increased risk and have higher levels of AGEs,” he said.
Potential ways to mitigate some of aging’s effects on the course of diabetes include caloric restriction, exercise, and taking metformin, Dr. LeRoith said. “There is a correlation between fitness and cognitive function, so the implication for clinical practice in individuals with diabetes is to encourage them to engage in physical activity on most days of the week,” he said. “It’s also known that depression makes the diabetes worse and depression makes cognitive function worse. It’s been suggested that if you have patients who are depressed, you should treat them with antidepressants if necessary, because this may help with their cognitive function.”
Meanwhile, an ongoing trial first announced in 2016 known as Targeting Aging with Metformin (TAME) is exploring the effects of metformin in helping to delay the aging process (Cell Metab 2016;23[6]:1060-5). Early support exists that metformin may delay cognitive decline and Alzheimer’s, even in non–type 2 diabetes. “An intended consequence of this effort is to create a paradigm for evaluation of pharmacologic approaches to delay aging,” the researchers wrote in an article describing the project, which is funded by the National Institute on Aging. “The randomized, controlled clinical trial we have proposed, if successful, could profoundly change the approach to aging and its diseases and affect health care delivery and costs.”
Dr. LeRoith reported having no financial disclosures.
EXPERT ANALYSIS FROM WCIRDC 2018
Osteomyelitis amputation risk linked to comorbidity burden
BOSTON – The higher the comorbidity burden, the greater the likelihood that osteomyelitis will lead to amputation within 2 years, according to a review of 1,186 adult osteomyelitis patients at the University of Michigan, Ann Arbor.
The limb amputation incidence was 7.2% over 2 years in patients with no comorbidities, 21.4% among patients with heart failure, 36.1% in patients with diabetes, and 36.7% among those with peripheral vascular disease (PVD).
The 2-year incidence marched steadily upward with combined comorbidities to 47.4% in patients with diabetes and heart failure; 64.5% in patients with diabetes and PVD; and 75.0% in patients with diabetes, heart failure, and PVD.
“What this means is that looking at diabetes versus no diabetes alone is not sufficient to gauge the risk of amputation. We have to look at the patient’s comorbidity profile as a whole; greater comorbidity burden and different combinations of comorbidities [increase] amputation incidence, but there’s considerable risk [7.2%] even among otherwise healthy patients,” said lead investigator Toby Keeney-Bonthrone, a medical student at the university.
The ultimate goal of the work is to develop an osteomyelitis amputation risk calculator for physicians and patients to improve decision making, validated by nationwide data. “The question is if some patients would benefit from [an earlier,] more prophylactic amputation. Would it be better to just take off the limb and be done with it, and would that decrease overall morbidity?” he said at the annual clinical congress of the American College of Surgeons.
“We often find ourselves reacting to osteomyelitis as it progresses. I think patients deserve a better deal than that. They deserve for us to think one or two steps ahead,” Mr. Keeney-Bonthrone said.
The immediate goal of the study was to fill the data gap on long-term osteomyelitis outcomes, something that hasn’t been addressed much in the literature. The team reviewed adult patients from 2004 to 2015 who were followed for at least 2 years after diagnosis; 610 had diabetes, a known risk factor for osteomyelitis and amputation, and 576 did not.
Comorbidities were considerably more common in the diabetes group, including PVD and heart failure, but also chronic obstructive pulmonary disease, previous heart attack, prior amputation, and especially renal disease. The 2-year amputation incidence was also higher in the diabetes group (43.1% vs. 12.3%), as was 2-year mortality (22.3% vs. 15.5%).
Odds ratios for lower limb amputation climbed in a stepwise fashion on multivariate analysis, from almost a 100% increase in men and in black patients to a 158% increase among patients with past amputations; a 206% increase with PVD; a 256% increase in patients with type 2 diabetes, and a 349% increase among patients with type 1 diabetes. The investigators were puzzled that the amputation risk was higher among type 1 patients than in those with type 2, because comorbidity burdens are generally higher in type 2 diabetes.
No data was provided on treatment differences between the groups, including antibiotic use.
The work was funded by the National Institutes of Health. The investigators reported no relevant disclosures.
SOURCE: Keeney-Bonthrone T et al. J Am Coll Surg. 2018 Oct;227(4), S105.
BOSTON – The higher the comorbidity burden, the greater the likelihood that osteomyelitis will lead to amputation within 2 years, according to a review of 1,186 adult osteomyelitis patients at the University of Michigan, Ann Arbor.
The limb amputation incidence was 7.2% over 2 years in patients with no comorbidities, 21.4% among patients with heart failure, 36.1% in patients with diabetes, and 36.7% among those with peripheral vascular disease (PVD).
The 2-year incidence marched steadily upward with combined comorbidities to 47.4% in patients with diabetes and heart failure; 64.5% in patients with diabetes and PVD; and 75.0% in patients with diabetes, heart failure, and PVD.
“What this means is that looking at diabetes versus no diabetes alone is not sufficient to gauge the risk of amputation. We have to look at the patient’s comorbidity profile as a whole; greater comorbidity burden and different combinations of comorbidities [increase] amputation incidence, but there’s considerable risk [7.2%] even among otherwise healthy patients,” said lead investigator Toby Keeney-Bonthrone, a medical student at the university.
The ultimate goal of the work is to develop an osteomyelitis amputation risk calculator for physicians and patients to improve decision making, validated by nationwide data. “The question is if some patients would benefit from [an earlier,] more prophylactic amputation. Would it be better to just take off the limb and be done with it, and would that decrease overall morbidity?” he said at the annual clinical congress of the American College of Surgeons.
“We often find ourselves reacting to osteomyelitis as it progresses. I think patients deserve a better deal than that. They deserve for us to think one or two steps ahead,” Mr. Keeney-Bonthrone said.
The immediate goal of the study was to fill the data gap on long-term osteomyelitis outcomes, something that hasn’t been addressed much in the literature. The team reviewed adult patients from 2004 to 2015 who were followed for at least 2 years after diagnosis; 610 had diabetes, a known risk factor for osteomyelitis and amputation, and 576 did not.
Comorbidities were considerably more common in the diabetes group, including PVD and heart failure, but also chronic obstructive pulmonary disease, previous heart attack, prior amputation, and especially renal disease. The 2-year amputation incidence was also higher in the diabetes group (43.1% vs. 12.3%), as was 2-year mortality (22.3% vs. 15.5%).
Odds ratios for lower limb amputation climbed in a stepwise fashion on multivariate analysis, from almost a 100% increase in men and in black patients to a 158% increase among patients with past amputations; a 206% increase with PVD; a 256% increase in patients with type 2 diabetes, and a 349% increase among patients with type 1 diabetes. The investigators were puzzled that the amputation risk was higher among type 1 patients than in those with type 2, because comorbidity burdens are generally higher in type 2 diabetes.
No data was provided on treatment differences between the groups, including antibiotic use.
The work was funded by the National Institutes of Health. The investigators reported no relevant disclosures.
SOURCE: Keeney-Bonthrone T et al. J Am Coll Surg. 2018 Oct;227(4), S105.
BOSTON – The higher the comorbidity burden, the greater the likelihood that osteomyelitis will lead to amputation within 2 years, according to a review of 1,186 adult osteomyelitis patients at the University of Michigan, Ann Arbor.
The limb amputation incidence was 7.2% over 2 years in patients with no comorbidities, 21.4% among patients with heart failure, 36.1% in patients with diabetes, and 36.7% among those with peripheral vascular disease (PVD).
The 2-year incidence marched steadily upward with combined comorbidities to 47.4% in patients with diabetes and heart failure; 64.5% in patients with diabetes and PVD; and 75.0% in patients with diabetes, heart failure, and PVD.
“What this means is that looking at diabetes versus no diabetes alone is not sufficient to gauge the risk of amputation. We have to look at the patient’s comorbidity profile as a whole; greater comorbidity burden and different combinations of comorbidities [increase] amputation incidence, but there’s considerable risk [7.2%] even among otherwise healthy patients,” said lead investigator Toby Keeney-Bonthrone, a medical student at the university.
The ultimate goal of the work is to develop an osteomyelitis amputation risk calculator for physicians and patients to improve decision making, validated by nationwide data. “The question is if some patients would benefit from [an earlier,] more prophylactic amputation. Would it be better to just take off the limb and be done with it, and would that decrease overall morbidity?” he said at the annual clinical congress of the American College of Surgeons.
“We often find ourselves reacting to osteomyelitis as it progresses. I think patients deserve a better deal than that. They deserve for us to think one or two steps ahead,” Mr. Keeney-Bonthrone said.
The immediate goal of the study was to fill the data gap on long-term osteomyelitis outcomes, something that hasn’t been addressed much in the literature. The team reviewed adult patients from 2004 to 2015 who were followed for at least 2 years after diagnosis; 610 had diabetes, a known risk factor for osteomyelitis and amputation, and 576 did not.
Comorbidities were considerably more common in the diabetes group, including PVD and heart failure, but also chronic obstructive pulmonary disease, previous heart attack, prior amputation, and especially renal disease. The 2-year amputation incidence was also higher in the diabetes group (43.1% vs. 12.3%), as was 2-year mortality (22.3% vs. 15.5%).
Odds ratios for lower limb amputation climbed in a stepwise fashion on multivariate analysis, from almost a 100% increase in men and in black patients to a 158% increase among patients with past amputations; a 206% increase with PVD; a 256% increase in patients with type 2 diabetes, and a 349% increase among patients with type 1 diabetes. The investigators were puzzled that the amputation risk was higher among type 1 patients than in those with type 2, because comorbidity burdens are generally higher in type 2 diabetes.
No data was provided on treatment differences between the groups, including antibiotic use.
The work was funded by the National Institutes of Health. The investigators reported no relevant disclosures.
SOURCE: Keeney-Bonthrone T et al. J Am Coll Surg. 2018 Oct;227(4), S105.
REPORTING FROM THE 2018 ACS CLINICAL CONGRESS
Key clinical point:
Major finding: The 2-year incidence marched steadily upward with combined comorbidities to 47.5% in patients with diabetes and heart failure; 64.5% in patients with diabetes and peripheral vascular disease, and 75% in patients with diabetes, heart failure, and peripheral vascular disease.
Study details: A review of 1,186 adult osteomyelitis patients
Disclosures: The work was funded by the National Institutes of Health. The investigators reported no relevant disclosures.
Source: Keeney-Bonthrone T et al. J Am Coll Surg. 2018 Oct;227(4), S105.
Prenatal valproate and ADHD
Also today, one expert calls for better ways to preserve beta cell function in youth, synthetic opioids drive a spike in the number of fatal overdoses, and mothers may play a role in the link between depression in fathers and daughters.
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Also today, one expert calls for better ways to preserve beta cell function in youth, synthetic opioids drive a spike in the number of fatal overdoses, and mothers may play a role in the link between depression in fathers and daughters.
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Apple Podcasts
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Spotify
Also today, one expert calls for better ways to preserve beta cell function in youth, synthetic opioids drive a spike in the number of fatal overdoses, and mothers may play a role in the link between depression in fathers and daughters.
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Apple Podcasts
Google Podcasts
Spotify
New diabetes drugs solidify their cardiovascular and renal benefits
CHICAGO – When the first results from a large trial that showed profound and unexpected benefits for preventing heart failure hospitalizations associated with use of the antihyperglycemic sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin came out – a little over 3 years ago – the general reaction from clinicians was some variant of “Could this be real?”
Since then, as results from some five other large, international trials have come out showing both similar benefits from two other drugs in the same SGLT2 inhibitor class, canagliflozin and dapagliflozin, as well as results showing clear cardiovascular disease benefits from three drugs in a second class of antihyperglycemics, the glucagonlike peptide–1 receptor agonists (GLP-1 RAs), the general consensus among cardiologists became: “The cardiovascular and renal benefits are real. How can we now best use these drugs to help patients?”
This change increasingly forces cardiologists, as well as the primary care physicians who often manage patients with type 2 diabetes mellitus, to become more comfortable prescribing these two classes of antihyperglycemic drugs. During a talk at the American Heart Association scientific sessions, Eugene Braunwald, MD, arguably the top thought leader in cardiology, coined a new name for the medical subspecialty that he foresees navigating this overlap between diabetes care and cardiovascular disease prevention: diabetocardiology (although a more euphonic alternative might be cardiodiabetology, while the more comprehensive name could be cardionephrodiabetology).
“I was certainly surprised” by the first report in 2015 from the EMPA-REG OUTCOME trial (N Engl J Med. 2015 Nov 26;373[22]:2117-28), said Dr. Braunwald, who is professor of medicine at Harvard Medical School in Boston. A lot of his colleagues were surprised and said, “It’s just one trial.”
“Now we have three trials,” with the addition of the CANVAS trial for canagliflozin (N Engl J Med. 2017 Aug 17;377[7]:644-57) and the DECLARE-TIMI 58 trial (N Engl J Med. 2018 Nov 10. doi:10.1056/NEJMoa1812389) for dapagliflozin reported at the AHA meeting in November.
“We are in the midst of two pandemics: heart failure and type 2 diabetes. As cardiologists, we have to learn how to deal with this,” said Dr. Braunwald, and the evidence now clearly shows that these drugs can help with that.
As another speaker at the meeting, Javed Butler, MD, a heart failure specialist, observed in a separate talk at the meeting, “Heart failure is one of the most common, if not the most common complication, of patients with diabetes.” This tight link between heart failure and diabetes helps make cardiovascular mortality “the number one cause of death” in patients with diabetes, said Dr. Butler, professor and chairman of medicine at the University of Mississippi in Jackson.
“Thanks to the cardiovascular outcome trials, we now have a much broader and deeper appreciation of heart failure and renal disease as integral components of the cardiovascular-renal spectrum in people with diabetes,” said Subodh Verma, MD, a professor at the University of Toronto and cardiac surgeon at St. Michael’s Hospital in Toronto. Dr. Braunwald spelled out in his talk some of the interrelationships of diabetes, heart failure, and renal dysfunction that together produce a downward-spiraling vicious circle for patients, a pathophysiological process that clinicians can now short-circuit by treatment with a SGLT2 inhibitor.
Cardiovascular outcome trials show the way
In the context of antihyperglycemic drugs, the “cardiovascular outcome trials” refers to a series of large trials mandated by the Food and Drug Administration in 2008 to assess the cardiovascular disease effects of new agents coming onto the U.S. market to treat type 2 diabetes mellitus (T2DM). By the time Dr. Verma spoke at the AHA meeting, he could cite reported results from 12 of these trials: 5 different drugs in the GLP-1 RA class, 4 drugs in the dipeptidyl peptidase-4 (DPP-4) inhibitor class, and 3 drugs from the SGLT2 inhibitor class. Dr. Verma summed what the findings have shown.
The four tested DDP-4 inhibitors (alogliptin, linagliptin, saxagliptin, and sitagliptin) consistently showed neutrality for the primary outcome of major adverse cardiovascular disease events (MACE), constituted by cardiovascular disease death, MI, or stroke.
The five tested GLP-1 RAs (albiglutide, exenatide, liraglutide, lixisenatide, and semaglutide) showed a mixed pattern of MACE results that seemed to be linked with the subclass the drug fell into. The two exedin-4–based drugs, exenatide and lixisenatide, each showed a statistically neutral effect for MACE, as well as collectively in a combined analysis. In contrast, three human GLP-1–based drugs, albiglutide, liraglutide, and semaglutide, each showed a consistent, statistically-significant MACE reduction in their respective outcome trials, and collectively they showed a highly significant 18% reduction in MACE, compared with placebo, Dr. Verma said. Further, recent analysis by Dr. Verma that used data from liraglutide treatment in the LEADER trial showed the MACE benefit occurred only among enrolled patients treated with liraglutide who had established atherosclerotic cardiovascular disease (ASCVD). Patients enrolled in the trial with only multiple risk factors (in addition to having T2DM) but without established ASCVD showed no significant benefit from liraglutide treatment for the MACE endpoint, compared with control patients.
Recently a press-release announcement of results from a sixth GLP-1 RA, dulaglutide, in the REWIND trial of MACE outcomes suggested that a drug in this class could have broader effect. The majority, 69%, of the 9,901 patients with T2DM enrolled in REWIND had risk factors but not established ASCVD at enrollment. A Nov. 5, 2018, statement from the company developing this drug, Lilly, reported that the study overall produced a statistically significant reduction in MACE, although it provided no additional details. As the released noted, this made REWIND the first trial to show a MACE benefit from a drug in the GLP-1 RA class in patients without established ASCVD.
The MACE outcome results from the three SGLT2 inhibitor trials showed a similar pattern as liraglutide: In patients with established ASCVD, the drugs individually each produced a MACE reduction, although dapagliflozin just missed having a statistically significant reduction. Collectively, the three drugs showed a statistically significant, 14% relative risk reduction for MACE, compared with control patients. But among patients with multiple risk factors only, but without established ASCVD, included in two of the three trials (CANVAS and DECLARE-TIMI 58), the results showed both individually and collectively a neutral MACE effect.
But unlike the other antihyperglycemic drugs tested in the cardiovascular outcome trials, the SGLT2 inhibitors have shown two additional, highly important secondary outcomes: a consistent reduction in hospitalization for heart failure and a consistent reduction in renal-disease progression.
A meta-analysis of the three SGLT2 inhibitor trials published coincident with the release of the DECLARE-TIMI 58 results showed that, for the outcome of either cardiovascular death or hospitalization for heart failure, the SGLT2 inhibitors collectively showed a significant 29% relative decrease in this incidence among patients with a history of heart failure, and a significant 21% relative decrease among patients without history of heart failure (Lancet. 2018 Nov 10. doi: 10.1016/S0140-6736(18)32590-X). Among the subset of patients with established ASCVD, treatment with a SGLT2 inhibitor across all three trials showed a significant 16% relative risk reduction, and in the subset with multiple risk factors but no established ASCVD, the two SGLT2 inhibitors collectively produced a 16% relative cut in cardiovascular death or heart failure hospitalization with a P value of .06. Finally, the Lancet meta-analysis showed that, for a combined endpoint that reflected renal worsening, the SGLT2 inhibitors showed a significant relative reduction of about 45% in both the subgroup of patients with established ASCVD and in the subgroup of those with just risk factors.
“This is a big step forward for patients with multiple risk factors and diabetes but without ASCVD, that both renal disease and hospitalization for heart failure are sensitive” to the SGLT2 inhibitors, Dr. Verma noted. “We see renal protection and reduction of heart failure hospitalization across both primary and secondary prevention patients, with no need to distinguish them based on ASCVD.” In contrast, he noted, the MACE benefit from the SGLT2 inhibitors seems limited to patients with ASCVD. The day before making this point in a talk during the meeting, Dr. Verma had published the same message in a commentary (Lancet. 2018 Nov 10. doi: 10.1016/S0140-6736(18)32824-1).
Although the “nomenclature of primary versus secondary prevention is appropriate for atherosclerotic outcomes, it is likely to be inappropriate for a person with type 2 diabetes who is at risk of hospitalization for heart failure and renal disease,” Dr. Verma wrote with his associates in the commentary.
What it means for clinicians
The upshot of all of these cardiovascular outcome trial results that came out over the past 3 years has been a new appreciation of how antihyperglycemic drugs can have cardiovascular and renal benefits that transcend their effects on glycemia. The evidence has put the SGLT2 inhibitors and GLP-1 RAs on track to challenge, and potentially displace, metformin as the top drug to prescribe for patients with T2DM.
Clinicians should realize that they should prescribe SGLT2 inhibitors and selected GLP-1 RAs “as early as metformin in patients with established ASCVD,” said Dr. Verma. “For patients with recalcitrant atherosclerotic disease and a history of MI and ischemia, I’d primarily treat with a GLP-1 RA. In a patient with left ventricular dysfunction or evidence of heart failure, I’d use an SGLT2 inhibitor. But it’s not a fight between these two. You could treat a patients with type 2 diabetes with both classes,” although the practicality of this approach is limited by the high cost of these drugs.
The SGLT2 inhibitors “should now be considered as first-line therapy after metformin in most people with type 2 diabetes, irrespective of whether or not they have established atherosclerotic vascular disease, chronic kidney disease, or heart failure,” he and his associates wrote in their recent commentary.
“What I struggle with the most is how we prioritize and individualize secondary-prevention therapies based on risk for ischemia and heart failure. Some therapies [the SGLT2 inhibitors] are predominantly for heart failure prevention, and some [the GLP-1 RAs] are primarily for ischemia. How do we choose when a patient cannot afford to take both? Does a combination of a SGLT2 inhibitor and a GLP-1 RA offer the greatest CVD benefit? We need to test this in a trial. And will metformin be displaced as first-line treatment?” Dr. Verma asked.
“The day will probably come when, for maximal protection, you treat with both classes. But right now we’re forced to choose because of the cost,” said John McMurray, MD, professor of cardiology at the University of Glasgow, in a talk during the meeting.
As to specifically which SGLT2 inhibitor to prescribe, “they all look pretty much the same” in the newly published meta-analysis, Dr. McMurray said, although he noted that safety differences among agents in the class remain possible.
“For patients similar to those studied in the three SGLT2 inhibitor trials, clinicians should use one of these drugs to reduce the risk for incident heart failure, irrespective of their effect on MACE,” said Dr. Butler. Reducing the risk for incident heart failure and of progressive renal dysfunction are two new goals for antihyperglycemic therapy that now overlay the long-standing goals of controlling glycemia and reducing cardiovascular disease risk and the more recent goals of cutting cardiovascular disease mortality and cutting the risk for a MACE event.
A current limitation for practice is that the none of the three drug companies that market the tested SGLT2 inhibitor drugs has sought regulatory approval for an indication of reducing the risk for heart failure hospitalization. Despite that, “these drugs should be used for renal protection and reducing heart failure hospitalizations,” Dr. Butler said. “We need to start thinking about this and not get lost thinking about only their MACE effect because, when you focus on MACE, there is a competition between the SGLT2 inhibitors and the GLP-1 RA. If we think of GLP-1 RAs as drugs to prevent MACE, and SGLT2 inhibitors as drugs that primarily prevent heart failure and renal dysfunction, then there is no competition. Perhaps combined treatment is where we need to go,” he said in an interview.
But the enthusiasm that experts like Dr. Butler, Dr. McMurray, and Dr. Verma have for wider use of both classes of drugs in appropriate patients is not necessarily matched right now among many community physicians. Cardiologist David J. Becker, MD, is an example of the clinicians who appreciate the growing evidence that supports wider use of these antihyperglycemic drugs but remain uneasy about applying this evidence in their practice.
Dr. Becker, associate director of the Preventive and Integrative Heart Health Program of the Temple Heart and Vascular Institute in Philadelphia, writes a column for the Philadelphia Inquirer on medical care. In a December 2018 piece, he said “like most cardiologists, I ‘don’t do diabetes’ – because it’s not my expertise. The new drugs, however, mean I need to learn more” about treating these patients. “The problem: There are so many of these medications that they present a bewildering choice for patients and doctors.”
Dr. Becker cited several barriers he sees for himself and his nonendocrinologist colleagues to prescribe these drugs – and for patients to take them:
- High cost, with prices that run close to $20/day for each medication.
- A thicket of names and choices that “lead to confusion and paralysis,” which has been exacerbated by “advertising wars” among competing drug companies.
- Cardiologists and primary care physicians usually defer to endocrinologists to prescribe these drugs, but most patients with T2DM aren’t seen by endocrinologists. The result: “Few doctors prescribe them.”
The cardiovascular disease benefits of these drugs have not been adequately promoted. Until that changes, “cardiologists like me will not realize their importance,” Dr. Becker concluded.
While christening the new diabetocardiology subspecialty, Dr. Braunwald placed the onus for managing this emerging facet of diabetes largely outside the scope of endocrinology.
“We can’t call in a consultant every time we have a patient with diabetes; it would bankrupt the system,” he said. Training of cardiologists now needs to include several months of treating patients with diabetes, Dr. Braunwald advised, just like 30 or so years ago when cardiologists like himself had to become more familiar with blood clotting to better manage thrombotic disease.
Dr. Braunwald has been a consultant to Cardurion, Myokardia, and Sanofi; an advisor to Endcardia; and has received research funding from AstraZeneca, Daiishi Sankyo, and Novartis. Dr. Butler has been a consultant or advisor to AstraZeneca, Amgen, Bayer, Boehringer Ingelheim, Janssen, Merck, Novartis, Novo Nordisk, and Sanofi. Dr. Verma has received honoraria and research funding from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Merck, Novartis, NovoNordisk, Sanofi, and Valeant. Dr. McMurray has received research funding from 12 companies. Dr. Becker had no disclosures.
CHICAGO – When the first results from a large trial that showed profound and unexpected benefits for preventing heart failure hospitalizations associated with use of the antihyperglycemic sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin came out – a little over 3 years ago – the general reaction from clinicians was some variant of “Could this be real?”
Since then, as results from some five other large, international trials have come out showing both similar benefits from two other drugs in the same SGLT2 inhibitor class, canagliflozin and dapagliflozin, as well as results showing clear cardiovascular disease benefits from three drugs in a second class of antihyperglycemics, the glucagonlike peptide–1 receptor agonists (GLP-1 RAs), the general consensus among cardiologists became: “The cardiovascular and renal benefits are real. How can we now best use these drugs to help patients?”
This change increasingly forces cardiologists, as well as the primary care physicians who often manage patients with type 2 diabetes mellitus, to become more comfortable prescribing these two classes of antihyperglycemic drugs. During a talk at the American Heart Association scientific sessions, Eugene Braunwald, MD, arguably the top thought leader in cardiology, coined a new name for the medical subspecialty that he foresees navigating this overlap between diabetes care and cardiovascular disease prevention: diabetocardiology (although a more euphonic alternative might be cardiodiabetology, while the more comprehensive name could be cardionephrodiabetology).
“I was certainly surprised” by the first report in 2015 from the EMPA-REG OUTCOME trial (N Engl J Med. 2015 Nov 26;373[22]:2117-28), said Dr. Braunwald, who is professor of medicine at Harvard Medical School in Boston. A lot of his colleagues were surprised and said, “It’s just one trial.”
“Now we have three trials,” with the addition of the CANVAS trial for canagliflozin (N Engl J Med. 2017 Aug 17;377[7]:644-57) and the DECLARE-TIMI 58 trial (N Engl J Med. 2018 Nov 10. doi:10.1056/NEJMoa1812389) for dapagliflozin reported at the AHA meeting in November.
“We are in the midst of two pandemics: heart failure and type 2 diabetes. As cardiologists, we have to learn how to deal with this,” said Dr. Braunwald, and the evidence now clearly shows that these drugs can help with that.
As another speaker at the meeting, Javed Butler, MD, a heart failure specialist, observed in a separate talk at the meeting, “Heart failure is one of the most common, if not the most common complication, of patients with diabetes.” This tight link between heart failure and diabetes helps make cardiovascular mortality “the number one cause of death” in patients with diabetes, said Dr. Butler, professor and chairman of medicine at the University of Mississippi in Jackson.
“Thanks to the cardiovascular outcome trials, we now have a much broader and deeper appreciation of heart failure and renal disease as integral components of the cardiovascular-renal spectrum in people with diabetes,” said Subodh Verma, MD, a professor at the University of Toronto and cardiac surgeon at St. Michael’s Hospital in Toronto. Dr. Braunwald spelled out in his talk some of the interrelationships of diabetes, heart failure, and renal dysfunction that together produce a downward-spiraling vicious circle for patients, a pathophysiological process that clinicians can now short-circuit by treatment with a SGLT2 inhibitor.
Cardiovascular outcome trials show the way
In the context of antihyperglycemic drugs, the “cardiovascular outcome trials” refers to a series of large trials mandated by the Food and Drug Administration in 2008 to assess the cardiovascular disease effects of new agents coming onto the U.S. market to treat type 2 diabetes mellitus (T2DM). By the time Dr. Verma spoke at the AHA meeting, he could cite reported results from 12 of these trials: 5 different drugs in the GLP-1 RA class, 4 drugs in the dipeptidyl peptidase-4 (DPP-4) inhibitor class, and 3 drugs from the SGLT2 inhibitor class. Dr. Verma summed what the findings have shown.
The four tested DDP-4 inhibitors (alogliptin, linagliptin, saxagliptin, and sitagliptin) consistently showed neutrality for the primary outcome of major adverse cardiovascular disease events (MACE), constituted by cardiovascular disease death, MI, or stroke.
The five tested GLP-1 RAs (albiglutide, exenatide, liraglutide, lixisenatide, and semaglutide) showed a mixed pattern of MACE results that seemed to be linked with the subclass the drug fell into. The two exedin-4–based drugs, exenatide and lixisenatide, each showed a statistically neutral effect for MACE, as well as collectively in a combined analysis. In contrast, three human GLP-1–based drugs, albiglutide, liraglutide, and semaglutide, each showed a consistent, statistically-significant MACE reduction in their respective outcome trials, and collectively they showed a highly significant 18% reduction in MACE, compared with placebo, Dr. Verma said. Further, recent analysis by Dr. Verma that used data from liraglutide treatment in the LEADER trial showed the MACE benefit occurred only among enrolled patients treated with liraglutide who had established atherosclerotic cardiovascular disease (ASCVD). Patients enrolled in the trial with only multiple risk factors (in addition to having T2DM) but without established ASCVD showed no significant benefit from liraglutide treatment for the MACE endpoint, compared with control patients.
Recently a press-release announcement of results from a sixth GLP-1 RA, dulaglutide, in the REWIND trial of MACE outcomes suggested that a drug in this class could have broader effect. The majority, 69%, of the 9,901 patients with T2DM enrolled in REWIND had risk factors but not established ASCVD at enrollment. A Nov. 5, 2018, statement from the company developing this drug, Lilly, reported that the study overall produced a statistically significant reduction in MACE, although it provided no additional details. As the released noted, this made REWIND the first trial to show a MACE benefit from a drug in the GLP-1 RA class in patients without established ASCVD.
The MACE outcome results from the three SGLT2 inhibitor trials showed a similar pattern as liraglutide: In patients with established ASCVD, the drugs individually each produced a MACE reduction, although dapagliflozin just missed having a statistically significant reduction. Collectively, the three drugs showed a statistically significant, 14% relative risk reduction for MACE, compared with control patients. But among patients with multiple risk factors only, but without established ASCVD, included in two of the three trials (CANVAS and DECLARE-TIMI 58), the results showed both individually and collectively a neutral MACE effect.
But unlike the other antihyperglycemic drugs tested in the cardiovascular outcome trials, the SGLT2 inhibitors have shown two additional, highly important secondary outcomes: a consistent reduction in hospitalization for heart failure and a consistent reduction in renal-disease progression.
A meta-analysis of the three SGLT2 inhibitor trials published coincident with the release of the DECLARE-TIMI 58 results showed that, for the outcome of either cardiovascular death or hospitalization for heart failure, the SGLT2 inhibitors collectively showed a significant 29% relative decrease in this incidence among patients with a history of heart failure, and a significant 21% relative decrease among patients without history of heart failure (Lancet. 2018 Nov 10. doi: 10.1016/S0140-6736(18)32590-X). Among the subset of patients with established ASCVD, treatment with a SGLT2 inhibitor across all three trials showed a significant 16% relative risk reduction, and in the subset with multiple risk factors but no established ASCVD, the two SGLT2 inhibitors collectively produced a 16% relative cut in cardiovascular death or heart failure hospitalization with a P value of .06. Finally, the Lancet meta-analysis showed that, for a combined endpoint that reflected renal worsening, the SGLT2 inhibitors showed a significant relative reduction of about 45% in both the subgroup of patients with established ASCVD and in the subgroup of those with just risk factors.
“This is a big step forward for patients with multiple risk factors and diabetes but without ASCVD, that both renal disease and hospitalization for heart failure are sensitive” to the SGLT2 inhibitors, Dr. Verma noted. “We see renal protection and reduction of heart failure hospitalization across both primary and secondary prevention patients, with no need to distinguish them based on ASCVD.” In contrast, he noted, the MACE benefit from the SGLT2 inhibitors seems limited to patients with ASCVD. The day before making this point in a talk during the meeting, Dr. Verma had published the same message in a commentary (Lancet. 2018 Nov 10. doi: 10.1016/S0140-6736(18)32824-1).
Although the “nomenclature of primary versus secondary prevention is appropriate for atherosclerotic outcomes, it is likely to be inappropriate for a person with type 2 diabetes who is at risk of hospitalization for heart failure and renal disease,” Dr. Verma wrote with his associates in the commentary.
What it means for clinicians
The upshot of all of these cardiovascular outcome trial results that came out over the past 3 years has been a new appreciation of how antihyperglycemic drugs can have cardiovascular and renal benefits that transcend their effects on glycemia. The evidence has put the SGLT2 inhibitors and GLP-1 RAs on track to challenge, and potentially displace, metformin as the top drug to prescribe for patients with T2DM.
Clinicians should realize that they should prescribe SGLT2 inhibitors and selected GLP-1 RAs “as early as metformin in patients with established ASCVD,” said Dr. Verma. “For patients with recalcitrant atherosclerotic disease and a history of MI and ischemia, I’d primarily treat with a GLP-1 RA. In a patient with left ventricular dysfunction or evidence of heart failure, I’d use an SGLT2 inhibitor. But it’s not a fight between these two. You could treat a patients with type 2 diabetes with both classes,” although the practicality of this approach is limited by the high cost of these drugs.
The SGLT2 inhibitors “should now be considered as first-line therapy after metformin in most people with type 2 diabetes, irrespective of whether or not they have established atherosclerotic vascular disease, chronic kidney disease, or heart failure,” he and his associates wrote in their recent commentary.
“What I struggle with the most is how we prioritize and individualize secondary-prevention therapies based on risk for ischemia and heart failure. Some therapies [the SGLT2 inhibitors] are predominantly for heart failure prevention, and some [the GLP-1 RAs] are primarily for ischemia. How do we choose when a patient cannot afford to take both? Does a combination of a SGLT2 inhibitor and a GLP-1 RA offer the greatest CVD benefit? We need to test this in a trial. And will metformin be displaced as first-line treatment?” Dr. Verma asked.
“The day will probably come when, for maximal protection, you treat with both classes. But right now we’re forced to choose because of the cost,” said John McMurray, MD, professor of cardiology at the University of Glasgow, in a talk during the meeting.
As to specifically which SGLT2 inhibitor to prescribe, “they all look pretty much the same” in the newly published meta-analysis, Dr. McMurray said, although he noted that safety differences among agents in the class remain possible.
“For patients similar to those studied in the three SGLT2 inhibitor trials, clinicians should use one of these drugs to reduce the risk for incident heart failure, irrespective of their effect on MACE,” said Dr. Butler. Reducing the risk for incident heart failure and of progressive renal dysfunction are two new goals for antihyperglycemic therapy that now overlay the long-standing goals of controlling glycemia and reducing cardiovascular disease risk and the more recent goals of cutting cardiovascular disease mortality and cutting the risk for a MACE event.
A current limitation for practice is that the none of the three drug companies that market the tested SGLT2 inhibitor drugs has sought regulatory approval for an indication of reducing the risk for heart failure hospitalization. Despite that, “these drugs should be used for renal protection and reducing heart failure hospitalizations,” Dr. Butler said. “We need to start thinking about this and not get lost thinking about only their MACE effect because, when you focus on MACE, there is a competition between the SGLT2 inhibitors and the GLP-1 RA. If we think of GLP-1 RAs as drugs to prevent MACE, and SGLT2 inhibitors as drugs that primarily prevent heart failure and renal dysfunction, then there is no competition. Perhaps combined treatment is where we need to go,” he said in an interview.
But the enthusiasm that experts like Dr. Butler, Dr. McMurray, and Dr. Verma have for wider use of both classes of drugs in appropriate patients is not necessarily matched right now among many community physicians. Cardiologist David J. Becker, MD, is an example of the clinicians who appreciate the growing evidence that supports wider use of these antihyperglycemic drugs but remain uneasy about applying this evidence in their practice.
Dr. Becker, associate director of the Preventive and Integrative Heart Health Program of the Temple Heart and Vascular Institute in Philadelphia, writes a column for the Philadelphia Inquirer on medical care. In a December 2018 piece, he said “like most cardiologists, I ‘don’t do diabetes’ – because it’s not my expertise. The new drugs, however, mean I need to learn more” about treating these patients. “The problem: There are so many of these medications that they present a bewildering choice for patients and doctors.”
Dr. Becker cited several barriers he sees for himself and his nonendocrinologist colleagues to prescribe these drugs – and for patients to take them:
- High cost, with prices that run close to $20/day for each medication.
- A thicket of names and choices that “lead to confusion and paralysis,” which has been exacerbated by “advertising wars” among competing drug companies.
- Cardiologists and primary care physicians usually defer to endocrinologists to prescribe these drugs, but most patients with T2DM aren’t seen by endocrinologists. The result: “Few doctors prescribe them.”
The cardiovascular disease benefits of these drugs have not been adequately promoted. Until that changes, “cardiologists like me will not realize their importance,” Dr. Becker concluded.
While christening the new diabetocardiology subspecialty, Dr. Braunwald placed the onus for managing this emerging facet of diabetes largely outside the scope of endocrinology.
“We can’t call in a consultant every time we have a patient with diabetes; it would bankrupt the system,” he said. Training of cardiologists now needs to include several months of treating patients with diabetes, Dr. Braunwald advised, just like 30 or so years ago when cardiologists like himself had to become more familiar with blood clotting to better manage thrombotic disease.
Dr. Braunwald has been a consultant to Cardurion, Myokardia, and Sanofi; an advisor to Endcardia; and has received research funding from AstraZeneca, Daiishi Sankyo, and Novartis. Dr. Butler has been a consultant or advisor to AstraZeneca, Amgen, Bayer, Boehringer Ingelheim, Janssen, Merck, Novartis, Novo Nordisk, and Sanofi. Dr. Verma has received honoraria and research funding from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Merck, Novartis, NovoNordisk, Sanofi, and Valeant. Dr. McMurray has received research funding from 12 companies. Dr. Becker had no disclosures.
CHICAGO – When the first results from a large trial that showed profound and unexpected benefits for preventing heart failure hospitalizations associated with use of the antihyperglycemic sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin came out – a little over 3 years ago – the general reaction from clinicians was some variant of “Could this be real?”
Since then, as results from some five other large, international trials have come out showing both similar benefits from two other drugs in the same SGLT2 inhibitor class, canagliflozin and dapagliflozin, as well as results showing clear cardiovascular disease benefits from three drugs in a second class of antihyperglycemics, the glucagonlike peptide–1 receptor agonists (GLP-1 RAs), the general consensus among cardiologists became: “The cardiovascular and renal benefits are real. How can we now best use these drugs to help patients?”
This change increasingly forces cardiologists, as well as the primary care physicians who often manage patients with type 2 diabetes mellitus, to become more comfortable prescribing these two classes of antihyperglycemic drugs. During a talk at the American Heart Association scientific sessions, Eugene Braunwald, MD, arguably the top thought leader in cardiology, coined a new name for the medical subspecialty that he foresees navigating this overlap between diabetes care and cardiovascular disease prevention: diabetocardiology (although a more euphonic alternative might be cardiodiabetology, while the more comprehensive name could be cardionephrodiabetology).
“I was certainly surprised” by the first report in 2015 from the EMPA-REG OUTCOME trial (N Engl J Med. 2015 Nov 26;373[22]:2117-28), said Dr. Braunwald, who is professor of medicine at Harvard Medical School in Boston. A lot of his colleagues were surprised and said, “It’s just one trial.”
“Now we have three trials,” with the addition of the CANVAS trial for canagliflozin (N Engl J Med. 2017 Aug 17;377[7]:644-57) and the DECLARE-TIMI 58 trial (N Engl J Med. 2018 Nov 10. doi:10.1056/NEJMoa1812389) for dapagliflozin reported at the AHA meeting in November.
“We are in the midst of two pandemics: heart failure and type 2 diabetes. As cardiologists, we have to learn how to deal with this,” said Dr. Braunwald, and the evidence now clearly shows that these drugs can help with that.
As another speaker at the meeting, Javed Butler, MD, a heart failure specialist, observed in a separate talk at the meeting, “Heart failure is one of the most common, if not the most common complication, of patients with diabetes.” This tight link between heart failure and diabetes helps make cardiovascular mortality “the number one cause of death” in patients with diabetes, said Dr. Butler, professor and chairman of medicine at the University of Mississippi in Jackson.
“Thanks to the cardiovascular outcome trials, we now have a much broader and deeper appreciation of heart failure and renal disease as integral components of the cardiovascular-renal spectrum in people with diabetes,” said Subodh Verma, MD, a professor at the University of Toronto and cardiac surgeon at St. Michael’s Hospital in Toronto. Dr. Braunwald spelled out in his talk some of the interrelationships of diabetes, heart failure, and renal dysfunction that together produce a downward-spiraling vicious circle for patients, a pathophysiological process that clinicians can now short-circuit by treatment with a SGLT2 inhibitor.
Cardiovascular outcome trials show the way
In the context of antihyperglycemic drugs, the “cardiovascular outcome trials” refers to a series of large trials mandated by the Food and Drug Administration in 2008 to assess the cardiovascular disease effects of new agents coming onto the U.S. market to treat type 2 diabetes mellitus (T2DM). By the time Dr. Verma spoke at the AHA meeting, he could cite reported results from 12 of these trials: 5 different drugs in the GLP-1 RA class, 4 drugs in the dipeptidyl peptidase-4 (DPP-4) inhibitor class, and 3 drugs from the SGLT2 inhibitor class. Dr. Verma summed what the findings have shown.
The four tested DDP-4 inhibitors (alogliptin, linagliptin, saxagliptin, and sitagliptin) consistently showed neutrality for the primary outcome of major adverse cardiovascular disease events (MACE), constituted by cardiovascular disease death, MI, or stroke.
The five tested GLP-1 RAs (albiglutide, exenatide, liraglutide, lixisenatide, and semaglutide) showed a mixed pattern of MACE results that seemed to be linked with the subclass the drug fell into. The two exedin-4–based drugs, exenatide and lixisenatide, each showed a statistically neutral effect for MACE, as well as collectively in a combined analysis. In contrast, three human GLP-1–based drugs, albiglutide, liraglutide, and semaglutide, each showed a consistent, statistically-significant MACE reduction in their respective outcome trials, and collectively they showed a highly significant 18% reduction in MACE, compared with placebo, Dr. Verma said. Further, recent analysis by Dr. Verma that used data from liraglutide treatment in the LEADER trial showed the MACE benefit occurred only among enrolled patients treated with liraglutide who had established atherosclerotic cardiovascular disease (ASCVD). Patients enrolled in the trial with only multiple risk factors (in addition to having T2DM) but without established ASCVD showed no significant benefit from liraglutide treatment for the MACE endpoint, compared with control patients.
Recently a press-release announcement of results from a sixth GLP-1 RA, dulaglutide, in the REWIND trial of MACE outcomes suggested that a drug in this class could have broader effect. The majority, 69%, of the 9,901 patients with T2DM enrolled in REWIND had risk factors but not established ASCVD at enrollment. A Nov. 5, 2018, statement from the company developing this drug, Lilly, reported that the study overall produced a statistically significant reduction in MACE, although it provided no additional details. As the released noted, this made REWIND the first trial to show a MACE benefit from a drug in the GLP-1 RA class in patients without established ASCVD.
The MACE outcome results from the three SGLT2 inhibitor trials showed a similar pattern as liraglutide: In patients with established ASCVD, the drugs individually each produced a MACE reduction, although dapagliflozin just missed having a statistically significant reduction. Collectively, the three drugs showed a statistically significant, 14% relative risk reduction for MACE, compared with control patients. But among patients with multiple risk factors only, but without established ASCVD, included in two of the three trials (CANVAS and DECLARE-TIMI 58), the results showed both individually and collectively a neutral MACE effect.
But unlike the other antihyperglycemic drugs tested in the cardiovascular outcome trials, the SGLT2 inhibitors have shown two additional, highly important secondary outcomes: a consistent reduction in hospitalization for heart failure and a consistent reduction in renal-disease progression.
A meta-analysis of the three SGLT2 inhibitor trials published coincident with the release of the DECLARE-TIMI 58 results showed that, for the outcome of either cardiovascular death or hospitalization for heart failure, the SGLT2 inhibitors collectively showed a significant 29% relative decrease in this incidence among patients with a history of heart failure, and a significant 21% relative decrease among patients without history of heart failure (Lancet. 2018 Nov 10. doi: 10.1016/S0140-6736(18)32590-X). Among the subset of patients with established ASCVD, treatment with a SGLT2 inhibitor across all three trials showed a significant 16% relative risk reduction, and in the subset with multiple risk factors but no established ASCVD, the two SGLT2 inhibitors collectively produced a 16% relative cut in cardiovascular death or heart failure hospitalization with a P value of .06. Finally, the Lancet meta-analysis showed that, for a combined endpoint that reflected renal worsening, the SGLT2 inhibitors showed a significant relative reduction of about 45% in both the subgroup of patients with established ASCVD and in the subgroup of those with just risk factors.
“This is a big step forward for patients with multiple risk factors and diabetes but without ASCVD, that both renal disease and hospitalization for heart failure are sensitive” to the SGLT2 inhibitors, Dr. Verma noted. “We see renal protection and reduction of heart failure hospitalization across both primary and secondary prevention patients, with no need to distinguish them based on ASCVD.” In contrast, he noted, the MACE benefit from the SGLT2 inhibitors seems limited to patients with ASCVD. The day before making this point in a talk during the meeting, Dr. Verma had published the same message in a commentary (Lancet. 2018 Nov 10. doi: 10.1016/S0140-6736(18)32824-1).
Although the “nomenclature of primary versus secondary prevention is appropriate for atherosclerotic outcomes, it is likely to be inappropriate for a person with type 2 diabetes who is at risk of hospitalization for heart failure and renal disease,” Dr. Verma wrote with his associates in the commentary.
What it means for clinicians
The upshot of all of these cardiovascular outcome trial results that came out over the past 3 years has been a new appreciation of how antihyperglycemic drugs can have cardiovascular and renal benefits that transcend their effects on glycemia. The evidence has put the SGLT2 inhibitors and GLP-1 RAs on track to challenge, and potentially displace, metformin as the top drug to prescribe for patients with T2DM.
Clinicians should realize that they should prescribe SGLT2 inhibitors and selected GLP-1 RAs “as early as metformin in patients with established ASCVD,” said Dr. Verma. “For patients with recalcitrant atherosclerotic disease and a history of MI and ischemia, I’d primarily treat with a GLP-1 RA. In a patient with left ventricular dysfunction or evidence of heart failure, I’d use an SGLT2 inhibitor. But it’s not a fight between these two. You could treat a patients with type 2 diabetes with both classes,” although the practicality of this approach is limited by the high cost of these drugs.
The SGLT2 inhibitors “should now be considered as first-line therapy after metformin in most people with type 2 diabetes, irrespective of whether or not they have established atherosclerotic vascular disease, chronic kidney disease, or heart failure,” he and his associates wrote in their recent commentary.
“What I struggle with the most is how we prioritize and individualize secondary-prevention therapies based on risk for ischemia and heart failure. Some therapies [the SGLT2 inhibitors] are predominantly for heart failure prevention, and some [the GLP-1 RAs] are primarily for ischemia. How do we choose when a patient cannot afford to take both? Does a combination of a SGLT2 inhibitor and a GLP-1 RA offer the greatest CVD benefit? We need to test this in a trial. And will metformin be displaced as first-line treatment?” Dr. Verma asked.
“The day will probably come when, for maximal protection, you treat with both classes. But right now we’re forced to choose because of the cost,” said John McMurray, MD, professor of cardiology at the University of Glasgow, in a talk during the meeting.
As to specifically which SGLT2 inhibitor to prescribe, “they all look pretty much the same” in the newly published meta-analysis, Dr. McMurray said, although he noted that safety differences among agents in the class remain possible.
“For patients similar to those studied in the three SGLT2 inhibitor trials, clinicians should use one of these drugs to reduce the risk for incident heart failure, irrespective of their effect on MACE,” said Dr. Butler. Reducing the risk for incident heart failure and of progressive renal dysfunction are two new goals for antihyperglycemic therapy that now overlay the long-standing goals of controlling glycemia and reducing cardiovascular disease risk and the more recent goals of cutting cardiovascular disease mortality and cutting the risk for a MACE event.
A current limitation for practice is that the none of the three drug companies that market the tested SGLT2 inhibitor drugs has sought regulatory approval for an indication of reducing the risk for heart failure hospitalization. Despite that, “these drugs should be used for renal protection and reducing heart failure hospitalizations,” Dr. Butler said. “We need to start thinking about this and not get lost thinking about only their MACE effect because, when you focus on MACE, there is a competition between the SGLT2 inhibitors and the GLP-1 RA. If we think of GLP-1 RAs as drugs to prevent MACE, and SGLT2 inhibitors as drugs that primarily prevent heart failure and renal dysfunction, then there is no competition. Perhaps combined treatment is where we need to go,” he said in an interview.
But the enthusiasm that experts like Dr. Butler, Dr. McMurray, and Dr. Verma have for wider use of both classes of drugs in appropriate patients is not necessarily matched right now among many community physicians. Cardiologist David J. Becker, MD, is an example of the clinicians who appreciate the growing evidence that supports wider use of these antihyperglycemic drugs but remain uneasy about applying this evidence in their practice.
Dr. Becker, associate director of the Preventive and Integrative Heart Health Program of the Temple Heart and Vascular Institute in Philadelphia, writes a column for the Philadelphia Inquirer on medical care. In a December 2018 piece, he said “like most cardiologists, I ‘don’t do diabetes’ – because it’s not my expertise. The new drugs, however, mean I need to learn more” about treating these patients. “The problem: There are so many of these medications that they present a bewildering choice for patients and doctors.”
Dr. Becker cited several barriers he sees for himself and his nonendocrinologist colleagues to prescribe these drugs – and for patients to take them:
- High cost, with prices that run close to $20/day for each medication.
- A thicket of names and choices that “lead to confusion and paralysis,” which has been exacerbated by “advertising wars” among competing drug companies.
- Cardiologists and primary care physicians usually defer to endocrinologists to prescribe these drugs, but most patients with T2DM aren’t seen by endocrinologists. The result: “Few doctors prescribe them.”
The cardiovascular disease benefits of these drugs have not been adequately promoted. Until that changes, “cardiologists like me will not realize their importance,” Dr. Becker concluded.
While christening the new diabetocardiology subspecialty, Dr. Braunwald placed the onus for managing this emerging facet of diabetes largely outside the scope of endocrinology.
“We can’t call in a consultant every time we have a patient with diabetes; it would bankrupt the system,” he said. Training of cardiologists now needs to include several months of treating patients with diabetes, Dr. Braunwald advised, just like 30 or so years ago when cardiologists like himself had to become more familiar with blood clotting to better manage thrombotic disease.
Dr. Braunwald has been a consultant to Cardurion, Myokardia, and Sanofi; an advisor to Endcardia; and has received research funding from AstraZeneca, Daiishi Sankyo, and Novartis. Dr. Butler has been a consultant or advisor to AstraZeneca, Amgen, Bayer, Boehringer Ingelheim, Janssen, Merck, Novartis, Novo Nordisk, and Sanofi. Dr. Verma has received honoraria and research funding from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Merck, Novartis, NovoNordisk, Sanofi, and Valeant. Dr. McMurray has received research funding from 12 companies. Dr. Becker had no disclosures.
REPORTING FROM THE AHA SCIENTIFIC SESSIONS
Quincy the (diabetic) koala leaves behind more than memories
SAN DIEGO – A miracle of marsupial medicine is no more.
An endocrinologist is no longer checking his blood sugar levels on her smartphone a couple times a day, and zookeepers have stopped responding to glucose alerts by preparing tiny doses of insulin. But Quincy, the recipient of a continuous glucose monitor, has provided valuable insight that may benefit a variety of creatures beyond our furry, eucalyptus-eating cousins.
“Through this experience, I am hopeful that we’ll be able to offer better treatment in the future for any animals that are found to have diabetes,” the endocrinologist, Athena Philis-Tsimikas, MD, of Scripps Whittier Diabetes Institute, said in an interview.
And, she added, the experience of working with Quincy “provided an indication of where remote management of diabetes is going for the future, whether this is humans or animals.”
Quincy, a Queensland koala, reportedly died at the San Diego Zoo on Dec. 13 of pneumonia at the age of about 3 years. (Koalas can live into their teens.)
It’s not clear if his death was related to his diabetes. Dr. Philis-Tsimikas said. “Although infection can worsen with poor glucose control, my understanding from the veterinarian was that his diabetes had stabilized and was being successfully treated with a small dose of daily basal insulin,” she said. “He was not having wide fluctuations in glucose control, and the CGM had been removed to make it easier for him to get around his enclosures.”
Nine months before his death, Quincy was diagnosed with type 1 diabetes and transferred from the Los Angeles Zoo for medical reasons. Last June, after veterinarians consulted with Dr. Philis-Tsimikas, Quincy underwent an operation to fit him with a CGM so zookeepers could avoid having to wake him multiple times a day for skin pricks.
Koalas are among many species that can develop the equivalent of human diabetes. Dogs, cats, pigs, apes, horses, and even dolphins can become diabetic.
“The providers and caretakers could all respond with appropriate interventions based on the real-time readings. Improved treatment decisions were made despite not having any verbal communication,” Dr. Philis-Tsimikas said.
“I found it amazing that the CGM device could be placed on such a small body with very little subcutaneous fat,” she said. “It stayed in place and functioned successfully despite movement of the koala around his enclosure.”
In light of his small body and lack of body fat, could Quincy’s experience offer insight into the use of CGM technology in fragile humans such as babies and the elderly? Absolutely, Dr. Philis-Tsimikas said, noting that babies have been diagnosed with diabetes at as young as 9 months.
She said Quincy’s story, which got extensive media attention, provided another benefit. “His story was very relatable to many people with newly diagnosed type 1 diabetes and how difficult it can be to manage the highs and lows,” she said. “Quincy helped show us how this could be addressed with the new technology of a CGM and new types of basal insulin and pens that deliver half units.”
Dr. Philis-Tsimikas reports that her center conducts research with Dexcom and Novo Nordisk.
SAN DIEGO – A miracle of marsupial medicine is no more.
An endocrinologist is no longer checking his blood sugar levels on her smartphone a couple times a day, and zookeepers have stopped responding to glucose alerts by preparing tiny doses of insulin. But Quincy, the recipient of a continuous glucose monitor, has provided valuable insight that may benefit a variety of creatures beyond our furry, eucalyptus-eating cousins.
“Through this experience, I am hopeful that we’ll be able to offer better treatment in the future for any animals that are found to have diabetes,” the endocrinologist, Athena Philis-Tsimikas, MD, of Scripps Whittier Diabetes Institute, said in an interview.
And, she added, the experience of working with Quincy “provided an indication of where remote management of diabetes is going for the future, whether this is humans or animals.”
Quincy, a Queensland koala, reportedly died at the San Diego Zoo on Dec. 13 of pneumonia at the age of about 3 years. (Koalas can live into their teens.)
It’s not clear if his death was related to his diabetes. Dr. Philis-Tsimikas said. “Although infection can worsen with poor glucose control, my understanding from the veterinarian was that his diabetes had stabilized and was being successfully treated with a small dose of daily basal insulin,” she said. “He was not having wide fluctuations in glucose control, and the CGM had been removed to make it easier for him to get around his enclosures.”
Nine months before his death, Quincy was diagnosed with type 1 diabetes and transferred from the Los Angeles Zoo for medical reasons. Last June, after veterinarians consulted with Dr. Philis-Tsimikas, Quincy underwent an operation to fit him with a CGM so zookeepers could avoid having to wake him multiple times a day for skin pricks.
Koalas are among many species that can develop the equivalent of human diabetes. Dogs, cats, pigs, apes, horses, and even dolphins can become diabetic.
“The providers and caretakers could all respond with appropriate interventions based on the real-time readings. Improved treatment decisions were made despite not having any verbal communication,” Dr. Philis-Tsimikas said.
“I found it amazing that the CGM device could be placed on such a small body with very little subcutaneous fat,” she said. “It stayed in place and functioned successfully despite movement of the koala around his enclosure.”
In light of his small body and lack of body fat, could Quincy’s experience offer insight into the use of CGM technology in fragile humans such as babies and the elderly? Absolutely, Dr. Philis-Tsimikas said, noting that babies have been diagnosed with diabetes at as young as 9 months.
She said Quincy’s story, which got extensive media attention, provided another benefit. “His story was very relatable to many people with newly diagnosed type 1 diabetes and how difficult it can be to manage the highs and lows,” she said. “Quincy helped show us how this could be addressed with the new technology of a CGM and new types of basal insulin and pens that deliver half units.”
Dr. Philis-Tsimikas reports that her center conducts research with Dexcom and Novo Nordisk.
SAN DIEGO – A miracle of marsupial medicine is no more.
An endocrinologist is no longer checking his blood sugar levels on her smartphone a couple times a day, and zookeepers have stopped responding to glucose alerts by preparing tiny doses of insulin. But Quincy, the recipient of a continuous glucose monitor, has provided valuable insight that may benefit a variety of creatures beyond our furry, eucalyptus-eating cousins.
“Through this experience, I am hopeful that we’ll be able to offer better treatment in the future for any animals that are found to have diabetes,” the endocrinologist, Athena Philis-Tsimikas, MD, of Scripps Whittier Diabetes Institute, said in an interview.
And, she added, the experience of working with Quincy “provided an indication of where remote management of diabetes is going for the future, whether this is humans or animals.”
Quincy, a Queensland koala, reportedly died at the San Diego Zoo on Dec. 13 of pneumonia at the age of about 3 years. (Koalas can live into their teens.)
It’s not clear if his death was related to his diabetes. Dr. Philis-Tsimikas said. “Although infection can worsen with poor glucose control, my understanding from the veterinarian was that his diabetes had stabilized and was being successfully treated with a small dose of daily basal insulin,” she said. “He was not having wide fluctuations in glucose control, and the CGM had been removed to make it easier for him to get around his enclosures.”
Nine months before his death, Quincy was diagnosed with type 1 diabetes and transferred from the Los Angeles Zoo for medical reasons. Last June, after veterinarians consulted with Dr. Philis-Tsimikas, Quincy underwent an operation to fit him with a CGM so zookeepers could avoid having to wake him multiple times a day for skin pricks.
Koalas are among many species that can develop the equivalent of human diabetes. Dogs, cats, pigs, apes, horses, and even dolphins can become diabetic.
“The providers and caretakers could all respond with appropriate interventions based on the real-time readings. Improved treatment decisions were made despite not having any verbal communication,” Dr. Philis-Tsimikas said.
“I found it amazing that the CGM device could be placed on such a small body with very little subcutaneous fat,” she said. “It stayed in place and functioned successfully despite movement of the koala around his enclosure.”
In light of his small body and lack of body fat, could Quincy’s experience offer insight into the use of CGM technology in fragile humans such as babies and the elderly? Absolutely, Dr. Philis-Tsimikas said, noting that babies have been diagnosed with diabetes at as young as 9 months.
She said Quincy’s story, which got extensive media attention, provided another benefit. “His story was very relatable to many people with newly diagnosed type 1 diabetes and how difficult it can be to manage the highs and lows,” she said. “Quincy helped show us how this could be addressed with the new technology of a CGM and new types of basal insulin and pens that deliver half units.”
Dr. Philis-Tsimikas reports that her center conducts research with Dexcom and Novo Nordisk.
REPORTING FROM THE DIABETIC KOALA BEAT
Cerebral small vessel and cognitive impairment
Also today, antidepressants are tied to greater hip fracture incidence, a hospital readmission reduction program may be doing more harm than good, and the flu season rages on with 19 states showing high activity in the final week of 2018.
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Also today, antidepressants are tied to greater hip fracture incidence, a hospital readmission reduction program may be doing more harm than good, and the flu season rages on with 19 states showing high activity in the final week of 2018.
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Also today, antidepressants are tied to greater hip fracture incidence, a hospital readmission reduction program may be doing more harm than good, and the flu season rages on with 19 states showing high activity in the final week of 2018.
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Expert calls for better ways to preserve beta cell function in youth
LOS ANGELES –
At the same time, the SEARCH for Diabetes in Youth trial showed that the incidence of T2DM in U.S. youth continues to rise, especially among Native Americans and non-Hispanic blacks (P less than .001 for both associations; N Engl J Med. 2017;376:1419-29). In addition, the earlier Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study showed that rapid treatment failure in youth-onset T2DM was associated with loss of beta cell function (N Engl J Med. 2012;366:2247-56).
“Early treatment of youth with impaired glucose tolerance or type 2 diabetes may require other medications alone or in combination or for longer periods of time to combat the severe insulin resistance of puberty and arrest progressive loss of beta cell function,” Sonia Caprio, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease.
She based her remarks on a review of the recently completed multicenter Restoring Insulin Secretion (RISE) Pediatric Medication Study, (Diabetes Care 2018;41[8]:1717-25). It set out to answer the following question: In adolescents with impaired glucose tolerance or recently diagnosed T2DM, can beta cell function be preserved or improved during 12 months of active treatment and maintained for 3 months following the withdrawal of therapy?
To find out, Dr. Caprio, a pediatric endocrinologist at Yale University, New Haven, Conn., and her colleagues enrolled 91 youth who were randomized to one of two treatment arms: metformin alone titrated over 4 weeks from 500 mg/day to a 1,000 mg twice daily dose (modified if necessary due to GI symptoms), or to glargine followed by metformin. This group received once-daily insulin glargine, titrated twice weekly over 1 month based on daily self-monitoring of blood glucose to a goal of 80-90 mg/dL. Glargine was discontinued after 3 months and metformin was titrated. Beta-cell function (insulin sensitivity paired with beta-cell responses) was assessed by the two-step hyperglycemic clamp at baseline, 12 months (on treatment), and 15 months (3 months off treatment). All clinical data were collected 3 months after discontinuation of active treatment.
Dr. Caprio described the two-step hyperglycemic clamp as “a robust approach to quantification of insulin sensitivity and beta-cell responses to both glucose and the nonglucose secretagogue arginine. It provides mechanistic insights into how the tested interventions affected two key metabolic defects of type 2 diabetes: insulin sensitivity and beta cell responses.”
The mean age of patients was 14 years, 71% were female, their mean body mass index was 37 kg/m2. The researchers observed no significant differences between treatment groups at baseline, 12 months, or 15 months in beta cell function, BMI percentile, hemoglobin A1c, fasting glucose, or oral glucose tolerance test 2-hour glucose results. In both treatment groups, clamp-measured beta cell function was significantly lower at 12 and 15 months, compared with baseline. HbA1c fell transiently at 6 months within both groups. BMI was higher in the glargine followed by metformin versus metformin alone group between 3 and 9 months. Only 5% of participants discontinued the interventions, and both treatments were well tolerated.
“These findings are discouraging,” Dr. Caprio said. “They contrast with previous studies in adults showing an improvement in beta cell function with metformin or insulin for type 2 diabetes prevention and treatment.” Results of the RISE Pediatric Medication Study “call for further studies to better understand the physiology underlying beta cell dysfunction in youth to identify effective treatment options. Better approaches to prevent and treat obesity in youth are critically needed.”
Dr. Caprio reported having no disclosures.
LOS ANGELES –
At the same time, the SEARCH for Diabetes in Youth trial showed that the incidence of T2DM in U.S. youth continues to rise, especially among Native Americans and non-Hispanic blacks (P less than .001 for both associations; N Engl J Med. 2017;376:1419-29). In addition, the earlier Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study showed that rapid treatment failure in youth-onset T2DM was associated with loss of beta cell function (N Engl J Med. 2012;366:2247-56).
“Early treatment of youth with impaired glucose tolerance or type 2 diabetes may require other medications alone or in combination or for longer periods of time to combat the severe insulin resistance of puberty and arrest progressive loss of beta cell function,” Sonia Caprio, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease.
She based her remarks on a review of the recently completed multicenter Restoring Insulin Secretion (RISE) Pediatric Medication Study, (Diabetes Care 2018;41[8]:1717-25). It set out to answer the following question: In adolescents with impaired glucose tolerance or recently diagnosed T2DM, can beta cell function be preserved or improved during 12 months of active treatment and maintained for 3 months following the withdrawal of therapy?
To find out, Dr. Caprio, a pediatric endocrinologist at Yale University, New Haven, Conn., and her colleagues enrolled 91 youth who were randomized to one of two treatment arms: metformin alone titrated over 4 weeks from 500 mg/day to a 1,000 mg twice daily dose (modified if necessary due to GI symptoms), or to glargine followed by metformin. This group received once-daily insulin glargine, titrated twice weekly over 1 month based on daily self-monitoring of blood glucose to a goal of 80-90 mg/dL. Glargine was discontinued after 3 months and metformin was titrated. Beta-cell function (insulin sensitivity paired with beta-cell responses) was assessed by the two-step hyperglycemic clamp at baseline, 12 months (on treatment), and 15 months (3 months off treatment). All clinical data were collected 3 months after discontinuation of active treatment.
Dr. Caprio described the two-step hyperglycemic clamp as “a robust approach to quantification of insulin sensitivity and beta-cell responses to both glucose and the nonglucose secretagogue arginine. It provides mechanistic insights into how the tested interventions affected two key metabolic defects of type 2 diabetes: insulin sensitivity and beta cell responses.”
The mean age of patients was 14 years, 71% were female, their mean body mass index was 37 kg/m2. The researchers observed no significant differences between treatment groups at baseline, 12 months, or 15 months in beta cell function, BMI percentile, hemoglobin A1c, fasting glucose, or oral glucose tolerance test 2-hour glucose results. In both treatment groups, clamp-measured beta cell function was significantly lower at 12 and 15 months, compared with baseline. HbA1c fell transiently at 6 months within both groups. BMI was higher in the glargine followed by metformin versus metformin alone group between 3 and 9 months. Only 5% of participants discontinued the interventions, and both treatments were well tolerated.
“These findings are discouraging,” Dr. Caprio said. “They contrast with previous studies in adults showing an improvement in beta cell function with metformin or insulin for type 2 diabetes prevention and treatment.” Results of the RISE Pediatric Medication Study “call for further studies to better understand the physiology underlying beta cell dysfunction in youth to identify effective treatment options. Better approaches to prevent and treat obesity in youth are critically needed.”
Dr. Caprio reported having no disclosures.
LOS ANGELES –
At the same time, the SEARCH for Diabetes in Youth trial showed that the incidence of T2DM in U.S. youth continues to rise, especially among Native Americans and non-Hispanic blacks (P less than .001 for both associations; N Engl J Med. 2017;376:1419-29). In addition, the earlier Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study showed that rapid treatment failure in youth-onset T2DM was associated with loss of beta cell function (N Engl J Med. 2012;366:2247-56).
“Early treatment of youth with impaired glucose tolerance or type 2 diabetes may require other medications alone or in combination or for longer periods of time to combat the severe insulin resistance of puberty and arrest progressive loss of beta cell function,” Sonia Caprio, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease.
She based her remarks on a review of the recently completed multicenter Restoring Insulin Secretion (RISE) Pediatric Medication Study, (Diabetes Care 2018;41[8]:1717-25). It set out to answer the following question: In adolescents with impaired glucose tolerance or recently diagnosed T2DM, can beta cell function be preserved or improved during 12 months of active treatment and maintained for 3 months following the withdrawal of therapy?
To find out, Dr. Caprio, a pediatric endocrinologist at Yale University, New Haven, Conn., and her colleagues enrolled 91 youth who were randomized to one of two treatment arms: metformin alone titrated over 4 weeks from 500 mg/day to a 1,000 mg twice daily dose (modified if necessary due to GI symptoms), or to glargine followed by metformin. This group received once-daily insulin glargine, titrated twice weekly over 1 month based on daily self-monitoring of blood glucose to a goal of 80-90 mg/dL. Glargine was discontinued after 3 months and metformin was titrated. Beta-cell function (insulin sensitivity paired with beta-cell responses) was assessed by the two-step hyperglycemic clamp at baseline, 12 months (on treatment), and 15 months (3 months off treatment). All clinical data were collected 3 months after discontinuation of active treatment.
Dr. Caprio described the two-step hyperglycemic clamp as “a robust approach to quantification of insulin sensitivity and beta-cell responses to both glucose and the nonglucose secretagogue arginine. It provides mechanistic insights into how the tested interventions affected two key metabolic defects of type 2 diabetes: insulin sensitivity and beta cell responses.”
The mean age of patients was 14 years, 71% were female, their mean body mass index was 37 kg/m2. The researchers observed no significant differences between treatment groups at baseline, 12 months, or 15 months in beta cell function, BMI percentile, hemoglobin A1c, fasting glucose, or oral glucose tolerance test 2-hour glucose results. In both treatment groups, clamp-measured beta cell function was significantly lower at 12 and 15 months, compared with baseline. HbA1c fell transiently at 6 months within both groups. BMI was higher in the glargine followed by metformin versus metformin alone group between 3 and 9 months. Only 5% of participants discontinued the interventions, and both treatments were well tolerated.
“These findings are discouraging,” Dr. Caprio said. “They contrast with previous studies in adults showing an improvement in beta cell function with metformin or insulin for type 2 diabetes prevention and treatment.” Results of the RISE Pediatric Medication Study “call for further studies to better understand the physiology underlying beta cell dysfunction in youth to identify effective treatment options. Better approaches to prevent and treat obesity in youth are critically needed.”
Dr. Caprio reported having no disclosures.
EXPERT ANALYSIS FROM WCIRDC 2018
Should metformin be used in every patient with type 2 diabetes?
Most patients should receive it, with exceptions as noted below. Metformin is the cornerstone of diabetes therapy and should be considered in all patients with type 2 diabetes. Both the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists (AACE)1,2 recommend it as first-line treatment for type 2 diabetes. It lowers blood glucose levels by inhibiting hepatic glucose production, and it does not tend to cause hypoglycemia.
However, metformin is underused. A 2012 study showed that only 50% to 70% of patients with type 2 diabetes treated with a sulfonylurea, dipeptidyl peptidase-4 (DPP-4) inhibitor, thiazolidinedione, or glucagon-like peptide-1 analogue also received metformin.3 This occurred despite guidelines recommending continuing metformin when starting other diabetes drugs.4
EVIDENCE METFORMIN IS EFFECTIVE
The United Kingdom Prospective Diabetes Study (UKPDS)5 found that metformin significantly reduced the incidence of:
- Any diabetes-related end point (hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.53–0.87)
- Myocardial infarction (HR 0.61, 95% CI 0.41–0.89)
- Diabetes-related death (HR 0.58, 95% CI 0.37–0.91)
- All-cause mortality (HR 0.64; 95% CI 0.45–0.91).
The Hyperinsulinemia: Outcomes of Its Metabolic Effects (HOME) trial,6 a multicenter trial conducted in the Netherlands, evaluated the effect of adding metformin (vs placebo) to existing insulin regimens. Metformin recipients had a significantly lower rate of macrovascular mortality (HR 0.61, 95% CI 0.40–0.94, P = .02), but not of the primary end point, an aggregate of microvascular and macrovascular morbidity and mortality.
The Study on the Prognosis and Effect of Antidiabetic Drugs on Type 2 Diabetes Mellitus With Coronary Artery Disease trial,7 a multicenter trial conducted in China, compared the effects of metformin vs glipizide on cardiovascular outcomes. At about 3 years of treatment, the metformin group had a significantly lower rate of the composite primary end point of recurrent cardiovascular events (HR 0.54, 95% CI 0.30–0.90). This end point included nonfatal myocardial infarction, nonfatal stroke, arterial revascularization by percutaneous transluminal coronary angioplasty or by coronary artery bypass graft, death from a cardiovascular cause, and death from any cause.
These studies prompted the ADA to emphasize that metformin can reduce the risk of cardiovascular events or death. Metformin also has been shown to be weight-neutral or to induce slight weight loss. Furthermore, it is inexpensive.
WHAT ABOUT THE RENAL EFFECTS?
Because metformin is renally cleared, it has caused some concern about nephrotoxicity, especially lactic acidosis, in patients with impaired renal function. But the most recent guidelines have relaxed the criteria for metformin use in this patient population.
Revised labeling
Metformin’s labeling,8 revised in 2016, states the following:
- If the estimated glomerular filtration rate (eGFR) is below 30 mL/min/1.73 m2, metformin is contraindicated
- If the eGFR is between 30 and 45 mL/min/1.73 m2, metformin is not recommended
- If the eGFR is below 45 mL/min/1.73 m2 in a patient taking metformin, the risks and benefits of continuing treatment should be assessed, the dosage may need to be adjusted, and renal function should be monitored more frequently.8
These labeling revisions were based on a systematic review by Inzucchi et al9 that found metformin is not associated with increased rates of lactic acidosis in patients with mild to moderate kidney disease. Subsequently, an observational study published in 2018 by Lazarus et al10 showed that metformin increases the risk of acidosis only at eGFR levels below 30 mL/min/1.73 m2. Also, a Cochrane review published in 2003 did not find a single case of lactic acidosis in 347 trials with 70,490 patient-years of metformin treatment.11
Previous guidelines used serum creatinine levels, with metformin contraindicated at levels of 1.5 mg/dL or above for men and 1.4 mg/dL for women, or with abnormal creatinine clearance. The ADA and the AACE now use the eGFR1,2 instead of the serum creatinine level to measure kidney function because it better accounts for factors such as the patient’s age, sex, race, and weight.
Despite the evidence, the common patient perception is that metformin is nephrotoxic, and it is important for practitioners to dispel this myth during clinic visits.
What about metformin use with contrast agents?
Labeling has a precautionary note stating that metformin should be held at the time of, or prior to, any imaging procedure involving iodinated contrast agents in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will receive intra-arterial iodinated contrast. The eGFR should be reevaluated 48 hours after the imaging procedure.8
Additionally, if the iodinated contrast agent causes acute kidney injury, metformin could accumulate, with resultant lactate accumulation.
The American College of Radiology (ACR) has proposed less stringent guidelines for metformin during radiocontrast imaging studies. This change is based on evidence that lactic acidosis is rare—about 10 cases per 100,000 patient-years—and that there are no reports of lactic acidosis after intravenously administered iodinated contrast in properly selected patients.12,13
The ACR divides patients taking metformin into 2 categories:
- No evidence of acute kidney injury and eGFR greater than 30 mL/min/1.73 m2
- Either acute kidney injury or chronic kidney disease with eGFR below 30 mL/min/1.73 m2 or undergoing arterial catheter studies with a high chance of embolization to the renal arteries.14
For the first group, they recommend against discontinuing metformin before or after giving iodinated contrast or checking kidney function after the procedure.
For the second group, they recommend holding metformin before and 48 hours after the procedure. It should not be restarted until renal function is confirmed to be normal.
METFORMIN AND INSULIN
The ADA recommends1 continuing metformin after initiating insulin. However, in clinical practice, it is often not done.
Clinical trials have shown that combining metformin with insulin significantly improves glycemic control, prevents weight gain, and decreases insulin requirements.15,16 One trial16 also looked at cardiovascular end points during a 4-year follow-up period; combining metformin with insulin decreased the macrovascular disease-related event rate compared with insulin alone.
In the HOME trial,6 which added metformin to the existing insulin regimen, both groups gained weight, but the metformin group had gained about 3 kg less than the placebo group at the end of the 4.3-year trial. Metformin did not increase the risk of hypoglycemia, but it also did not reduce the risk of microvascular disease.
Concomitant metformin reduces costs
These days, practitioners can choose from a large selection of diabetes drugs. These include insulins with better pharmacokinetic profiles, as well as newer classes of noninsulin agents such as sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 analogues.
Metformin is less expensive than these newer drugs, and using it concomitantly with other diabetes drugs can decrease their dosage requirements, which in turn decreases their monthly costs.
GASTROINTESTINAL EFFECTS
Metformin’s gastrointestinal adverse effects such as diarrhea, flatulence, nausea, and vomiting are a barrier to its use. The actual incidence rate of diarrhea varies widely in randomized trials and observational studies, and gastrointestinal effects are worse in metformin-naive patients, as well as those who have chronic gastritis or Helicobacter pylori infection.17
We have found that starting metformin at a low dose and up-titrating it over several weeks increases tolerability. We often start patients at 500 mg/day and increase the dosage by 1 500-mg tablet every 1 to 2 weeks. Also, we have noticed that intolerance is more likely in patients who eat a high-carbohydrate diet, but there is no high-level evidence to back this up because patients in clinical trials all undergo nutrition counseling and are therefore more likely to adhere to the low-carbohydrate diet.
Also, the extended-release formulation is more tolerable than the immediate-release formulation and has similar glycemic efficacy. It may be an option as first-line therapy or for patients who have significant adverse effects from immediate-release metformin.18 For patients on the immediate-release formulation, taking it with meals helps lessen some gastrointestinal effects, and this should be emphasized at every visit.
Finally, we limit the metformin dose to 2,000 mg/day, rather than the 2,550 mg/day allowed on labeling. Garber et al19 found that the lower dosage still provides the maximum clinical efficacy.
OTHER CAUTIONS
Metformin should be avoided in patients with acute or unstable heart failure because of the increased risk of lactic acidosis.
It also should be avoided in patients with hepatic impairment, according to the labeling. But this remains controversial in practice. Zhang et al20 showed that continuing metformin in patients with diabetes and cirrhosis decreases the mortality risk by 57% compared with those taken off metformin.
Diet and lifestyle measures need to be emphasized at each visit. Wing et al21 showed that calorie restriction regardless of weight loss is beneficial for glycemic control and insulin sensitivity in obese patients with diabetes.
TAKE-HOME POINTS
Metformin improves glycemic control without tending to cause weight gain or hypoglycemia. It may also have cardiovascular benefits. Metformin is an inexpensive agent that should be continued, if tolerated, in those who need additional agents for glycemic control. It should be considered in all adult patients with type 2 diabetes.
- American Diabetes Association. 8. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2018. Diabetes Care 2018; 41(suppl 1):S73–S85. doi:10.2337/dc18-S008
- Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm—2018 executive summary. Endocr Pract 2018; 24(1):91–120. doi:10.4158/CS-2017-0153
- Hampp C, Borders-Hemphill V, Moeny DG, Wysowski DK. Use of antidiabetic drugs in the US, 2003–2012. Diabetes Care 2014; 37(5):1367–1374. doi:10.2337/dc13-2289
- Inzucchi SE, Bergenstal RM, Buse JB, et al; American Diabetes Association (ADA); European Association for the Study of Diabetes (EASD). Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2012; 35(6):1364–1379. doi:10.2337/dc12-0413
- Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352(9131):854–865. pmid:9742977
- Kooy A, de Jager J, Lehert P, et al. Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch Intern Med 2009; 169(6):616–625. doi:10.1001/archinternmed.2009.20
- Hong J, Zhang Y, Lai S, et al; SPREAD-DIMCAD Investigators. Effects of metformin versus glipizide on cardiovascular outcomes in patients with type 2 diabetes and coronary artery disease. Diabetes Care 2013; 36(5):1304–1311. doi:10.2337/dc12-0719
- Glucophage (metformin hydrochloride) and Glucophage XR (extended-release) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company. www.accessdata.fda.gov/drugsatfda_docs/label/2018/020357s034,021202s018lbl.pdf. Accessed December 5, 2018.
- Inzucchi SE, Lipska KJ, Mayo H, Bailey CJ, McGuire DK. Metformin in patients with type 2 diabetes and kidney disease: a systematic review. JAMA 2014; 312(24):2668–2675. doi:10.1001/jama.2014.15298
- Lazarus B, Wu A, Shin JI, et al. Association of metformin use with risk of lactic acidosis across the range of kidney function: a community-based cohort study. JAMA Intern Med 2018; 178(7):903–910. doi:10.1001/jamainternmed.2018.0292
- Salpeter S, Greyber E, Pasternak G, Salpeter E. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev 2003; (2):CD002967. doi:10.1002/14651858.CD002967
- Eppenga WL, Lalmohamed A, Geerts AF, et al. Risk of lactic acidosis or elevated lactate concentrations in metformin users with renal impairment: a population-based cohort study. Diabetes Care 2014; 37(8):2218–2224. doi:10.2337/dc13-3023
- Richy FF, Sabidó-Espin M, Guedes S, Corvino FA, Gottwald-Hostalek U. Incidence of lactic acidosis in patients with type 2 diabetes with and without renal impairment treated with metformin: a retrospective cohort study. Diabetes Care 2014; 37(8):2291–2295. doi:10.2337/dc14-0464
- American College of Radiology (ACR). Manual on Contrast Media. Version 10.3. www.acr.org/Clinical-Resources/Contrast-Manual. Accessed December 5, 2018.
- Wulffele MG, Kooy A, Lehert P, et al. Combination of insulin and metformin in the treatment of type 2 diabetes. Diabetes Care 2002; 25(12):2133–2140. pmid:12453950
- Kooy A, de Jager J, Lehert P, et al. Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch Intern Med 2009; 169(6):616–625. doi:10.1001/archinternmed.2009.20
- Bonnet F, Scheen A. Understanding and overcoming metformin gastrointestinal intolerance, Diabetes Obes Metab 2017; 19(4):473–481. doi:10.1111/dom.12854
- Jabbour S, Ziring B. Advantages of extended-release metformin in patients with type 2 diabetes mellitus. Postgrad Med 2011; 123(1):15–23. doi:10.3810/pgm.2011.01.2241
- Garber AJ, Duncan TG, Goodman AM, Mills DJ, Rohlf JL. Efficacy of metformin in type II diabetes: results of a double-blind, placebo-controlled, dose-response trial. Am J Med 1997; 103(6):491–497. pmid:9428832
- Zhang X, Harmsen WS, Mettler TA, et al. Continuation of metformin use after a diagnosis of cirrhosis significantly improves survival of patients with diabetes. Hepatology 2014; 60(6):2008–2016. doi:10.1002/hep.27199
- Wing RR, Blair EH, Bononi P, Marcus MD, Watanabe R, Bergman RN. Caloric restriction per se is a significant factor in improvements in glycemic control and insulin sensitivity during weight loss in obese NIDDM patients. Diabetes Care 1994; 17(1):30–36. pmid:8112186
Most patients should receive it, with exceptions as noted below. Metformin is the cornerstone of diabetes therapy and should be considered in all patients with type 2 diabetes. Both the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists (AACE)1,2 recommend it as first-line treatment for type 2 diabetes. It lowers blood glucose levels by inhibiting hepatic glucose production, and it does not tend to cause hypoglycemia.
However, metformin is underused. A 2012 study showed that only 50% to 70% of patients with type 2 diabetes treated with a sulfonylurea, dipeptidyl peptidase-4 (DPP-4) inhibitor, thiazolidinedione, or glucagon-like peptide-1 analogue also received metformin.3 This occurred despite guidelines recommending continuing metformin when starting other diabetes drugs.4
EVIDENCE METFORMIN IS EFFECTIVE
The United Kingdom Prospective Diabetes Study (UKPDS)5 found that metformin significantly reduced the incidence of:
- Any diabetes-related end point (hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.53–0.87)
- Myocardial infarction (HR 0.61, 95% CI 0.41–0.89)
- Diabetes-related death (HR 0.58, 95% CI 0.37–0.91)
- All-cause mortality (HR 0.64; 95% CI 0.45–0.91).
The Hyperinsulinemia: Outcomes of Its Metabolic Effects (HOME) trial,6 a multicenter trial conducted in the Netherlands, evaluated the effect of adding metformin (vs placebo) to existing insulin regimens. Metformin recipients had a significantly lower rate of macrovascular mortality (HR 0.61, 95% CI 0.40–0.94, P = .02), but not of the primary end point, an aggregate of microvascular and macrovascular morbidity and mortality.
The Study on the Prognosis and Effect of Antidiabetic Drugs on Type 2 Diabetes Mellitus With Coronary Artery Disease trial,7 a multicenter trial conducted in China, compared the effects of metformin vs glipizide on cardiovascular outcomes. At about 3 years of treatment, the metformin group had a significantly lower rate of the composite primary end point of recurrent cardiovascular events (HR 0.54, 95% CI 0.30–0.90). This end point included nonfatal myocardial infarction, nonfatal stroke, arterial revascularization by percutaneous transluminal coronary angioplasty or by coronary artery bypass graft, death from a cardiovascular cause, and death from any cause.
These studies prompted the ADA to emphasize that metformin can reduce the risk of cardiovascular events or death. Metformin also has been shown to be weight-neutral or to induce slight weight loss. Furthermore, it is inexpensive.
WHAT ABOUT THE RENAL EFFECTS?
Because metformin is renally cleared, it has caused some concern about nephrotoxicity, especially lactic acidosis, in patients with impaired renal function. But the most recent guidelines have relaxed the criteria for metformin use in this patient population.
Revised labeling
Metformin’s labeling,8 revised in 2016, states the following:
- If the estimated glomerular filtration rate (eGFR) is below 30 mL/min/1.73 m2, metformin is contraindicated
- If the eGFR is between 30 and 45 mL/min/1.73 m2, metformin is not recommended
- If the eGFR is below 45 mL/min/1.73 m2 in a patient taking metformin, the risks and benefits of continuing treatment should be assessed, the dosage may need to be adjusted, and renal function should be monitored more frequently.8
These labeling revisions were based on a systematic review by Inzucchi et al9 that found metformin is not associated with increased rates of lactic acidosis in patients with mild to moderate kidney disease. Subsequently, an observational study published in 2018 by Lazarus et al10 showed that metformin increases the risk of acidosis only at eGFR levels below 30 mL/min/1.73 m2. Also, a Cochrane review published in 2003 did not find a single case of lactic acidosis in 347 trials with 70,490 patient-years of metformin treatment.11
Previous guidelines used serum creatinine levels, with metformin contraindicated at levels of 1.5 mg/dL or above for men and 1.4 mg/dL for women, or with abnormal creatinine clearance. The ADA and the AACE now use the eGFR1,2 instead of the serum creatinine level to measure kidney function because it better accounts for factors such as the patient’s age, sex, race, and weight.
Despite the evidence, the common patient perception is that metformin is nephrotoxic, and it is important for practitioners to dispel this myth during clinic visits.
What about metformin use with contrast agents?
Labeling has a precautionary note stating that metformin should be held at the time of, or prior to, any imaging procedure involving iodinated contrast agents in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will receive intra-arterial iodinated contrast. The eGFR should be reevaluated 48 hours after the imaging procedure.8
Additionally, if the iodinated contrast agent causes acute kidney injury, metformin could accumulate, with resultant lactate accumulation.
The American College of Radiology (ACR) has proposed less stringent guidelines for metformin during radiocontrast imaging studies. This change is based on evidence that lactic acidosis is rare—about 10 cases per 100,000 patient-years—and that there are no reports of lactic acidosis after intravenously administered iodinated contrast in properly selected patients.12,13
The ACR divides patients taking metformin into 2 categories:
- No evidence of acute kidney injury and eGFR greater than 30 mL/min/1.73 m2
- Either acute kidney injury or chronic kidney disease with eGFR below 30 mL/min/1.73 m2 or undergoing arterial catheter studies with a high chance of embolization to the renal arteries.14
For the first group, they recommend against discontinuing metformin before or after giving iodinated contrast or checking kidney function after the procedure.
For the second group, they recommend holding metformin before and 48 hours after the procedure. It should not be restarted until renal function is confirmed to be normal.
METFORMIN AND INSULIN
The ADA recommends1 continuing metformin after initiating insulin. However, in clinical practice, it is often not done.
Clinical trials have shown that combining metformin with insulin significantly improves glycemic control, prevents weight gain, and decreases insulin requirements.15,16 One trial16 also looked at cardiovascular end points during a 4-year follow-up period; combining metformin with insulin decreased the macrovascular disease-related event rate compared with insulin alone.
In the HOME trial,6 which added metformin to the existing insulin regimen, both groups gained weight, but the metformin group had gained about 3 kg less than the placebo group at the end of the 4.3-year trial. Metformin did not increase the risk of hypoglycemia, but it also did not reduce the risk of microvascular disease.
Concomitant metformin reduces costs
These days, practitioners can choose from a large selection of diabetes drugs. These include insulins with better pharmacokinetic profiles, as well as newer classes of noninsulin agents such as sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 analogues.
Metformin is less expensive than these newer drugs, and using it concomitantly with other diabetes drugs can decrease their dosage requirements, which in turn decreases their monthly costs.
GASTROINTESTINAL EFFECTS
Metformin’s gastrointestinal adverse effects such as diarrhea, flatulence, nausea, and vomiting are a barrier to its use. The actual incidence rate of diarrhea varies widely in randomized trials and observational studies, and gastrointestinal effects are worse in metformin-naive patients, as well as those who have chronic gastritis or Helicobacter pylori infection.17
We have found that starting metformin at a low dose and up-titrating it over several weeks increases tolerability. We often start patients at 500 mg/day and increase the dosage by 1 500-mg tablet every 1 to 2 weeks. Also, we have noticed that intolerance is more likely in patients who eat a high-carbohydrate diet, but there is no high-level evidence to back this up because patients in clinical trials all undergo nutrition counseling and are therefore more likely to adhere to the low-carbohydrate diet.
Also, the extended-release formulation is more tolerable than the immediate-release formulation and has similar glycemic efficacy. It may be an option as first-line therapy or for patients who have significant adverse effects from immediate-release metformin.18 For patients on the immediate-release formulation, taking it with meals helps lessen some gastrointestinal effects, and this should be emphasized at every visit.
Finally, we limit the metformin dose to 2,000 mg/day, rather than the 2,550 mg/day allowed on labeling. Garber et al19 found that the lower dosage still provides the maximum clinical efficacy.
OTHER CAUTIONS
Metformin should be avoided in patients with acute or unstable heart failure because of the increased risk of lactic acidosis.
It also should be avoided in patients with hepatic impairment, according to the labeling. But this remains controversial in practice. Zhang et al20 showed that continuing metformin in patients with diabetes and cirrhosis decreases the mortality risk by 57% compared with those taken off metformin.
Diet and lifestyle measures need to be emphasized at each visit. Wing et al21 showed that calorie restriction regardless of weight loss is beneficial for glycemic control and insulin sensitivity in obese patients with diabetes.
TAKE-HOME POINTS
Metformin improves glycemic control without tending to cause weight gain or hypoglycemia. It may also have cardiovascular benefits. Metformin is an inexpensive agent that should be continued, if tolerated, in those who need additional agents for glycemic control. It should be considered in all adult patients with type 2 diabetes.
Most patients should receive it, with exceptions as noted below. Metformin is the cornerstone of diabetes therapy and should be considered in all patients with type 2 diabetes. Both the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists (AACE)1,2 recommend it as first-line treatment for type 2 diabetes. It lowers blood glucose levels by inhibiting hepatic glucose production, and it does not tend to cause hypoglycemia.
However, metformin is underused. A 2012 study showed that only 50% to 70% of patients with type 2 diabetes treated with a sulfonylurea, dipeptidyl peptidase-4 (DPP-4) inhibitor, thiazolidinedione, or glucagon-like peptide-1 analogue also received metformin.3 This occurred despite guidelines recommending continuing metformin when starting other diabetes drugs.4
EVIDENCE METFORMIN IS EFFECTIVE
The United Kingdom Prospective Diabetes Study (UKPDS)5 found that metformin significantly reduced the incidence of:
- Any diabetes-related end point (hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.53–0.87)
- Myocardial infarction (HR 0.61, 95% CI 0.41–0.89)
- Diabetes-related death (HR 0.58, 95% CI 0.37–0.91)
- All-cause mortality (HR 0.64; 95% CI 0.45–0.91).
The Hyperinsulinemia: Outcomes of Its Metabolic Effects (HOME) trial,6 a multicenter trial conducted in the Netherlands, evaluated the effect of adding metformin (vs placebo) to existing insulin regimens. Metformin recipients had a significantly lower rate of macrovascular mortality (HR 0.61, 95% CI 0.40–0.94, P = .02), but not of the primary end point, an aggregate of microvascular and macrovascular morbidity and mortality.
The Study on the Prognosis and Effect of Antidiabetic Drugs on Type 2 Diabetes Mellitus With Coronary Artery Disease trial,7 a multicenter trial conducted in China, compared the effects of metformin vs glipizide on cardiovascular outcomes. At about 3 years of treatment, the metformin group had a significantly lower rate of the composite primary end point of recurrent cardiovascular events (HR 0.54, 95% CI 0.30–0.90). This end point included nonfatal myocardial infarction, nonfatal stroke, arterial revascularization by percutaneous transluminal coronary angioplasty or by coronary artery bypass graft, death from a cardiovascular cause, and death from any cause.
These studies prompted the ADA to emphasize that metformin can reduce the risk of cardiovascular events or death. Metformin also has been shown to be weight-neutral or to induce slight weight loss. Furthermore, it is inexpensive.
WHAT ABOUT THE RENAL EFFECTS?
Because metformin is renally cleared, it has caused some concern about nephrotoxicity, especially lactic acidosis, in patients with impaired renal function. But the most recent guidelines have relaxed the criteria for metformin use in this patient population.
Revised labeling
Metformin’s labeling,8 revised in 2016, states the following:
- If the estimated glomerular filtration rate (eGFR) is below 30 mL/min/1.73 m2, metformin is contraindicated
- If the eGFR is between 30 and 45 mL/min/1.73 m2, metformin is not recommended
- If the eGFR is below 45 mL/min/1.73 m2 in a patient taking metformin, the risks and benefits of continuing treatment should be assessed, the dosage may need to be adjusted, and renal function should be monitored more frequently.8
These labeling revisions were based on a systematic review by Inzucchi et al9 that found metformin is not associated with increased rates of lactic acidosis in patients with mild to moderate kidney disease. Subsequently, an observational study published in 2018 by Lazarus et al10 showed that metformin increases the risk of acidosis only at eGFR levels below 30 mL/min/1.73 m2. Also, a Cochrane review published in 2003 did not find a single case of lactic acidosis in 347 trials with 70,490 patient-years of metformin treatment.11
Previous guidelines used serum creatinine levels, with metformin contraindicated at levels of 1.5 mg/dL or above for men and 1.4 mg/dL for women, or with abnormal creatinine clearance. The ADA and the AACE now use the eGFR1,2 instead of the serum creatinine level to measure kidney function because it better accounts for factors such as the patient’s age, sex, race, and weight.
Despite the evidence, the common patient perception is that metformin is nephrotoxic, and it is important for practitioners to dispel this myth during clinic visits.
What about metformin use with contrast agents?
Labeling has a precautionary note stating that metformin should be held at the time of, or prior to, any imaging procedure involving iodinated contrast agents in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will receive intra-arterial iodinated contrast. The eGFR should be reevaluated 48 hours after the imaging procedure.8
Additionally, if the iodinated contrast agent causes acute kidney injury, metformin could accumulate, with resultant lactate accumulation.
The American College of Radiology (ACR) has proposed less stringent guidelines for metformin during radiocontrast imaging studies. This change is based on evidence that lactic acidosis is rare—about 10 cases per 100,000 patient-years—and that there are no reports of lactic acidosis after intravenously administered iodinated contrast in properly selected patients.12,13
The ACR divides patients taking metformin into 2 categories:
- No evidence of acute kidney injury and eGFR greater than 30 mL/min/1.73 m2
- Either acute kidney injury or chronic kidney disease with eGFR below 30 mL/min/1.73 m2 or undergoing arterial catheter studies with a high chance of embolization to the renal arteries.14
For the first group, they recommend against discontinuing metformin before or after giving iodinated contrast or checking kidney function after the procedure.
For the second group, they recommend holding metformin before and 48 hours after the procedure. It should not be restarted until renal function is confirmed to be normal.
METFORMIN AND INSULIN
The ADA recommends1 continuing metformin after initiating insulin. However, in clinical practice, it is often not done.
Clinical trials have shown that combining metformin with insulin significantly improves glycemic control, prevents weight gain, and decreases insulin requirements.15,16 One trial16 also looked at cardiovascular end points during a 4-year follow-up period; combining metformin with insulin decreased the macrovascular disease-related event rate compared with insulin alone.
In the HOME trial,6 which added metformin to the existing insulin regimen, both groups gained weight, but the metformin group had gained about 3 kg less than the placebo group at the end of the 4.3-year trial. Metformin did not increase the risk of hypoglycemia, but it also did not reduce the risk of microvascular disease.
Concomitant metformin reduces costs
These days, practitioners can choose from a large selection of diabetes drugs. These include insulins with better pharmacokinetic profiles, as well as newer classes of noninsulin agents such as sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 analogues.
Metformin is less expensive than these newer drugs, and using it concomitantly with other diabetes drugs can decrease their dosage requirements, which in turn decreases their monthly costs.
GASTROINTESTINAL EFFECTS
Metformin’s gastrointestinal adverse effects such as diarrhea, flatulence, nausea, and vomiting are a barrier to its use. The actual incidence rate of diarrhea varies widely in randomized trials and observational studies, and gastrointestinal effects are worse in metformin-naive patients, as well as those who have chronic gastritis or Helicobacter pylori infection.17
We have found that starting metformin at a low dose and up-titrating it over several weeks increases tolerability. We often start patients at 500 mg/day and increase the dosage by 1 500-mg tablet every 1 to 2 weeks. Also, we have noticed that intolerance is more likely in patients who eat a high-carbohydrate diet, but there is no high-level evidence to back this up because patients in clinical trials all undergo nutrition counseling and are therefore more likely to adhere to the low-carbohydrate diet.
Also, the extended-release formulation is more tolerable than the immediate-release formulation and has similar glycemic efficacy. It may be an option as first-line therapy or for patients who have significant adverse effects from immediate-release metformin.18 For patients on the immediate-release formulation, taking it with meals helps lessen some gastrointestinal effects, and this should be emphasized at every visit.
Finally, we limit the metformin dose to 2,000 mg/day, rather than the 2,550 mg/day allowed on labeling. Garber et al19 found that the lower dosage still provides the maximum clinical efficacy.
OTHER CAUTIONS
Metformin should be avoided in patients with acute or unstable heart failure because of the increased risk of lactic acidosis.
It also should be avoided in patients with hepatic impairment, according to the labeling. But this remains controversial in practice. Zhang et al20 showed that continuing metformin in patients with diabetes and cirrhosis decreases the mortality risk by 57% compared with those taken off metformin.
Diet and lifestyle measures need to be emphasized at each visit. Wing et al21 showed that calorie restriction regardless of weight loss is beneficial for glycemic control and insulin sensitivity in obese patients with diabetes.
TAKE-HOME POINTS
Metformin improves glycemic control without tending to cause weight gain or hypoglycemia. It may also have cardiovascular benefits. Metformin is an inexpensive agent that should be continued, if tolerated, in those who need additional agents for glycemic control. It should be considered in all adult patients with type 2 diabetes.
- American Diabetes Association. 8. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2018. Diabetes Care 2018; 41(suppl 1):S73–S85. doi:10.2337/dc18-S008
- Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm—2018 executive summary. Endocr Pract 2018; 24(1):91–120. doi:10.4158/CS-2017-0153
- Hampp C, Borders-Hemphill V, Moeny DG, Wysowski DK. Use of antidiabetic drugs in the US, 2003–2012. Diabetes Care 2014; 37(5):1367–1374. doi:10.2337/dc13-2289
- Inzucchi SE, Bergenstal RM, Buse JB, et al; American Diabetes Association (ADA); European Association for the Study of Diabetes (EASD). Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2012; 35(6):1364–1379. doi:10.2337/dc12-0413
- Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352(9131):854–865. pmid:9742977
- Kooy A, de Jager J, Lehert P, et al. Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch Intern Med 2009; 169(6):616–625. doi:10.1001/archinternmed.2009.20
- Hong J, Zhang Y, Lai S, et al; SPREAD-DIMCAD Investigators. Effects of metformin versus glipizide on cardiovascular outcomes in patients with type 2 diabetes and coronary artery disease. Diabetes Care 2013; 36(5):1304–1311. doi:10.2337/dc12-0719
- Glucophage (metformin hydrochloride) and Glucophage XR (extended-release) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company. www.accessdata.fda.gov/drugsatfda_docs/label/2018/020357s034,021202s018lbl.pdf. Accessed December 5, 2018.
- Inzucchi SE, Lipska KJ, Mayo H, Bailey CJ, McGuire DK. Metformin in patients with type 2 diabetes and kidney disease: a systematic review. JAMA 2014; 312(24):2668–2675. doi:10.1001/jama.2014.15298
- Lazarus B, Wu A, Shin JI, et al. Association of metformin use with risk of lactic acidosis across the range of kidney function: a community-based cohort study. JAMA Intern Med 2018; 178(7):903–910. doi:10.1001/jamainternmed.2018.0292
- Salpeter S, Greyber E, Pasternak G, Salpeter E. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev 2003; (2):CD002967. doi:10.1002/14651858.CD002967
- Eppenga WL, Lalmohamed A, Geerts AF, et al. Risk of lactic acidosis or elevated lactate concentrations in metformin users with renal impairment: a population-based cohort study. Diabetes Care 2014; 37(8):2218–2224. doi:10.2337/dc13-3023
- Richy FF, Sabidó-Espin M, Guedes S, Corvino FA, Gottwald-Hostalek U. Incidence of lactic acidosis in patients with type 2 diabetes with and without renal impairment treated with metformin: a retrospective cohort study. Diabetes Care 2014; 37(8):2291–2295. doi:10.2337/dc14-0464
- American College of Radiology (ACR). Manual on Contrast Media. Version 10.3. www.acr.org/Clinical-Resources/Contrast-Manual. Accessed December 5, 2018.
- Wulffele MG, Kooy A, Lehert P, et al. Combination of insulin and metformin in the treatment of type 2 diabetes. Diabetes Care 2002; 25(12):2133–2140. pmid:12453950
- Kooy A, de Jager J, Lehert P, et al. Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch Intern Med 2009; 169(6):616–625. doi:10.1001/archinternmed.2009.20
- Bonnet F, Scheen A. Understanding and overcoming metformin gastrointestinal intolerance, Diabetes Obes Metab 2017; 19(4):473–481. doi:10.1111/dom.12854
- Jabbour S, Ziring B. Advantages of extended-release metformin in patients with type 2 diabetes mellitus. Postgrad Med 2011; 123(1):15–23. doi:10.3810/pgm.2011.01.2241
- Garber AJ, Duncan TG, Goodman AM, Mills DJ, Rohlf JL. Efficacy of metformin in type II diabetes: results of a double-blind, placebo-controlled, dose-response trial. Am J Med 1997; 103(6):491–497. pmid:9428832
- Zhang X, Harmsen WS, Mettler TA, et al. Continuation of metformin use after a diagnosis of cirrhosis significantly improves survival of patients with diabetes. Hepatology 2014; 60(6):2008–2016. doi:10.1002/hep.27199
- Wing RR, Blair EH, Bononi P, Marcus MD, Watanabe R, Bergman RN. Caloric restriction per se is a significant factor in improvements in glycemic control and insulin sensitivity during weight loss in obese NIDDM patients. Diabetes Care 1994; 17(1):30–36. pmid:8112186
- American Diabetes Association. 8. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2018. Diabetes Care 2018; 41(suppl 1):S73–S85. doi:10.2337/dc18-S008
- Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm—2018 executive summary. Endocr Pract 2018; 24(1):91–120. doi:10.4158/CS-2017-0153
- Hampp C, Borders-Hemphill V, Moeny DG, Wysowski DK. Use of antidiabetic drugs in the US, 2003–2012. Diabetes Care 2014; 37(5):1367–1374. doi:10.2337/dc13-2289
- Inzucchi SE, Bergenstal RM, Buse JB, et al; American Diabetes Association (ADA); European Association for the Study of Diabetes (EASD). Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2012; 35(6):1364–1379. doi:10.2337/dc12-0413
- Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352(9131):854–865. pmid:9742977
- Kooy A, de Jager J, Lehert P, et al. Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch Intern Med 2009; 169(6):616–625. doi:10.1001/archinternmed.2009.20
- Hong J, Zhang Y, Lai S, et al; SPREAD-DIMCAD Investigators. Effects of metformin versus glipizide on cardiovascular outcomes in patients with type 2 diabetes and coronary artery disease. Diabetes Care 2013; 36(5):1304–1311. doi:10.2337/dc12-0719
- Glucophage (metformin hydrochloride) and Glucophage XR (extended-release) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company. www.accessdata.fda.gov/drugsatfda_docs/label/2018/020357s034,021202s018lbl.pdf. Accessed December 5, 2018.
- Inzucchi SE, Lipska KJ, Mayo H, Bailey CJ, McGuire DK. Metformin in patients with type 2 diabetes and kidney disease: a systematic review. JAMA 2014; 312(24):2668–2675. doi:10.1001/jama.2014.15298
- Lazarus B, Wu A, Shin JI, et al. Association of metformin use with risk of lactic acidosis across the range of kidney function: a community-based cohort study. JAMA Intern Med 2018; 178(7):903–910. doi:10.1001/jamainternmed.2018.0292
- Salpeter S, Greyber E, Pasternak G, Salpeter E. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev 2003; (2):CD002967. doi:10.1002/14651858.CD002967
- Eppenga WL, Lalmohamed A, Geerts AF, et al. Risk of lactic acidosis or elevated lactate concentrations in metformin users with renal impairment: a population-based cohort study. Diabetes Care 2014; 37(8):2218–2224. doi:10.2337/dc13-3023
- Richy FF, Sabidó-Espin M, Guedes S, Corvino FA, Gottwald-Hostalek U. Incidence of lactic acidosis in patients with type 2 diabetes with and without renal impairment treated with metformin: a retrospective cohort study. Diabetes Care 2014; 37(8):2291–2295. doi:10.2337/dc14-0464
- American College of Radiology (ACR). Manual on Contrast Media. Version 10.3. www.acr.org/Clinical-Resources/Contrast-Manual. Accessed December 5, 2018.
- Wulffele MG, Kooy A, Lehert P, et al. Combination of insulin and metformin in the treatment of type 2 diabetes. Diabetes Care 2002; 25(12):2133–2140. pmid:12453950
- Kooy A, de Jager J, Lehert P, et al. Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch Intern Med 2009; 169(6):616–625. doi:10.1001/archinternmed.2009.20
- Bonnet F, Scheen A. Understanding and overcoming metformin gastrointestinal intolerance, Diabetes Obes Metab 2017; 19(4):473–481. doi:10.1111/dom.12854
- Jabbour S, Ziring B. Advantages of extended-release metformin in patients with type 2 diabetes mellitus. Postgrad Med 2011; 123(1):15–23. doi:10.3810/pgm.2011.01.2241
- Garber AJ, Duncan TG, Goodman AM, Mills DJ, Rohlf JL. Efficacy of metformin in type II diabetes: results of a double-blind, placebo-controlled, dose-response trial. Am J Med 1997; 103(6):491–497. pmid:9428832
- Zhang X, Harmsen WS, Mettler TA, et al. Continuation of metformin use after a diagnosis of cirrhosis significantly improves survival of patients with diabetes. Hepatology 2014; 60(6):2008–2016. doi:10.1002/hep.27199
- Wing RR, Blair EH, Bononi P, Marcus MD, Watanabe R, Bergman RN. Caloric restriction per se is a significant factor in improvements in glycemic control and insulin sensitivity during weight loss in obese NIDDM patients. Diabetes Care 1994; 17(1):30–36. pmid:8112186
