ADA Advanced Postgraduate Course

Humans can host up to 6 pounds of microbes in our gut alone. We comprise about 10 trillion human cells – they comprise 100 trillion bacterial cells. Their genetic material outstrips us even more impressively – we are the product of 20,000 human genes. But inside our gut, we carry up to 2 million microbial genes.

Emerging research suggests that these complex communities – which interact fluidly not only with their human host, but also with each other – play important roles in health and disease. They appear to confer both protection from and risk for many chronic illnesses, from asthma and allergies to obesity and diabetes.

And what we don’t know about them dwarfs what we do know, according to Dr. Robert Ratner, the chief medical officer of the American Diabetes Association.

“We’re literally at the forefront of an unknown universe,” Dr. Ratner said at the annual advanced postgraduate course held by the ADA. “Research into the microbiome and how it interacts with human health is one of our most intriguing investigations.”

The microbiome is as vastly individual as every person who carries it. The differences are myriad, in the amount and variety of species, and in the sheer numbers of microbes that make up each community. Each region of the gut, from mouth to rectum, hosts a completely different population.

Two main phyla populate the gut: Bacteroidetes, which are involved in protein and carbohydrate breakdown, and Firmicutes, which promote the absorption of fat. The ratios of these communities, however, has changed over the last 30 years, diverging along a path that mirrors global spikes in obesity, diabetes, and allergic and inflammatory disorders.

“We have seen dramatic increases worldwide in these disorders,” Dr. Ratner said. “We’ve also seen decreased diversity of the microbiome, with a progressive change in density from Bacteroidetes to Firmicutes. These are associations – not causations – but I think the time has come to ask ‘What are we doing to change these bacteria?’ ”

The rampant use of antibiotics is the first place suspicion falls – and it’s no wonder, since the epidemiologic changes Dr. Ratner described began to appear shortly after World War II. Antibiotics could exert their flora-changing effects a couple of ways, he noted.

They directly alter the composition of communities in the person who consumes the drug, even if just in the short-term. There is someevidence that early-life antibiotics, though changing the microbiome only temporarily, can change fat metabolism for the entire lifespan (Cell 2014;158:705-21).

The associations between an altered gut microbiome and long-term health is unproven. But a picture does seem to emerge when viewed in light of the exponential increases in obesity and its attendant rise in diabetes.

The Type 1 Diabetes Prediction and Prevention Project (DIPP) is an effort to predict and search for means to delay or prevent type 1 diabetes. Launched in 1994, it’s following a cohort of children who had genetic risk factors for type 1 diabetes. Data have consistently shown that those who develop the disease have significantly lower diversity in their gut flora, Dr. Ratner said. Certain species of Bacteroides increased the risk of autoimmunity by up to 20 times.

Again, he said, this is association, not causation. But some very new evidence suggests that these are functional, not just observational, links. “It does now appear that our microbes are actually controlling our metabolism,” he said. “Some of these species liberate lipopolysaccharides, which function as endotoxins. These cross the mucosal barrier in the intestine, enter the interstitial space, and set up an inflammation that impacts the liver and adipocytes, potentially decreasing insulin sensitivity.”

Unpublished data from the laboratory of Dr. Martin J. Blaser at New York University show for the first time that a specific bacterium can cause diabetes, and removing it cures the disease. The bacterium in question, Ralstonia, is a gram-negative pathogen that contaminates drinking water. Mice engineered as a model of prediabetes gained much more weight when they consumed live Ralstonia than when they got a heat-inactivated version. They also developed insulin resistance and hyperglycemia in the presence of the live version. But when the same mice were given a Ralstonia antibody, they lost weight and their glycemic profile normalized.

“This is the first direct evidence we have of causality,” Dr. Ratner said.

Strong evidence of causation is also emerging in the surgical realm. Roux-en-Y gastric bypass seems to change the microbiome in a way that facilitates weight loss, beyond caloric intake.Randy Seeley, Ph.D., of the University of Michigan, Ann Arbor, has been studying how weight-loss surgery affects the microbiome. He theorizes that the physical manipulation of the gut induces what he calls “enteroplasticity” – a fluid adaptation of both the gut’s structure and its bacterial communities to the altered physical and chemical environment. “There’s more going on during postsurgical weight loss than just food restriction and malabsorption,” Dr. Seeley said in an interview. “It’s logical to think that when you do this kind of surgery, the microbes in the intestine will change.”

Roseburia intestinalis is a Firmicute that typically increases after bariatric surgery. It’s also found to be deficient in people who have diabetes. Dr. Seeley coauthored an article showing that Roseburia and other beneficial firmicutes increased significantly in mice that underwent vertical sleeve gastrectomy (Nature 2014;509:183-8). These mice lost weight after surgery, as would be expected, but then showed a preference for the high-protein and carbohydrate-rich foods that Firmicutes need. Their microbiome also showed decreases in the concentration of fat-loving Bacteroides species.

But interestingly, weight loss and microbiome improvement happened only in mice that had a normal bile acid–signaling system. Immediately after surgery, mice engineered to lack bile acid receptors did eat less and lose weight. But a week later, their appetites came back full force, and they actually seemed driven to eat fat. They quickly returned to their presurgical weight. Their microbiome didn’t show the same improvement as their cousins with normal signaling pathways, suggesting that a complex interaction between bacteria and the gut’s physical alteration may be driving weight loss.

“Is weight-loss surgery, then, fixing this ‘broken’ component of the microbiome?” Dr. Seeley asked. “Is Roseburia the causal agent of improvement? Or is it a marker of improvement in an entire community? I would say it’s probably the entire community changing, and changing its interaction with its host organism.”

Dr. Seeley disclosed that he has received financial support from Johnson & Johnson, Novo Nordisk, and Eisai.

[email protected]

On Twitter @alz_gal

Humans can host up to 6 pounds of microbes in our gut alone. We comprise about 10 trillion human cells – they comprise 100 trillion bacterial cells. Their genetic material outstrips us even more impressively – we are the product of 20,000 human genes. But inside our gut, we carry up to 2 million microbial genes.

Emerging research suggests that these complex communities – which interact fluidly not only with their human host, but also with each other – play important roles in health and disease. They appear to confer both protection from and risk for many chronic illnesses, from asthma and allergies to obesity and diabetes.

And what we don’t know about them dwarfs what we do know, according to Dr. Robert Ratner, the chief medical officer of the American Diabetes Association.

“We’re literally at the forefront of an unknown universe,” Dr. Ratner said at the annual advanced postgraduate course held by the ADA. “Research into the microbiome and how it interacts with human health is one of our most intriguing investigations.”

The microbiome is as vastly individual as every person who carries it. The differences are myriad, in the amount and variety of species, and in the sheer numbers of microbes that make up each community. Each region of the gut, from mouth to rectum, hosts a completely different population.

Two main phyla populate the gut: Bacteroidetes, which are involved in protein and carbohydrate breakdown, and Firmicutes, which promote the absorption of fat. The ratios of these communities, however, has changed over the last 30 years, diverging along a path that mirrors global spikes in obesity, diabetes, and allergic and inflammatory disorders.

“We have seen dramatic increases worldwide in these disorders,” Dr. Ratner said. “We’ve also seen decreased diversity of the microbiome, with a progressive change in density from Bacteroidetes to Firmicutes. These are associations – not causations – but I think the time has come to ask ‘What are we doing to change these bacteria?’ ”

The rampant use of antibiotics is the first place suspicion falls – and it’s no wonder, since the epidemiologic changes Dr. Ratner described began to appear shortly after World War II. Antibiotics could exert their flora-changing effects a couple of ways, he noted.

They directly alter the composition of communities in the person who consumes the drug, even if just in the short-term. There is someevidence that early-life antibiotics, though changing the microbiome only temporarily, can change fat metabolism for the entire lifespan (Cell 2014;158:705-21).

The associations between an altered gut microbiome and long-term health is unproven. But a picture does seem to emerge when viewed in light of the exponential increases in obesity and its attendant rise in diabetes.

The Type 1 Diabetes Prediction and Prevention Project (DIPP) is an effort to predict and search for means to delay or prevent type 1 diabetes. Launched in 1994, it’s following a cohort of children who had genetic risk factors for type 1 diabetes. Data have consistently shown that those who develop the disease have significantly lower diversity in their gut flora, Dr. Ratner said. Certain species of Bacteroides increased the risk of autoimmunity by up to 20 times.

Again, he said, this is association, not causation. But some very new evidence suggests that these are functional, not just observational, links. “It does now appear that our microbes are actually controlling our metabolism,” he said. “Some of these species liberate lipopolysaccharides, which function as endotoxins. These cross the mucosal barrier in the intestine, enter the interstitial space, and set up an inflammation that impacts the liver and adipocytes, potentially decreasing insulin sensitivity.”

Unpublished data from the laboratory of Dr. Martin J. Blaser at New York University show for the first time that a specific bacterium can cause diabetes, and removing it cures the disease. The bacterium in question, Ralstonia, is a gram-negative pathogen that contaminates drinking water. Mice engineered as a model of prediabetes gained much more weight when they consumed live Ralstonia than when they got a heat-inactivated version. They also developed insulin resistance and hyperglycemia in the presence of the live version. But when the same mice were given a Ralstonia antibody, they lost weight and their glycemic profile normalized.

“This is the first direct evidence we have of causality,” Dr. Ratner said.

Strong evidence of causation is also emerging in the surgical realm. Roux-en-Y gastric bypass seems to change the microbiome in a way that facilitates weight loss, beyond caloric intake.Randy Seeley, Ph.D., of the University of Michigan, Ann Arbor, has been studying how weight-loss surgery affects the microbiome. He theorizes that the physical manipulation of the gut induces what he calls “enteroplasticity” – a fluid adaptation of both the gut’s structure and its bacterial communities to the altered physical and chemical environment. “There’s more going on during postsurgical weight loss than just food restriction and malabsorption,” Dr. Seeley said in an interview. “It’s logical to think that when you do this kind of surgery, the microbes in the intestine will change.”

Roseburia intestinalis is a Firmicute that typically increases after bariatric surgery. It’s also found to be deficient in people who have diabetes. Dr. Seeley coauthored an article showing that Roseburia and other beneficial firmicutes increased significantly in mice that underwent vertical sleeve gastrectomy (Nature 2014;509:183-8). These mice lost weight after surgery, as would be expected, but then showed a preference for the high-protein and carbohydrate-rich foods that Firmicutes need. Their microbiome also showed decreases in the concentration of fat-loving Bacteroides species.

But interestingly, weight loss and microbiome improvement happened only in mice that had a normal bile acid–signaling system. Immediately after surgery, mice engineered to lack bile acid receptors did eat less and lose weight. But a week later, their appetites came back full force, and they actually seemed driven to eat fat. They quickly returned to their presurgical weight. Their microbiome didn’t show the same improvement as their cousins with normal signaling pathways, suggesting that a complex interaction between bacteria and the gut’s physical alteration may be driving weight loss.

“Is weight-loss surgery, then, fixing this ‘broken’ component of the microbiome?” Dr. Seeley asked. “Is Roseburia the causal agent of improvement? Or is it a marker of improvement in an entire community? I would say it’s probably the entire community changing, and changing its interaction with its host organism.”

Dr. Seeley disclosed that he has received financial support from Johnson & Johnson, Novo Nordisk, and Eisai.

[email protected]

On Twitter @alz_gal

Humans can host up to 6 pounds of microbes in our gut alone. We comprise about 10 trillion human cells – they comprise 100 trillion bacterial cells. Their genetic material outstrips us even more impressively – we are the product of 20,000 human genes. But inside our gut, we carry up to 2 million microbial genes.

Emerging research suggests that these complex communities – which interact fluidly not only with their human host, but also with each other – play important roles in health and disease. They appear to confer both protection from and risk for many chronic illnesses, from asthma and allergies to obesity and diabetes.

And what we don’t know about them dwarfs what we do know, according to Dr. Robert Ratner, the chief medical officer of the American Diabetes Association.

“We’re literally at the forefront of an unknown universe,” Dr. Ratner said at the annual advanced postgraduate course held by the ADA. “Research into the microbiome and how it interacts with human health is one of our most intriguing investigations.”

The microbiome is as vastly individual as every person who carries it. The differences are myriad, in the amount and variety of species, and in the sheer numbers of microbes that make up each community. Each region of the gut, from mouth to rectum, hosts a completely different population.

Two main phyla populate the gut: Bacteroidetes, which are involved in protein and carbohydrate breakdown, and Firmicutes, which promote the absorption of fat. The ratios of these communities, however, has changed over the last 30 years, diverging along a path that mirrors global spikes in obesity, diabetes, and allergic and inflammatory disorders.

“We have seen dramatic increases worldwide in these disorders,” Dr. Ratner said. “We’ve also seen decreased diversity of the microbiome, with a progressive change in density from Bacteroidetes to Firmicutes. These are associations – not causations – but I think the time has come to ask ‘What are we doing to change these bacteria?’ ”

The rampant use of antibiotics is the first place suspicion falls – and it’s no wonder, since the epidemiologic changes Dr. Ratner described began to appear shortly after World War II. Antibiotics could exert their flora-changing effects a couple of ways, he noted.

They directly alter the composition of communities in the person who consumes the drug, even if just in the short-term. There is someevidence that early-life antibiotics, though changing the microbiome only temporarily, can change fat metabolism for the entire lifespan (Cell 2014;158:705-21).

The associations between an altered gut microbiome and long-term health is unproven. But a picture does seem to emerge when viewed in light of the exponential increases in obesity and its attendant rise in diabetes.

The Type 1 Diabetes Prediction and Prevention Project (DIPP) is an effort to predict and search for means to delay or prevent type 1 diabetes. Launched in 1994, it’s following a cohort of children who had genetic risk factors for type 1 diabetes. Data have consistently shown that those who develop the disease have significantly lower diversity in their gut flora, Dr. Ratner said. Certain species of Bacteroides increased the risk of autoimmunity by up to 20 times.

Again, he said, this is association, not causation. But some very new evidence suggests that these are functional, not just observational, links. “It does now appear that our microbes are actually controlling our metabolism,” he said. “Some of these species liberate lipopolysaccharides, which function as endotoxins. These cross the mucosal barrier in the intestine, enter the interstitial space, and set up an inflammation that impacts the liver and adipocytes, potentially decreasing insulin sensitivity.”

Unpublished data from the laboratory of Dr. Martin J. Blaser at New York University show for the first time that a specific bacterium can cause diabetes, and removing it cures the disease. The bacterium in question, Ralstonia, is a gram-negative pathogen that contaminates drinking water. Mice engineered as a model of prediabetes gained much more weight when they consumed live Ralstonia than when they got a heat-inactivated version. They also developed insulin resistance and hyperglycemia in the presence of the live version. But when the same mice were given a Ralstonia antibody, they lost weight and their glycemic profile normalized.

“This is the first direct evidence we have of causality,” Dr. Ratner said.

Strong evidence of causation is also emerging in the surgical realm. Roux-en-Y gastric bypass seems to change the microbiome in a way that facilitates weight loss, beyond caloric intake.Randy Seeley, Ph.D., of the University of Michigan, Ann Arbor, has been studying how weight-loss surgery affects the microbiome. He theorizes that the physical manipulation of the gut induces what he calls “enteroplasticity” – a fluid adaptation of both the gut’s structure and its bacterial communities to the altered physical and chemical environment. “There’s more going on during postsurgical weight loss than just food restriction and malabsorption,” Dr. Seeley said in an interview. “It’s logical to think that when you do this kind of surgery, the microbes in the intestine will change.”

Roseburia intestinalis is a Firmicute that typically increases after bariatric surgery. It’s also found to be deficient in people who have diabetes. Dr. Seeley coauthored an article showing that Roseburia and other beneficial firmicutes increased significantly in mice that underwent vertical sleeve gastrectomy (Nature 2014;509:183-8). These mice lost weight after surgery, as would be expected, but then showed a preference for the high-protein and carbohydrate-rich foods that Firmicutes need. Their microbiome also showed decreases in the concentration of fat-loving Bacteroides species.

But interestingly, weight loss and microbiome improvement happened only in mice that had a normal bile acid–signaling system. Immediately after surgery, mice engineered to lack bile acid receptors did eat less and lose weight. But a week later, their appetites came back full force, and they actually seemed driven to eat fat. They quickly returned to their presurgical weight. Their microbiome didn’t show the same improvement as their cousins with normal signaling pathways, suggesting that a complex interaction between bacteria and the gut’s physical alteration may be driving weight loss.

“Is weight-loss surgery, then, fixing this ‘broken’ component of the microbiome?” Dr. Seeley asked. “Is Roseburia the causal agent of improvement? Or is it a marker of improvement in an entire community? I would say it’s probably the entire community changing, and changing its interaction with its host organism.”

Dr. Seeley disclosed that he has received financial support from Johnson & Johnson, Novo Nordisk, and Eisai.

[email protected]

On Twitter @alz_gal

NEW YORK – Three new insulins hold the potential for decreasing the risk of severe hypoglycemia episodes in patients with diabetes, Dr. Elizabeth R. Seaquist said at the annual advanced postgraduate course held by the American Diabetes Association.

None of the products are yet available in the the United States, although one of the insulins was approved in February by the Food and Drug Administration and is expected to be on the market later this year. The new insulin glargine (Toujeo; Sanofi), a once-daily long-acting basal insulin, received its FDA approval on Feb. 25.

Toujeo has a flatter glycemic profile and a longer duration of action than does its predecessor insulin glargine, Lantus, said Dr. Seaquist, professor of medicine and the Pennock Family Chair in Diabetes Research at the University of Minnesota, Minneapolis.

The approval of Toujeo was based on results from the EDITION clinical trial series, which included more than 3,500 adults with type 1 or type 2 diabetes. In those studies, once-daily Toujeo was compared with once-daily insulin Lantus in open-label, randomized, active-control, parallel, treat-to-target studies of up to 26 weeks of duration with 6 months’ safety extension, according to a Sanofi press release.

Insulin degludec, a once-daily, long-acting basal insulin analogue, is available in the European Union as Tresiba (Novo Nordisk) at strengths of 100 U/mL and 200 U/mL. The FDA denied its approval in 2013, after a review committee expressed concern about a potential increased risk of major cardiovascular events. The FDA has requested that additional cardiovascular data from a dedicated cardiovascular outcomes trial be provided before considering approval.

Basal insulin peglispro (Lilly) has successfully completed all its phase III studies and is on track for FDA submission this year. The primary efficacy endpoint of noninferior HbA_1c, compared with insulin glargine was met in both the IMAGINE-1 and IMAGINE-3 trials, and significantly more patients taking basal insulin peglispro achieved an HbA_1c of less than 7%. Further, patients taking basal insulin peglispro experienced weight loss and patients taking insulin glargine experienced weight gain, according to Lilly press releases.

Both trials – in which patients were taking mealtime and basal insulin – also found a significantly lower rate of nocturnal hypoglycemia with basal insulin peglispro. Because of a higher rate of daytime hypoglycemic events, however, there was a statistically significant increase in the rate of total hypoglycemia for patients taking basal insulin peglispro.

In the open-label IMAGINE-1 trial, patients taking basal insulin peglispro reported a statistically significant higher rate of severe hypoglycemic events. However, in the larger, blinded IMAGINE-3 trial the rate of severe hypoglycemic events for treatment with basal insulin peglispro was numerically lower, but the difference was not statistically significant.

The fear of hypoglycemia can prompt patients to be nonadherent with their insulin regimen, Dr. Seaquist said. “And we all know that many patients don’t reach their glycemic goal, so they need additional medications that then put them at an increased risk of hypoglycemia.”

According to one review article, an intensively treated individual with type 1 diabetes can experience up to 10 episodes of symptomatic hypoglycemia per week and severe temporarily disabling hypoglycemia at least once a year. Hypoglycemia is also relatively common in type 2 diabetes, with prevalence rates of 70%-80% in clinical trials using insulin to achieve good metabolic control.

Dr. Seaquist disclosed that she is a consultant for Sanofi Aventis, the maker of Toujeo.

[email protected]

NEW YORK – Three new insulins hold the potential for decreasing the risk of severe hypoglycemia episodes in patients with diabetes, Dr. Elizabeth R. Seaquist said at the annual advanced postgraduate course held by the American Diabetes Association.

None of the products are yet available in the the United States, although one of the insulins was approved in February by the Food and Drug Administration and is expected to be on the market later this year. The new insulin glargine (Toujeo; Sanofi), a once-daily long-acting basal insulin, received its FDA approval on Feb. 25.

Toujeo has a flatter glycemic profile and a longer duration of action than does its predecessor insulin glargine, Lantus, said Dr. Seaquist, professor of medicine and the Pennock Family Chair in Diabetes Research at the University of Minnesota, Minneapolis.

The approval of Toujeo was based on results from the EDITION clinical trial series, which included more than 3,500 adults with type 1 or type 2 diabetes. In those studies, once-daily Toujeo was compared with once-daily insulin Lantus in open-label, randomized, active-control, parallel, treat-to-target studies of up to 26 weeks of duration with 6 months’ safety extension, according to a Sanofi press release.

Insulin degludec, a once-daily, long-acting basal insulin analogue, is available in the European Union as Tresiba (Novo Nordisk) at strengths of 100 U/mL and 200 U/mL. The FDA denied its approval in 2013, after a review committee expressed concern about a potential increased risk of major cardiovascular events. The FDA has requested that additional cardiovascular data from a dedicated cardiovascular outcomes trial be provided before considering approval.

Basal insulin peglispro (Lilly) has successfully completed all its phase III studies and is on track for FDA submission this year. The primary efficacy endpoint of noninferior HbA_1c, compared with insulin glargine was met in both the IMAGINE-1 and IMAGINE-3 trials, and significantly more patients taking basal insulin peglispro achieved an HbA_1c of less than 7%. Further, patients taking basal insulin peglispro experienced weight loss and patients taking insulin glargine experienced weight gain, according to Lilly press releases.

Both trials – in which patients were taking mealtime and basal insulin – also found a significantly lower rate of nocturnal hypoglycemia with basal insulin peglispro. Because of a higher rate of daytime hypoglycemic events, however, there was a statistically significant increase in the rate of total hypoglycemia for patients taking basal insulin peglispro.

In the open-label IMAGINE-1 trial, patients taking basal insulin peglispro reported a statistically significant higher rate of severe hypoglycemic events. However, in the larger, blinded IMAGINE-3 trial the rate of severe hypoglycemic events for treatment with basal insulin peglispro was numerically lower, but the difference was not statistically significant.

The fear of hypoglycemia can prompt patients to be nonadherent with their insulin regimen, Dr. Seaquist said. “And we all know that many patients don’t reach their glycemic goal, so they need additional medications that then put them at an increased risk of hypoglycemia.”

According to one review article, an intensively treated individual with type 1 diabetes can experience up to 10 episodes of symptomatic hypoglycemia per week and severe temporarily disabling hypoglycemia at least once a year. Hypoglycemia is also relatively common in type 2 diabetes, with prevalence rates of 70%-80% in clinical trials using insulin to achieve good metabolic control.

Dr. Seaquist disclosed that she is a consultant for Sanofi Aventis, the maker of Toujeo.

[email protected]

NEW YORK – Three new insulins hold the potential for decreasing the risk of severe hypoglycemia episodes in patients with diabetes, Dr. Elizabeth R. Seaquist said at the annual advanced postgraduate course held by the American Diabetes Association.

None of the products are yet available in the the United States, although one of the insulins was approved in February by the Food and Drug Administration and is expected to be on the market later this year. The new insulin glargine (Toujeo; Sanofi), a once-daily long-acting basal insulin, received its FDA approval on Feb. 25.

Toujeo has a flatter glycemic profile and a longer duration of action than does its predecessor insulin glargine, Lantus, said Dr. Seaquist, professor of medicine and the Pennock Family Chair in Diabetes Research at the University of Minnesota, Minneapolis.

The approval of Toujeo was based on results from the EDITION clinical trial series, which included more than 3,500 adults with type 1 or type 2 diabetes. In those studies, once-daily Toujeo was compared with once-daily insulin Lantus in open-label, randomized, active-control, parallel, treat-to-target studies of up to 26 weeks of duration with 6 months’ safety extension, according to a Sanofi press release.

Insulin degludec, a once-daily, long-acting basal insulin analogue, is available in the European Union as Tresiba (Novo Nordisk) at strengths of 100 U/mL and 200 U/mL. The FDA denied its approval in 2013, after a review committee expressed concern about a potential increased risk of major cardiovascular events. The FDA has requested that additional cardiovascular data from a dedicated cardiovascular outcomes trial be provided before considering approval.

Basal insulin peglispro (Lilly) has successfully completed all its phase III studies and is on track for FDA submission this year. The primary efficacy endpoint of noninferior HbA_1c, compared with insulin glargine was met in both the IMAGINE-1 and IMAGINE-3 trials, and significantly more patients taking basal insulin peglispro achieved an HbA_1c of less than 7%. Further, patients taking basal insulin peglispro experienced weight loss and patients taking insulin glargine experienced weight gain, according to Lilly press releases.

Both trials – in which patients were taking mealtime and basal insulin – also found a significantly lower rate of nocturnal hypoglycemia with basal insulin peglispro. Because of a higher rate of daytime hypoglycemic events, however, there was a statistically significant increase in the rate of total hypoglycemia for patients taking basal insulin peglispro.

In the open-label IMAGINE-1 trial, patients taking basal insulin peglispro reported a statistically significant higher rate of severe hypoglycemic events. However, in the larger, blinded IMAGINE-3 trial the rate of severe hypoglycemic events for treatment with basal insulin peglispro was numerically lower, but the difference was not statistically significant.

The fear of hypoglycemia can prompt patients to be nonadherent with their insulin regimen, Dr. Seaquist said. “And we all know that many patients don’t reach their glycemic goal, so they need additional medications that then put them at an increased risk of hypoglycemia.”

According to one review article, an intensively treated individual with type 1 diabetes can experience up to 10 episodes of symptomatic hypoglycemia per week and severe temporarily disabling hypoglycemia at least once a year. Hypoglycemia is also relatively common in type 2 diabetes, with prevalence rates of 70%-80% in clinical trials using insulin to achieve good metabolic control.

Dr. Seaquist disclosed that she is a consultant for Sanofi Aventis, the maker of Toujeo.

[email protected]

Balancing blood sugar in any hospitalized patient can be a tightrope walk, but it is especially challenging when patients can’t eat or are taking steroids.

These patients need a proactive approach that prevents both hyper- and hypoglycemia, both of which have long been tied to poorer outcomes in critically ill patients, Dr. Mary Korytkowski said at the annual advanced postgraduate course held by the American Diabetes Association.

All hospitalized patients should have a blood glucose test on admission. This baseline measure will determine in-hospital glycemic management, which can be fairly straightforward as long as patients are eating regularly. Things get tricky if patients can’t take any food orally and need enteral or parenteral nutrition. Glucocorticoids can also wreak havoc on blood sugars, even in nondiabetic patients.

“There is no question that [blood sugar extremes] impact outcomes, whether or not the patient has [a history of] diabetes,” said Dr. Korytkowski of the University of Pittsburgh. “The question is, what do we do about it?”

The NICE-SUGAR study determined that low-end blood sugar targets may actually be dangerous for hospitalized patients. Since its publication in 2012, glycemic goals have been increased. For non–critically ill patients, a pre-meal blood glucose level should be somewhere between 100-140 mg/dL. For critically ill patients, the goal is more generous at 110-180 mg/dL. Management should aim to sustain those levels, with as few out-of-goal fluctuations as possible.

Patients who have diabetes and are NPO (nothing by mouth) should have their scheduled nutritional insulin held, and their glucose levels maintained with basal and correction insulin, Dr. Korytkowski said. The dose of insulin glargine or insulin detemir will have to be decreased by up to 40% to stay within target; the dose of NPH insulin will probably have to be decreased by 30%-50%.

Those who are converted to NPO after getting their full insulin dose should then be put on a 5% or 10% dextrose solution, which should continue as long as they are getting insulin. “We have this written into our standing orders now,” Dr. Korytkowski said. Of course, routine blood glucose monitoring is essential here.

All patients who receive enteral or parenteral nutrition need a baseline blood glucose level and point-of-care testing regardless of their diabetes history. For those without diabetes, testing can be discontinued if blood glucose stays below 140 mg/dL for 48 hours without insulin.

Those with diabetes should get basal insulin twice a day in addition to their normal regimen, plus correction insulin doses as needed. If this regimen stabilizes glucose at 140-180 mg/dL, it can continue. If levels are above 180 mg/dL on at least two measurements within 24 hours, then adding 25%-50% to the correction insulin dose, along with the scheduled insulin, is indicated.

Steroid diabetes is not uncommon among patients who have been getting glucocorticoids for an extended time, such as those with chronic inflammatory disorders. Steroids oppose insulin action and stimulate gluconeogenesis, leading to an increase in hepatic glucose output. NPH insulin is indicated for these patients. A suggested schedule is 0.1 unit of NPH insulin for every 10 mg prednisone. For example, 0.4 U/kg per day for 40 mg prednisone; 0.3 U/kg per day for 30 mg, and so on.

Dr. Korytkowski disclosed that she is a consultant for Sanofi-Aventis.

[email protected]

On Twitter @alz_gal

Balancing blood sugar in any hospitalized patient can be a tightrope walk, but it is especially challenging when patients can’t eat or are taking steroids.

These patients need a proactive approach that prevents both hyper- and hypoglycemia, both of which have long been tied to poorer outcomes in critically ill patients, Dr. Mary Korytkowski said at the annual advanced postgraduate course held by the American Diabetes Association.

All hospitalized patients should have a blood glucose test on admission. This baseline measure will determine in-hospital glycemic management, which can be fairly straightforward as long as patients are eating regularly. Things get tricky if patients can’t take any food orally and need enteral or parenteral nutrition. Glucocorticoids can also wreak havoc on blood sugars, even in nondiabetic patients.

“There is no question that [blood sugar extremes] impact outcomes, whether or not the patient has [a history of] diabetes,” said Dr. Korytkowski of the University of Pittsburgh. “The question is, what do we do about it?”

The NICE-SUGAR study determined that low-end blood sugar targets may actually be dangerous for hospitalized patients. Since its publication in 2012, glycemic goals have been increased. For non–critically ill patients, a pre-meal blood glucose level should be somewhere between 100-140 mg/dL. For critically ill patients, the goal is more generous at 110-180 mg/dL. Management should aim to sustain those levels, with as few out-of-goal fluctuations as possible.

Patients who have diabetes and are NPO (nothing by mouth) should have their scheduled nutritional insulin held, and their glucose levels maintained with basal and correction insulin, Dr. Korytkowski said. The dose of insulin glargine or insulin detemir will have to be decreased by up to 40% to stay within target; the dose of NPH insulin will probably have to be decreased by 30%-50%.

Those who are converted to NPO after getting their full insulin dose should then be put on a 5% or 10% dextrose solution, which should continue as long as they are getting insulin. “We have this written into our standing orders now,” Dr. Korytkowski said. Of course, routine blood glucose monitoring is essential here.

All patients who receive enteral or parenteral nutrition need a baseline blood glucose level and point-of-care testing regardless of their diabetes history. For those without diabetes, testing can be discontinued if blood glucose stays below 140 mg/dL for 48 hours without insulin.

Those with diabetes should get basal insulin twice a day in addition to their normal regimen, plus correction insulin doses as needed. If this regimen stabilizes glucose at 140-180 mg/dL, it can continue. If levels are above 180 mg/dL on at least two measurements within 24 hours, then adding 25%-50% to the correction insulin dose, along with the scheduled insulin, is indicated.

Steroid diabetes is not uncommon among patients who have been getting glucocorticoids for an extended time, such as those with chronic inflammatory disorders. Steroids oppose insulin action and stimulate gluconeogenesis, leading to an increase in hepatic glucose output. NPH insulin is indicated for these patients. A suggested schedule is 0.1 unit of NPH insulin for every 10 mg prednisone. For example, 0.4 U/kg per day for 40 mg prednisone; 0.3 U/kg per day for 30 mg, and so on.

Dr. Korytkowski disclosed that she is a consultant for Sanofi-Aventis.

[email protected]

On Twitter @alz_gal

Balancing blood sugar in any hospitalized patient can be a tightrope walk, but it is especially challenging when patients can’t eat or are taking steroids.

These patients need a proactive approach that prevents both hyper- and hypoglycemia, both of which have long been tied to poorer outcomes in critically ill patients, Dr. Mary Korytkowski said at the annual advanced postgraduate course held by the American Diabetes Association.

All hospitalized patients should have a blood glucose test on admission. This baseline measure will determine in-hospital glycemic management, which can be fairly straightforward as long as patients are eating regularly. Things get tricky if patients can’t take any food orally and need enteral or parenteral nutrition. Glucocorticoids can also wreak havoc on blood sugars, even in nondiabetic patients.

“There is no question that [blood sugar extremes] impact outcomes, whether or not the patient has [a history of] diabetes,” said Dr. Korytkowski of the University of Pittsburgh. “The question is, what do we do about it?”

The NICE-SUGAR study determined that low-end blood sugar targets may actually be dangerous for hospitalized patients. Since its publication in 2012, glycemic goals have been increased. For non–critically ill patients, a pre-meal blood glucose level should be somewhere between 100-140 mg/dL. For critically ill patients, the goal is more generous at 110-180 mg/dL. Management should aim to sustain those levels, with as few out-of-goal fluctuations as possible.

Patients who have diabetes and are NPO (nothing by mouth) should have their scheduled nutritional insulin held, and their glucose levels maintained with basal and correction insulin, Dr. Korytkowski said. The dose of insulin glargine or insulin detemir will have to be decreased by up to 40% to stay within target; the dose of NPH insulin will probably have to be decreased by 30%-50%.

Those who are converted to NPO after getting their full insulin dose should then be put on a 5% or 10% dextrose solution, which should continue as long as they are getting insulin. “We have this written into our standing orders now,” Dr. Korytkowski said. Of course, routine blood glucose monitoring is essential here.

All patients who receive enteral or parenteral nutrition need a baseline blood glucose level and point-of-care testing regardless of their diabetes history. For those without diabetes, testing can be discontinued if blood glucose stays below 140 mg/dL for 48 hours without insulin.

Those with diabetes should get basal insulin twice a day in addition to their normal regimen, plus correction insulin doses as needed. If this regimen stabilizes glucose at 140-180 mg/dL, it can continue. If levels are above 180 mg/dL on at least two measurements within 24 hours, then adding 25%-50% to the correction insulin dose, along with the scheduled insulin, is indicated.

Steroid diabetes is not uncommon among patients who have been getting glucocorticoids for an extended time, such as those with chronic inflammatory disorders. Steroids oppose insulin action and stimulate gluconeogenesis, leading to an increase in hepatic glucose output. NPH insulin is indicated for these patients. A suggested schedule is 0.1 unit of NPH insulin for every 10 mg prednisone. For example, 0.4 U/kg per day for 40 mg prednisone; 0.3 U/kg per day for 30 mg, and so on.

Dr. Korytkowski disclosed that she is a consultant for Sanofi-Aventis.

[email protected]

On Twitter @alz_gal

NEW YORK–Incretin-based diabetes medications may not be as harmful to the pancreas as previously feared.

Emerging clinical data, combined with concerns about the accuracy of polyclonal GLP-1 receptor antibody staining, suggest that there may be little to no risk for either treatment-related pancreatitis or pancreatic cancer in patients with diabetes, Dr. Vanita R. Aroda said at the annual advanced postgraduate course held by the American Diabetes Association.

“No study has definitely concluded that there is a causal link, and but we should still keep the risk as something to at least be aware of,” said Dr. Aroda of the MedStar Research Institute, Hyattsville, Md. “Until we have more information, patients who have pancreatic risk factors probably shouldn’t receive the drugs.”

A number of confounders cast doubt on past studies showing a pathologic association between incretins and pancreatic adverse events. Although there are suggestive clinical data, preclinical data based on GLP-1 receptor staining is unreliable, because the polyclonal antibodies generally used don’t consistently stain GLP-1 transfected cells.

“In nontransfected cells, you would expect to see no uptake, but with two of the antibodies, you see quite a bit of uptake in nontransfected as well as transfected cells.”

A third polyclonal antibody has difficulty showing uptake in either type of cell. Only one, the monoclonal 3F52 antibody released in 2013, seems to reliably differentiate GLP1 receptors in these models.

In Dr. Aroda’s opinion, the more reliable results from the monoclonal antibody cast much doubt on all previous preclinical studies that used the polyclonal antibodies.

Nonrandomized data based on case reporting also add to the uncertainty, she said. Data in the Food and Drug Administration’s adverse events reporting system have shown a five- to six-time increased risk of incretin-associated pancreatitis and pancreatic cancer, but “even the FDA has said that spontaneous reports cannot be used to determine the true incidence rates of drug adverse events.” Issues of underreporting, lack of established background rates, and inadequate documentation of clinical details (comorbidities, concomitant medications, and medication errors) cloud the picture. Clarity will remain uncertain as long as decisions about safety are made based on such data.

Similar problems plague studies of discharge data, reflected in the fact that many of them have come to conflicting determinations. The most recent data, however, come from a meta-analysis comprising more than 1.3 million patients among nine insurance claims databases in North America and the European Union. The analysis found no increased risk of acute pancreatitis and any incretin-based therapy (Diabetes Obes. Metab. 2015;17:32-41).

Another recent meta-analysis showed that the adjusted risk of acute pancreatitis was not increased among Danes who had been treated with an incretin drug (Diabetes Care 2015 [doi:10.2337/dc13-2983])

A 2013 study of brain-dead organ donors did find a 40% increased pancreatic mass in diabetes patients treated with incretin therapy, compared to those who didn’t get it and to control patients. Treated patients also over-expressed both exocrine cell proliferation and pancreatic intraepithelial neoplasia (Diabetes 2013;62:2595-604).

“This study has been analyzed and reanalyzed,” Dr. Aroda said. “But it’s really comparing apples to oranges. Five patients with diabetes weren’t on any medication; four were on insulin and four on metformin only; and seven were on two or more agents. Age ranged from 40 to 58 years, and we know age is a big risk factor here.”

Dr. Aroda also examined individual drugs in her own extensive patient database. She found no differences in pancreatitis or cancer associated with liraglutide, exenatide, lixisenatide, or sitagliptin.

The European Medicines Agency is conducting a large evaluation of cardiovascular, cerebrovascular, renal and pancreatic events among diabetes patients taking noninsulin glucose-lowering agents.(SAFEGUARD). It will include combined data covering more than 240 million patient/years.

The National Institutes of Health is also looking at the issue with a consortium study of chronic pancreatitis and pancreatic cancer in diabetes patients.

These projects should result in a considerable amount of reliable data on the issue, Dr. Aroda said.

In the meantime, neither the American Diabetes Association, the Endocrine Society or any European agencies have changed their treatment guidelines with regard to incretin-based therapies.

Dr. Aroda had no financial disclosures.

[email protected]

On Twitter @alz_gal

NEW YORK–Incretin-based diabetes medications may not be as harmful to the pancreas as previously feared.

Emerging clinical data, combined with concerns about the accuracy of polyclonal GLP-1 receptor antibody staining, suggest that there may be little to no risk for either treatment-related pancreatitis or pancreatic cancer in patients with diabetes, Dr. Vanita R. Aroda said at the annual advanced postgraduate course held by the American Diabetes Association.

“No study has definitely concluded that there is a causal link, and but we should still keep the risk as something to at least be aware of,” said Dr. Aroda of the MedStar Research Institute, Hyattsville, Md. “Until we have more information, patients who have pancreatic risk factors probably shouldn’t receive the drugs.”

A number of confounders cast doubt on past studies showing a pathologic association between incretins and pancreatic adverse events. Although there are suggestive clinical data, preclinical data based on GLP-1 receptor staining is unreliable, because the polyclonal antibodies generally used don’t consistently stain GLP-1 transfected cells.

“In nontransfected cells, you would expect to see no uptake, but with two of the antibodies, you see quite a bit of uptake in nontransfected as well as transfected cells.”

A third polyclonal antibody has difficulty showing uptake in either type of cell. Only one, the monoclonal 3F52 antibody released in 2013, seems to reliably differentiate GLP1 receptors in these models.

In Dr. Aroda’s opinion, the more reliable results from the monoclonal antibody cast much doubt on all previous preclinical studies that used the polyclonal antibodies.

Nonrandomized data based on case reporting also add to the uncertainty, she said. Data in the Food and Drug Administration’s adverse events reporting system have shown a five- to six-time increased risk of incretin-associated pancreatitis and pancreatic cancer, but “even the FDA has said that spontaneous reports cannot be used to determine the true incidence rates of drug adverse events.” Issues of underreporting, lack of established background rates, and inadequate documentation of clinical details (comorbidities, concomitant medications, and medication errors) cloud the picture. Clarity will remain uncertain as long as decisions about safety are made based on such data.

Similar problems plague studies of discharge data, reflected in the fact that many of them have come to conflicting determinations. The most recent data, however, come from a meta-analysis comprising more than 1.3 million patients among nine insurance claims databases in North America and the European Union. The analysis found no increased risk of acute pancreatitis and any incretin-based therapy (Diabetes Obes. Metab. 2015;17:32-41).

Another recent meta-analysis showed that the adjusted risk of acute pancreatitis was not increased among Danes who had been treated with an incretin drug (Diabetes Care 2015 [doi:10.2337/dc13-2983])

A 2013 study of brain-dead organ donors did find a 40% increased pancreatic mass in diabetes patients treated with incretin therapy, compared to those who didn’t get it and to control patients. Treated patients also over-expressed both exocrine cell proliferation and pancreatic intraepithelial neoplasia (Diabetes 2013;62:2595-604).

“This study has been analyzed and reanalyzed,” Dr. Aroda said. “But it’s really comparing apples to oranges. Five patients with diabetes weren’t on any medication; four were on insulin and four on metformin only; and seven were on two or more agents. Age ranged from 40 to 58 years, and we know age is a big risk factor here.”

Dr. Aroda also examined individual drugs in her own extensive patient database. She found no differences in pancreatitis or cancer associated with liraglutide, exenatide, lixisenatide, or sitagliptin.

The European Medicines Agency is conducting a large evaluation of cardiovascular, cerebrovascular, renal and pancreatic events among diabetes patients taking noninsulin glucose-lowering agents.(SAFEGUARD). It will include combined data covering more than 240 million patient/years.

The National Institutes of Health is also looking at the issue with a consortium study of chronic pancreatitis and pancreatic cancer in diabetes patients.

These projects should result in a considerable amount of reliable data on the issue, Dr. Aroda said.

In the meantime, neither the American Diabetes Association, the Endocrine Society or any European agencies have changed their treatment guidelines with regard to incretin-based therapies.

Dr. Aroda had no financial disclosures.

[email protected]

On Twitter @alz_gal

NEW YORK–Incretin-based diabetes medications may not be as harmful to the pancreas as previously feared.

Emerging clinical data, combined with concerns about the accuracy of polyclonal GLP-1 receptor antibody staining, suggest that there may be little to no risk for either treatment-related pancreatitis or pancreatic cancer in patients with diabetes, Dr. Vanita R. Aroda said at the annual advanced postgraduate course held by the American Diabetes Association.

“No study has definitely concluded that there is a causal link, and but we should still keep the risk as something to at least be aware of,” said Dr. Aroda of the MedStar Research Institute, Hyattsville, Md. “Until we have more information, patients who have pancreatic risk factors probably shouldn’t receive the drugs.”

A number of confounders cast doubt on past studies showing a pathologic association between incretins and pancreatic adverse events. Although there are suggestive clinical data, preclinical data based on GLP-1 receptor staining is unreliable, because the polyclonal antibodies generally used don’t consistently stain GLP-1 transfected cells.

“In nontransfected cells, you would expect to see no uptake, but with two of the antibodies, you see quite a bit of uptake in nontransfected as well as transfected cells.”

A third polyclonal antibody has difficulty showing uptake in either type of cell. Only one, the monoclonal 3F52 antibody released in 2013, seems to reliably differentiate GLP1 receptors in these models.

In Dr. Aroda’s opinion, the more reliable results from the monoclonal antibody cast much doubt on all previous preclinical studies that used the polyclonal antibodies.

Nonrandomized data based on case reporting also add to the uncertainty, she said. Data in the Food and Drug Administration’s adverse events reporting system have shown a five- to six-time increased risk of incretin-associated pancreatitis and pancreatic cancer, but “even the FDA has said that spontaneous reports cannot be used to determine the true incidence rates of drug adverse events.” Issues of underreporting, lack of established background rates, and inadequate documentation of clinical details (comorbidities, concomitant medications, and medication errors) cloud the picture. Clarity will remain uncertain as long as decisions about safety are made based on such data.

Similar problems plague studies of discharge data, reflected in the fact that many of them have come to conflicting determinations. The most recent data, however, come from a meta-analysis comprising more than 1.3 million patients among nine insurance claims databases in North America and the European Union. The analysis found no increased risk of acute pancreatitis and any incretin-based therapy (Diabetes Obes. Metab. 2015;17:32-41).

Another recent meta-analysis showed that the adjusted risk of acute pancreatitis was not increased among Danes who had been treated with an incretin drug (Diabetes Care 2015 [doi:10.2337/dc13-2983])

A 2013 study of brain-dead organ donors did find a 40% increased pancreatic mass in diabetes patients treated with incretin therapy, compared to those who didn’t get it and to control patients. Treated patients also over-expressed both exocrine cell proliferation and pancreatic intraepithelial neoplasia (Diabetes 2013;62:2595-604).

“This study has been analyzed and reanalyzed,” Dr. Aroda said. “But it’s really comparing apples to oranges. Five patients with diabetes weren’t on any medication; four were on insulin and four on metformin only; and seven were on two or more agents. Age ranged from 40 to 58 years, and we know age is a big risk factor here.”

Dr. Aroda also examined individual drugs in her own extensive patient database. She found no differences in pancreatitis or cancer associated with liraglutide, exenatide, lixisenatide, or sitagliptin.

The European Medicines Agency is conducting a large evaluation of cardiovascular, cerebrovascular, renal and pancreatic events among diabetes patients taking noninsulin glucose-lowering agents.(SAFEGUARD). It will include combined data covering more than 240 million patient/years.

The National Institutes of Health is also looking at the issue with a consortium study of chronic pancreatitis and pancreatic cancer in diabetes patients.

These projects should result in a considerable amount of reliable data on the issue, Dr. Aroda said.

In the meantime, neither the American Diabetes Association, the Endocrine Society or any European agencies have changed their treatment guidelines with regard to incretin-based therapies.

Dr. Aroda had no financial disclosures.

[email protected]

On Twitter @alz_gal