Diabetes Hub

STOCKHOLM – Clinicians might want to consider more routinely monitoring levels of vitamin B₁₂ in their diabetic patients who are using metformin, according to new data from the HOME (Hyperinsulinaemia: the Outcome of Its Metabolic Effects) randomized controlled trial, which showed that B₁₂ depletion was linked to neurotoxicity.

The new study findings, presented at the annual meeting of the European Association for the Study of Diabetes, showed that metformin increased levels of serum methylmalonic acid (MMA), the gold standard biomarker of tissue B₁₂ deficiency, and that this in turn was linked to neuropathy measured using a validated score.

“We earlier showed that metformin causes B₁₂ deficiency (<150 pmol/L) with a number needed to harm of 14 after 4.3 years,” said study investigator Dr. Mattijs Out of Bethesda Diabetes Research Center in Hoogeveen, the Netherlands, referring to the original results of the trial (BMJ. 2010;340:c2181).

“Today I showed you that metformin increases MMA, dose dependently and progressively over time,” he added. “Metformin has two opposite effects on neuropathy,” he continued, “a neuroprotective effect by improving glycemic control and a neurotoxic effect by inducing B₁₂ depletion.”

Dr. Out noted that metformin remains the cornerstone of type 2 diabetes therapy with over 100 million prescriptions per year, putting many patients at risk for B₁₂ deficiency and its consequences.

Current guidelines from the American Diabetes Association and EASD mention B₁₂ deficiency as a potential downside of metformin use but do not go so far as giving specific recommendations because of lack of evidence on whether screening should be routinely performed or if vitamin B₁₂ supplements should be given.

“Consequences of vitamin B₁₂ deficiency, such as neuropathy or mental changes, may be profound,” Dr. Out said. Changes because of B₁₂ deficits can be difficult to diagnose because they may be ascribed to old age or diabetes itself, and they may become irreversible if unchecked, he observed. Diagnosing and managing B₁₂ deficiency is, in theory, “easy, cheap, and effective,” he said. A new trial would be needed, however, to determine whether screening for B₁₂ deficiency or supplementation would be the better approach.

In the current study, structural equation monitoring (SEM) was used to determine the likely effects of metformin on the Valk neuropathy score (Diabetes Med. 1992;9:716-21) directly and via effects on hemoglobin A_1c and MMA. The analysis involved 390 insulin-treated patients with type 2 diabetes who were also treated with 850 mg metformin or placebo up to three times daily for 52 months. Over a 4.3-year follow-up period, patients had HbA_1c and neuropathy scores measured 17 times, and MMA was measured at six visits.

Compared with placebo, metformin use was associated with a significant (P= .001) 0.039 micromol/L (95% confidence interval, 0.019-0.055) increase in MMA over the course of the study.

While there was no significant difference in neuropathy scores between the placebo- and metformin-treated groups, SEM showed that metformin had a beneficial effect on lowering the neuropathy score via lowering HbA_1c and an adverse effect on the neuropathy score by increasing MMA levels. Overall, metformin was associated with a 0.25-point increase in the neuropathy score, suggesting the net effect of the oral hypoglycemic drug is a negative one as higher scores mean worse neuropathy.

After the presentation of the findings, session chair Dr. Guntram Schernthaner commented: “In my center in Vienna, we have been using metformin for 30 years, but we have never used this high dosage [850 mg]. We have suspected several times the B₁₂ deficiency and we measured it in many cases, but we never found any cases of severe B₁₂ deficiency.”

Dr. Schernthaner, who is professor of medicine at the University of Vienna in Austria, suggested the next step would be to perform a large trial of maybe 2,000 metformin users to see how often B₁₂ deficiency really occurs.

Dr. Out agreed a larger trial would be the ideal and conceded that the effect size was small. However, with such a large number of patients using the drug worldwide, potentially “many patients are at risk.”

He said a direct effect of metformin on neuropathy would perhaps not be found by general screening because of its protective effect via improved glycemic control, “so you may miss B₁₂ deficiency–induced neuropathy.” Measuring MMA, where possible, may be a solution.

STOCKHOLM – Clinicians might want to consider more routinely monitoring levels of vitamin B₁₂ in their diabetic patients who are using metformin, according to new data from the HOME (Hyperinsulinaemia: the Outcome of Its Metabolic Effects) randomized controlled trial, which showed that B₁₂ depletion was linked to neurotoxicity.

The new study findings, presented at the annual meeting of the European Association for the Study of Diabetes, showed that metformin increased levels of serum methylmalonic acid (MMA), the gold standard biomarker of tissue B₁₂ deficiency, and that this in turn was linked to neuropathy measured using a validated score.

“We earlier showed that metformin causes B₁₂ deficiency (<150 pmol/L) with a number needed to harm of 14 after 4.3 years,” said study investigator Dr. Mattijs Out of Bethesda Diabetes Research Center in Hoogeveen, the Netherlands, referring to the original results of the trial (BMJ. 2010;340:c2181).

“Today I showed you that metformin increases MMA, dose dependently and progressively over time,” he added. “Metformin has two opposite effects on neuropathy,” he continued, “a neuroprotective effect by improving glycemic control and a neurotoxic effect by inducing B₁₂ depletion.”

Dr. Out noted that metformin remains the cornerstone of type 2 diabetes therapy with over 100 million prescriptions per year, putting many patients at risk for B₁₂ deficiency and its consequences.

Current guidelines from the American Diabetes Association and EASD mention B₁₂ deficiency as a potential downside of metformin use but do not go so far as giving specific recommendations because of lack of evidence on whether screening should be routinely performed or if vitamin B₁₂ supplements should be given.

“Consequences of vitamin B₁₂ deficiency, such as neuropathy or mental changes, may be profound,” Dr. Out said. Changes because of B₁₂ deficits can be difficult to diagnose because they may be ascribed to old age or diabetes itself, and they may become irreversible if unchecked, he observed. Diagnosing and managing B₁₂ deficiency is, in theory, “easy, cheap, and effective,” he said. A new trial would be needed, however, to determine whether screening for B₁₂ deficiency or supplementation would be the better approach.

In the current study, structural equation monitoring (SEM) was used to determine the likely effects of metformin on the Valk neuropathy score (Diabetes Med. 1992;9:716-21) directly and via effects on hemoglobin A_1c and MMA. The analysis involved 390 insulin-treated patients with type 2 diabetes who were also treated with 850 mg metformin or placebo up to three times daily for 52 months. Over a 4.3-year follow-up period, patients had HbA_1c and neuropathy scores measured 17 times, and MMA was measured at six visits.

Compared with placebo, metformin use was associated with a significant (P= .001) 0.039 micromol/L (95% confidence interval, 0.019-0.055) increase in MMA over the course of the study.

While there was no significant difference in neuropathy scores between the placebo- and metformin-treated groups, SEM showed that metformin had a beneficial effect on lowering the neuropathy score via lowering HbA_1c and an adverse effect on the neuropathy score by increasing MMA levels. Overall, metformin was associated with a 0.25-point increase in the neuropathy score, suggesting the net effect of the oral hypoglycemic drug is a negative one as higher scores mean worse neuropathy.

After the presentation of the findings, session chair Dr. Guntram Schernthaner commented: “In my center in Vienna, we have been using metformin for 30 years, but we have never used this high dosage [850 mg]. We have suspected several times the B₁₂ deficiency and we measured it in many cases, but we never found any cases of severe B₁₂ deficiency.”

Dr. Schernthaner, who is professor of medicine at the University of Vienna in Austria, suggested the next step would be to perform a large trial of maybe 2,000 metformin users to see how often B₁₂ deficiency really occurs.

Dr. Out agreed a larger trial would be the ideal and conceded that the effect size was small. However, with such a large number of patients using the drug worldwide, potentially “many patients are at risk.”

He said a direct effect of metformin on neuropathy would perhaps not be found by general screening because of its protective effect via improved glycemic control, “so you may miss B₁₂ deficiency–induced neuropathy.” Measuring MMA, where possible, may be a solution.

STOCKHOLM – Clinicians might want to consider more routinely monitoring levels of vitamin B₁₂ in their diabetic patients who are using metformin, according to new data from the HOME (Hyperinsulinaemia: the Outcome of Its Metabolic Effects) randomized controlled trial, which showed that B₁₂ depletion was linked to neurotoxicity.

The new study findings, presented at the annual meeting of the European Association for the Study of Diabetes, showed that metformin increased levels of serum methylmalonic acid (MMA), the gold standard biomarker of tissue B₁₂ deficiency, and that this in turn was linked to neuropathy measured using a validated score.

“We earlier showed that metformin causes B₁₂ deficiency (<150 pmol/L) with a number needed to harm of 14 after 4.3 years,” said study investigator Dr. Mattijs Out of Bethesda Diabetes Research Center in Hoogeveen, the Netherlands, referring to the original results of the trial (BMJ. 2010;340:c2181).

“Today I showed you that metformin increases MMA, dose dependently and progressively over time,” he added. “Metformin has two opposite effects on neuropathy,” he continued, “a neuroprotective effect by improving glycemic control and a neurotoxic effect by inducing B₁₂ depletion.”

Dr. Out noted that metformin remains the cornerstone of type 2 diabetes therapy with over 100 million prescriptions per year, putting many patients at risk for B₁₂ deficiency and its consequences.

Current guidelines from the American Diabetes Association and EASD mention B₁₂ deficiency as a potential downside of metformin use but do not go so far as giving specific recommendations because of lack of evidence on whether screening should be routinely performed or if vitamin B₁₂ supplements should be given.

“Consequences of vitamin B₁₂ deficiency, such as neuropathy or mental changes, may be profound,” Dr. Out said. Changes because of B₁₂ deficits can be difficult to diagnose because they may be ascribed to old age or diabetes itself, and they may become irreversible if unchecked, he observed. Diagnosing and managing B₁₂ deficiency is, in theory, “easy, cheap, and effective,” he said. A new trial would be needed, however, to determine whether screening for B₁₂ deficiency or supplementation would be the better approach.

In the current study, structural equation monitoring (SEM) was used to determine the likely effects of metformin on the Valk neuropathy score (Diabetes Med. 1992;9:716-21) directly and via effects on hemoglobin A_1c and MMA. The analysis involved 390 insulin-treated patients with type 2 diabetes who were also treated with 850 mg metformin or placebo up to three times daily for 52 months. Over a 4.3-year follow-up period, patients had HbA_1c and neuropathy scores measured 17 times, and MMA was measured at six visits.

Compared with placebo, metformin use was associated with a significant (P= .001) 0.039 micromol/L (95% confidence interval, 0.019-0.055) increase in MMA over the course of the study.

While there was no significant difference in neuropathy scores between the placebo- and metformin-treated groups, SEM showed that metformin had a beneficial effect on lowering the neuropathy score via lowering HbA_1c and an adverse effect on the neuropathy score by increasing MMA levels. Overall, metformin was associated with a 0.25-point increase in the neuropathy score, suggesting the net effect of the oral hypoglycemic drug is a negative one as higher scores mean worse neuropathy.

After the presentation of the findings, session chair Dr. Guntram Schernthaner commented: “In my center in Vienna, we have been using metformin for 30 years, but we have never used this high dosage [850 mg]. We have suspected several times the B₁₂ deficiency and we measured it in many cases, but we never found any cases of severe B₁₂ deficiency.”

Dr. Schernthaner, who is professor of medicine at the University of Vienna in Austria, suggested the next step would be to perform a large trial of maybe 2,000 metformin users to see how often B₁₂ deficiency really occurs.

Dr. Out agreed a larger trial would be the ideal and conceded that the effect size was small. However, with such a large number of patients using the drug worldwide, potentially “many patients are at risk.”

He said a direct effect of metformin on neuropathy would perhaps not be found by general screening because of its protective effect via improved glycemic control, “so you may miss B₁₂ deficiency–induced neuropathy.” Measuring MMA, where possible, may be a solution.

STOCKHOLM – Adding liraglutide to multiple daily insulin injections helped stabilize blood glucose in patients with type 2 diabetes, while also resulting in weight loss and reduction of daily insulin doses.

All this was accomplished without an increase in the risk of hypoglycemia, Dr. Marcus Lind said at the annual meeting of the European Association for the Study of Diabetes.

A randomized, placebo-controlled study showed that the approach was successful in patients with long-standing disease, said Dr. Lind of the University of Gothenburg, Sweden. “We used to think that incretin-based therapies were most helpful in early type 2 diabetes. This seems to confirm that they are effective during the entire disease process.”

The soon-to-be-published 24-week study examined the addition of liraglutide in 124 patients with type 2 diabetes of long duration (a mean of 17 years). They were overweight, with a mean body mass index of 33.5 (about 218 pounds). At baseline, their mean hemoglobin A1c was 9%; they were taking a mean of 105 units of insulin each day in about four injections.

The study’s primary endpoint was change in HbA1c at 24 weeks. This declined significantly more among those taking liraglutide than those taking a placebo (–1.6% vs. –0.4%). “This is a difference of 1.1%, which is very clinically significant,” Dr. Lind said.

Dr. Lind assigned individualized HbA1c goals to patients, with the cutpoints of 7%, 7.5%, and 8%. Significantly more patients taking liraglutide were able to achieve those goals (see chart).

They also lost about 8 pounds more weight than did the placebo patients, and experienced a greater decrease in systolic blood pressure (–5.5 mm Hg more than placebo). There was no effect on diastolic blood pressure or lipids.

There were no severe hypoglycemic events in either group, nor any between-group difference in nonsevere events.

There were three serious adverse events among three patients taking liraglutide, and eight among four patients taking placebo; none of these were pancreatitis or pancreatic cancer.

Patients taking the study drug experienced significantly more nausea, especially at the beginning of the study, compared to the end of the study (22% vs. 5%).

The study was investigator initiated but received financial support from Novo Nordisk, which provided the drug. Dr. Lind disclosed financial relationships with numerous pharmaceutical companies, including honoraria from Novo Nordisk.

[email protected]

STOCKHOLM – Adding liraglutide to multiple daily insulin injections helped stabilize blood glucose in patients with type 2 diabetes, while also resulting in weight loss and reduction of daily insulin doses.

All this was accomplished without an increase in the risk of hypoglycemia, Dr. Marcus Lind said at the annual meeting of the European Association for the Study of Diabetes.

A randomized, placebo-controlled study showed that the approach was successful in patients with long-standing disease, said Dr. Lind of the University of Gothenburg, Sweden. “We used to think that incretin-based therapies were most helpful in early type 2 diabetes. This seems to confirm that they are effective during the entire disease process.”

The soon-to-be-published 24-week study examined the addition of liraglutide in 124 patients with type 2 diabetes of long duration (a mean of 17 years). They were overweight, with a mean body mass index of 33.5 (about 218 pounds). At baseline, their mean hemoglobin A1c was 9%; they were taking a mean of 105 units of insulin each day in about four injections.

The study’s primary endpoint was change in HbA1c at 24 weeks. This declined significantly more among those taking liraglutide than those taking a placebo (–1.6% vs. –0.4%). “This is a difference of 1.1%, which is very clinically significant,” Dr. Lind said.

Dr. Lind assigned individualized HbA1c goals to patients, with the cutpoints of 7%, 7.5%, and 8%. Significantly more patients taking liraglutide were able to achieve those goals (see chart).

They also lost about 8 pounds more weight than did the placebo patients, and experienced a greater decrease in systolic blood pressure (–5.5 mm Hg more than placebo). There was no effect on diastolic blood pressure or lipids.

There were no severe hypoglycemic events in either group, nor any between-group difference in nonsevere events.

There were three serious adverse events among three patients taking liraglutide, and eight among four patients taking placebo; none of these were pancreatitis or pancreatic cancer.

Patients taking the study drug experienced significantly more nausea, especially at the beginning of the study, compared to the end of the study (22% vs. 5%).

The study was investigator initiated but received financial support from Novo Nordisk, which provided the drug. Dr. Lind disclosed financial relationships with numerous pharmaceutical companies, including honoraria from Novo Nordisk.

[email protected]

STOCKHOLM – Adding liraglutide to multiple daily insulin injections helped stabilize blood glucose in patients with type 2 diabetes, while also resulting in weight loss and reduction of daily insulin doses.

All this was accomplished without an increase in the risk of hypoglycemia, Dr. Marcus Lind said at the annual meeting of the European Association for the Study of Diabetes.

A randomized, placebo-controlled study showed that the approach was successful in patients with long-standing disease, said Dr. Lind of the University of Gothenburg, Sweden. “We used to think that incretin-based therapies were most helpful in early type 2 diabetes. This seems to confirm that they are effective during the entire disease process.”

The soon-to-be-published 24-week study examined the addition of liraglutide in 124 patients with type 2 diabetes of long duration (a mean of 17 years). They were overweight, with a mean body mass index of 33.5 (about 218 pounds). At baseline, their mean hemoglobin A1c was 9%; they were taking a mean of 105 units of insulin each day in about four injections.

The study’s primary endpoint was change in HbA1c at 24 weeks. This declined significantly more among those taking liraglutide than those taking a placebo (–1.6% vs. –0.4%). “This is a difference of 1.1%, which is very clinically significant,” Dr. Lind said.

Dr. Lind assigned individualized HbA1c goals to patients, with the cutpoints of 7%, 7.5%, and 8%. Significantly more patients taking liraglutide were able to achieve those goals (see chart).

They also lost about 8 pounds more weight than did the placebo patients, and experienced a greater decrease in systolic blood pressure (–5.5 mm Hg more than placebo). There was no effect on diastolic blood pressure or lipids.

There were no severe hypoglycemic events in either group, nor any between-group difference in nonsevere events.

There were three serious adverse events among three patients taking liraglutide, and eight among four patients taking placebo; none of these were pancreatitis or pancreatic cancer.

Patients taking the study drug experienced significantly more nausea, especially at the beginning of the study, compared to the end of the study (22% vs. 5%).

The study was investigator initiated but received financial support from Novo Nordisk, which provided the drug. Dr. Lind disclosed financial relationships with numerous pharmaceutical companies, including honoraria from Novo Nordisk.

[email protected]

Cash register receipts, tin can linings, and a range of cosmetics and other common household products increasingly are implicated in the most intractable of society’s diseases such as obesity and diabetes.

So-called endocrine-disrupting chemicals have become so common, according to the Washington-based Endocrine Society, that nearly every human alive has been exposed to at least one such chemical, probably more than once, and just as likely, over an extended period of time.

©tezzstock/thinkstockphotos.com

The World Health Organization reports that there are more than 800 known endocrine disrupting chemicals (EDCs) used in products globally, but only a fraction of them have been tested in humans. What effects, if any, this exposure is having on individuals is still unknown, but data linking the ability of EDCs – either singularly or in combination – to mimic, block, or otherwise interfere with the body’s natural hormone signaling has some experts sounding the alarm.

“The evidence is more definitive than ever before – EDCs disrupt hormones in a manner that harms human health,” Andrea C. Gore, Ph.D., a pharmacology professor at the University of Texas at Austin, said in a press conference. Dr. Gore chairs the Endocrine Society task force that recently released an executive summary of its second scientific statement on EDCs. The Society presented the statement, an update of one released in 2009, at this year’s International Conference on Chemicals Management annual meeting in Geneva.

Because the endocrine system’s role is to interact with the environment, it is predisposed to react to triggers increasingly found in everything from pesticides to shower curtains, which have now made their way into waterways and the food chain primarily without any studies on their impact. “Both natural hormones and EDCs have unique dose-response properties [and can] act at very-low doses,” Dr. Gore told reporters. “We’re exposed throughout our lives.”

The use of EDCs largely began post-WWII with pesticides such as DDT (dichlorodiphenyltrichloroethane), but over time came to include use as thickeners, plastic softeners, and scent in many common household items. Dr. Gore told a reporter that even though these chemicals were not intended to enter the environment at large, decades of use has made their entry into the food chain inevitable. The population health effects of this are only now becoming evident as data accumulate linking EDCs to a constellation of ill health effects.

“In humans, there are strong epidemiological associations between EDCs and chronic diseases.” Dr. Gore said.

She specifically cited obesity, diabetes, and a range of reproductive disorders, including infertility and certain hormone-related cancers. Research also shows a link between prenatal EDC exposure in animals to obesity, insulin resistance, and overabundant insulin later in life.

The Society’s meta-analysis of more than 1,300 studies published in the last 5 years also implicated EDCs in disorders of the prostate gland, the thyroid, and the neuroendocrine systems, the latter two being particularly vulnerable because of their role in hormone regulation at all stages of development.

“We’re particularly concerned about fetuses and how exposure can set the stage for later development of diseases,” Dr. Gore said, noting that human studies have shown a link between higher EDC exposures over time and cognitive deficits and other adverse neurocognitive outcomes.

Because the effect of EDC exposure differs according to the dose, length, and timing of exposure, designing studies to measure any harm has been difficult, said Dr. Gore, although in the past 5 years, there has been increased insight into the molecular mechanisms underlying EDCs.

Among the most common EDCs are bisphenol A (BPA) and phthalates, synthetic chemicals that bind to hormone receptors and depending upon the dose, either potentiate, inhibit – or both – the hormone’s effect on receptors. These EDCs frequently occur in toys, bottle nipples, rain coats, shower curtains, and in medical supplies such as blood bags, IV tubing, and catheters.

Initially registered as a pesticide, the EDC triclosan’s antimicrobial power has meant it is now used in deodorants and even in toothpaste. Triclosan has been shown to disrupt the thyroid, and to have antiestrogenic, and antiandrogenic properties. It also has been linked to asthma.

Plastic water bottles and disposable, plastic-based food packaging commonly found in microwaveable products often are high in BPAs, according to Dr. Gore, who urged all primary care physicians to counsel patients on the importance of avoiding products that contain them whenever possible, particularly in cases of pediatric obesity or diabetes, and for patients who are pregnant or in the family-planning stages. “You might not see an adverse outcome until years or decades later.”

Because many EDCs are lipophilic, our bodies often store them in our fat cells, often for years at a time.

While bisphenol A tends to exit the body quickly, we are commonly exposed to it on a daily basis, usually through a compound that leaches into our food, allowing the chemical an opportunity to exert an effect, even if the results of this effect aren’t immediately apparent. “If it’s a pregnant woman or someone planning a family, that exposure can change something,” Dr. Gore warned.

Although earlier studies had linked EDC exposure to a variety of reproductive health concerns, Dr. Gore said that since the Society’s last statement, there is much more corroborating evidence. In particular, polycystic ovarian syndrome in humans has been associated with higher body burdens of BPA and other chemicals, as have endometriosis, fibroids, and some adverse birth outcomes. Still, much of the data come from animal studies, and studies of specific links between EDCs and reproductive outcomes and cancers are inconsistent.

According to Dr. Renee Howard, a pediatric dermatologist with Sutter Health in San Francisco, who regularly gives presentations on the effects of EDCs in cosmetics and other skin care products, although much of the current research shows a link between EDCs and chronic illness, so far a causal relationship has not been established. Still, she said she routinely tells other physicians to keep an “open mind” when discussing EDCs with patients.

“We can acknowledge there is uncertainty, and we can tell patients that these chemicals are actively being studied, but that the studies are, as of now, inconclusive, and that there are still no documented adverse health effects associated with skin care products,” Dr. Howard said. Nevertheless, she said common sense dictates her to counsel patients to avoid products containing the EDC triclosan such as antimicrobials and scented products. She also advises them to eat organic produce in order to avoid pesticides.

Dr. Gore and her coauthors hope the statement will help bump EDC oversight higher up the policy chain globally.

“Exposure to endocrine disrupting chemicals during early development can have long-lasting, even permanent consequences,” Endocrine Society member Dr. Jean-Pierre Bourguignon, a professor of pediatric endocrinology at the University of Liège in Belgium, said in a statement. “The science is clear, and it’s time for policy makers to take this wealth of evidence into account as they develop legislation.”

To that end, earlier this year, twin bills are now before the House and Senate, which – if passed – will take effect in 2018, banning the sale of any personal care products containing microbeads, BPA-rich, microscopic plastic particles that have entered much of the natural water supply, threatening marine life which often mistake the tiny bits as food. Meanwhile, Minnesota has banned the use of triclosan statewide as of 2017.

Dr. Gore also said in addition to funding for this research being made a priority, it’s time to rethink who gets to be in on the science. Rather than just industrial chemists, she believes the teams should include so-called “green chemists,” basic, translational, and clinical scientists; epidemiologists, as well as public health professionals. Health care providers should be familiar with endocrine science and the latest developments in EDC research, accordingly, because, said Dr. Gore, “The [health] costs of EDCs have been estimated in the hundreds of millions of dollars. Prevention might seem expensive, but it’s far-less-expensive than all the ensuing diseases.”

Most of all, Dr. Gore and her colleagues emphasize that there will never be “absolute proof” of anything, but that taking action to stem exposure is essential.

The analysis was sponsored by the Endocrine Society. Dr. Gore is editor in chief of Endocrinology. Dr. Howard disclosed no relevant financial relationships.

[email protected]

On Twitter @whitneymcknight

Cash register receipts, tin can linings, and a range of cosmetics and other common household products increasingly are implicated in the most intractable of society’s diseases such as obesity and diabetes.

So-called endocrine-disrupting chemicals have become so common, according to the Washington-based Endocrine Society, that nearly every human alive has been exposed to at least one such chemical, probably more than once, and just as likely, over an extended period of time.

©tezzstock/thinkstockphotos.com

The World Health Organization reports that there are more than 800 known endocrine disrupting chemicals (EDCs) used in products globally, but only a fraction of them have been tested in humans. What effects, if any, this exposure is having on individuals is still unknown, but data linking the ability of EDCs – either singularly or in combination – to mimic, block, or otherwise interfere with the body’s natural hormone signaling has some experts sounding the alarm.

“The evidence is more definitive than ever before – EDCs disrupt hormones in a manner that harms human health,” Andrea C. Gore, Ph.D., a pharmacology professor at the University of Texas at Austin, said in a press conference. Dr. Gore chairs the Endocrine Society task force that recently released an executive summary of its second scientific statement on EDCs. The Society presented the statement, an update of one released in 2009, at this year’s International Conference on Chemicals Management annual meeting in Geneva.

Because the endocrine system’s role is to interact with the environment, it is predisposed to react to triggers increasingly found in everything from pesticides to shower curtains, which have now made their way into waterways and the food chain primarily without any studies on their impact. “Both natural hormones and EDCs have unique dose-response properties [and can] act at very-low doses,” Dr. Gore told reporters. “We’re exposed throughout our lives.”

The use of EDCs largely began post-WWII with pesticides such as DDT (dichlorodiphenyltrichloroethane), but over time came to include use as thickeners, plastic softeners, and scent in many common household items. Dr. Gore told a reporter that even though these chemicals were not intended to enter the environment at large, decades of use has made their entry into the food chain inevitable. The population health effects of this are only now becoming evident as data accumulate linking EDCs to a constellation of ill health effects.

“In humans, there are strong epidemiological associations between EDCs and chronic diseases.” Dr. Gore said.

She specifically cited obesity, diabetes, and a range of reproductive disorders, including infertility and certain hormone-related cancers. Research also shows a link between prenatal EDC exposure in animals to obesity, insulin resistance, and overabundant insulin later in life.

The Society’s meta-analysis of more than 1,300 studies published in the last 5 years also implicated EDCs in disorders of the prostate gland, the thyroid, and the neuroendocrine systems, the latter two being particularly vulnerable because of their role in hormone regulation at all stages of development.

“We’re particularly concerned about fetuses and how exposure can set the stage for later development of diseases,” Dr. Gore said, noting that human studies have shown a link between higher EDC exposures over time and cognitive deficits and other adverse neurocognitive outcomes.

Because the effect of EDC exposure differs according to the dose, length, and timing of exposure, designing studies to measure any harm has been difficult, said Dr. Gore, although in the past 5 years, there has been increased insight into the molecular mechanisms underlying EDCs.

Among the most common EDCs are bisphenol A (BPA) and phthalates, synthetic chemicals that bind to hormone receptors and depending upon the dose, either potentiate, inhibit – or both – the hormone’s effect on receptors. These EDCs frequently occur in toys, bottle nipples, rain coats, shower curtains, and in medical supplies such as blood bags, IV tubing, and catheters.

Initially registered as a pesticide, the EDC triclosan’s antimicrobial power has meant it is now used in deodorants and even in toothpaste. Triclosan has been shown to disrupt the thyroid, and to have antiestrogenic, and antiandrogenic properties. It also has been linked to asthma.

Plastic water bottles and disposable, plastic-based food packaging commonly found in microwaveable products often are high in BPAs, according to Dr. Gore, who urged all primary care physicians to counsel patients on the importance of avoiding products that contain them whenever possible, particularly in cases of pediatric obesity or diabetes, and for patients who are pregnant or in the family-planning stages. “You might not see an adverse outcome until years or decades later.”

Because many EDCs are lipophilic, our bodies often store them in our fat cells, often for years at a time.

While bisphenol A tends to exit the body quickly, we are commonly exposed to it on a daily basis, usually through a compound that leaches into our food, allowing the chemical an opportunity to exert an effect, even if the results of this effect aren’t immediately apparent. “If it’s a pregnant woman or someone planning a family, that exposure can change something,” Dr. Gore warned.

Although earlier studies had linked EDC exposure to a variety of reproductive health concerns, Dr. Gore said that since the Society’s last statement, there is much more corroborating evidence. In particular, polycystic ovarian syndrome in humans has been associated with higher body burdens of BPA and other chemicals, as have endometriosis, fibroids, and some adverse birth outcomes. Still, much of the data come from animal studies, and studies of specific links between EDCs and reproductive outcomes and cancers are inconsistent.

According to Dr. Renee Howard, a pediatric dermatologist with Sutter Health in San Francisco, who regularly gives presentations on the effects of EDCs in cosmetics and other skin care products, although much of the current research shows a link between EDCs and chronic illness, so far a causal relationship has not been established. Still, she said she routinely tells other physicians to keep an “open mind” when discussing EDCs with patients.

“We can acknowledge there is uncertainty, and we can tell patients that these chemicals are actively being studied, but that the studies are, as of now, inconclusive, and that there are still no documented adverse health effects associated with skin care products,” Dr. Howard said. Nevertheless, she said common sense dictates her to counsel patients to avoid products containing the EDC triclosan such as antimicrobials and scented products. She also advises them to eat organic produce in order to avoid pesticides.

Dr. Gore and her coauthors hope the statement will help bump EDC oversight higher up the policy chain globally.

“Exposure to endocrine disrupting chemicals during early development can have long-lasting, even permanent consequences,” Endocrine Society member Dr. Jean-Pierre Bourguignon, a professor of pediatric endocrinology at the University of Liège in Belgium, said in a statement. “The science is clear, and it’s time for policy makers to take this wealth of evidence into account as they develop legislation.”

To that end, earlier this year, twin bills are now before the House and Senate, which – if passed – will take effect in 2018, banning the sale of any personal care products containing microbeads, BPA-rich, microscopic plastic particles that have entered much of the natural water supply, threatening marine life which often mistake the tiny bits as food. Meanwhile, Minnesota has banned the use of triclosan statewide as of 2017.

Dr. Gore also said in addition to funding for this research being made a priority, it’s time to rethink who gets to be in on the science. Rather than just industrial chemists, she believes the teams should include so-called “green chemists,” basic, translational, and clinical scientists; epidemiologists, as well as public health professionals. Health care providers should be familiar with endocrine science and the latest developments in EDC research, accordingly, because, said Dr. Gore, “The [health] costs of EDCs have been estimated in the hundreds of millions of dollars. Prevention might seem expensive, but it’s far-less-expensive than all the ensuing diseases.”

Most of all, Dr. Gore and her colleagues emphasize that there will never be “absolute proof” of anything, but that taking action to stem exposure is essential.

The analysis was sponsored by the Endocrine Society. Dr. Gore is editor in chief of Endocrinology. Dr. Howard disclosed no relevant financial relationships.

[email protected]

On Twitter @whitneymcknight

Cash register receipts, tin can linings, and a range of cosmetics and other common household products increasingly are implicated in the most intractable of society’s diseases such as obesity and diabetes.

So-called endocrine-disrupting chemicals have become so common, according to the Washington-based Endocrine Society, that nearly every human alive has been exposed to at least one such chemical, probably more than once, and just as likely, over an extended period of time.

©tezzstock/thinkstockphotos.com

The World Health Organization reports that there are more than 800 known endocrine disrupting chemicals (EDCs) used in products globally, but only a fraction of them have been tested in humans. What effects, if any, this exposure is having on individuals is still unknown, but data linking the ability of EDCs – either singularly or in combination – to mimic, block, or otherwise interfere with the body’s natural hormone signaling has some experts sounding the alarm.

“The evidence is more definitive than ever before – EDCs disrupt hormones in a manner that harms human health,” Andrea C. Gore, Ph.D., a pharmacology professor at the University of Texas at Austin, said in a press conference. Dr. Gore chairs the Endocrine Society task force that recently released an executive summary of its second scientific statement on EDCs. The Society presented the statement, an update of one released in 2009, at this year’s International Conference on Chemicals Management annual meeting in Geneva.

Because the endocrine system’s role is to interact with the environment, it is predisposed to react to triggers increasingly found in everything from pesticides to shower curtains, which have now made their way into waterways and the food chain primarily without any studies on their impact. “Both natural hormones and EDCs have unique dose-response properties [and can] act at very-low doses,” Dr. Gore told reporters. “We’re exposed throughout our lives.”

The use of EDCs largely began post-WWII with pesticides such as DDT (dichlorodiphenyltrichloroethane), but over time came to include use as thickeners, plastic softeners, and scent in many common household items. Dr. Gore told a reporter that even though these chemicals were not intended to enter the environment at large, decades of use has made their entry into the food chain inevitable. The population health effects of this are only now becoming evident as data accumulate linking EDCs to a constellation of ill health effects.

“In humans, there are strong epidemiological associations between EDCs and chronic diseases.” Dr. Gore said.

She specifically cited obesity, diabetes, and a range of reproductive disorders, including infertility and certain hormone-related cancers. Research also shows a link between prenatal EDC exposure in animals to obesity, insulin resistance, and overabundant insulin later in life.

The Society’s meta-analysis of more than 1,300 studies published in the last 5 years also implicated EDCs in disorders of the prostate gland, the thyroid, and the neuroendocrine systems, the latter two being particularly vulnerable because of their role in hormone regulation at all stages of development.

“We’re particularly concerned about fetuses and how exposure can set the stage for later development of diseases,” Dr. Gore said, noting that human studies have shown a link between higher EDC exposures over time and cognitive deficits and other adverse neurocognitive outcomes.

Because the effect of EDC exposure differs according to the dose, length, and timing of exposure, designing studies to measure any harm has been difficult, said Dr. Gore, although in the past 5 years, there has been increased insight into the molecular mechanisms underlying EDCs.

Among the most common EDCs are bisphenol A (BPA) and phthalates, synthetic chemicals that bind to hormone receptors and depending upon the dose, either potentiate, inhibit – or both – the hormone’s effect on receptors. These EDCs frequently occur in toys, bottle nipples, rain coats, shower curtains, and in medical supplies such as blood bags, IV tubing, and catheters.

Initially registered as a pesticide, the EDC triclosan’s antimicrobial power has meant it is now used in deodorants and even in toothpaste. Triclosan has been shown to disrupt the thyroid, and to have antiestrogenic, and antiandrogenic properties. It also has been linked to asthma.

Plastic water bottles and disposable, plastic-based food packaging commonly found in microwaveable products often are high in BPAs, according to Dr. Gore, who urged all primary care physicians to counsel patients on the importance of avoiding products that contain them whenever possible, particularly in cases of pediatric obesity or diabetes, and for patients who are pregnant or in the family-planning stages. “You might not see an adverse outcome until years or decades later.”

Because many EDCs are lipophilic, our bodies often store them in our fat cells, often for years at a time.

While bisphenol A tends to exit the body quickly, we are commonly exposed to it on a daily basis, usually through a compound that leaches into our food, allowing the chemical an opportunity to exert an effect, even if the results of this effect aren’t immediately apparent. “If it’s a pregnant woman or someone planning a family, that exposure can change something,” Dr. Gore warned.

Although earlier studies had linked EDC exposure to a variety of reproductive health concerns, Dr. Gore said that since the Society’s last statement, there is much more corroborating evidence. In particular, polycystic ovarian syndrome in humans has been associated with higher body burdens of BPA and other chemicals, as have endometriosis, fibroids, and some adverse birth outcomes. Still, much of the data come from animal studies, and studies of specific links between EDCs and reproductive outcomes and cancers are inconsistent.

According to Dr. Renee Howard, a pediatric dermatologist with Sutter Health in San Francisco, who regularly gives presentations on the effects of EDCs in cosmetics and other skin care products, although much of the current research shows a link between EDCs and chronic illness, so far a causal relationship has not been established. Still, she said she routinely tells other physicians to keep an “open mind” when discussing EDCs with patients.

“We can acknowledge there is uncertainty, and we can tell patients that these chemicals are actively being studied, but that the studies are, as of now, inconclusive, and that there are still no documented adverse health effects associated with skin care products,” Dr. Howard said. Nevertheless, she said common sense dictates her to counsel patients to avoid products containing the EDC triclosan such as antimicrobials and scented products. She also advises them to eat organic produce in order to avoid pesticides.

Dr. Gore and her coauthors hope the statement will help bump EDC oversight higher up the policy chain globally.

“Exposure to endocrine disrupting chemicals during early development can have long-lasting, even permanent consequences,” Endocrine Society member Dr. Jean-Pierre Bourguignon, a professor of pediatric endocrinology at the University of Liège in Belgium, said in a statement. “The science is clear, and it’s time for policy makers to take this wealth of evidence into account as they develop legislation.”

To that end, earlier this year, twin bills are now before the House and Senate, which – if passed – will take effect in 2018, banning the sale of any personal care products containing microbeads, BPA-rich, microscopic plastic particles that have entered much of the natural water supply, threatening marine life which often mistake the tiny bits as food. Meanwhile, Minnesota has banned the use of triclosan statewide as of 2017.

Dr. Gore also said in addition to funding for this research being made a priority, it’s time to rethink who gets to be in on the science. Rather than just industrial chemists, she believes the teams should include so-called “green chemists,” basic, translational, and clinical scientists; epidemiologists, as well as public health professionals. Health care providers should be familiar with endocrine science and the latest developments in EDC research, accordingly, because, said Dr. Gore, “The [health] costs of EDCs have been estimated in the hundreds of millions of dollars. Prevention might seem expensive, but it’s far-less-expensive than all the ensuing diseases.”

Most of all, Dr. Gore and her colleagues emphasize that there will never be “absolute proof” of anything, but that taking action to stem exposure is essential.

The analysis was sponsored by the Endocrine Society. Dr. Gore is editor in chief of Endocrinology. Dr. Howard disclosed no relevant financial relationships.

[email protected]

On Twitter @whitneymcknight

Two new insulins have gained FDA approval.

Insulin degludec (Tresiba) and insulin degludec/insulin aspart (Ryzodeg 70/30) – both manufactured by Novo Nordisk – have been shown to improve glucose control in adults with hard-to-regulate type 1 diabetes, and in patients with advanced type 2 diabetes, according to the Food and Drug Administration statement announcing the approvals on Sept. 25.

Insulin degludec is intended to be used as add-on therapy to prandial insulin or oral antidiabetic drugs. Findings from 9 randomized studies comprising almost 4,000 patients supported the approval: three in patients with type 1 disease and six in patients with type 2 disease.

Three trials comprising 1,102 patients with type 1 diabetes examined degludec in combination with prandial insulin or oral therapy. Six trials comprising 2,702 patients with type 2 diabetes also examined the drug in combination with prandial insulin or as an add-on to oral therapy. In all of these studies, degludec was associated with reductions in HbA_1c.

The combination of the long-acting insulin degludec and rapid-acting insulin aspart was evaluated in five studies – one with 362 patients with type 1 diabetes and four comprising 998 patients with type 2 disease.

In the first study, the drug was used with prandial insulin. In the second group of studies, it was administered once or twice a day as the sole treatment.

Both Tresiba and Ryzodeg have been approved in Europe, Mexico, and Japan.

The most common adverse reactions associated with both drugs in clinical trials were hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, itching, rash, edema, and weight gain, according to the FDA.

In 2013, FDA refused to approve either of these drugs, despite a positive recommendation from the review committee. The agency asked for additional cardiovascular risk data, which Novo Nordisk is now acquiring with a 7,600-patient study called DEVOTE. DEVOTE is set to be completed in 2016; it is designed to generate follow-up data for 2 additional years.

In April, the company resubmitted its new drug application based on the study’s interim results, which are not publicly available.

[email protected]

Two new insulins have gained FDA approval.

Insulin degludec (Tresiba) and insulin degludec/insulin aspart (Ryzodeg 70/30) – both manufactured by Novo Nordisk – have been shown to improve glucose control in adults with hard-to-regulate type 1 diabetes, and in patients with advanced type 2 diabetes, according to the Food and Drug Administration statement announcing the approvals on Sept. 25.

Insulin degludec is intended to be used as add-on therapy to prandial insulin or oral antidiabetic drugs. Findings from 9 randomized studies comprising almost 4,000 patients supported the approval: three in patients with type 1 disease and six in patients with type 2 disease.

Three trials comprising 1,102 patients with type 1 diabetes examined degludec in combination with prandial insulin or oral therapy. Six trials comprising 2,702 patients with type 2 diabetes also examined the drug in combination with prandial insulin or as an add-on to oral therapy. In all of these studies, degludec was associated with reductions in HbA_1c.

The combination of the long-acting insulin degludec and rapid-acting insulin aspart was evaluated in five studies – one with 362 patients with type 1 diabetes and four comprising 998 patients with type 2 disease.

In the first study, the drug was used with prandial insulin. In the second group of studies, it was administered once or twice a day as the sole treatment.

Both Tresiba and Ryzodeg have been approved in Europe, Mexico, and Japan.

The most common adverse reactions associated with both drugs in clinical trials were hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, itching, rash, edema, and weight gain, according to the FDA.

In 2013, FDA refused to approve either of these drugs, despite a positive recommendation from the review committee. The agency asked for additional cardiovascular risk data, which Novo Nordisk is now acquiring with a 7,600-patient study called DEVOTE. DEVOTE is set to be completed in 2016; it is designed to generate follow-up data for 2 additional years.

In April, the company resubmitted its new drug application based on the study’s interim results, which are not publicly available.

[email protected]

Two new insulins have gained FDA approval.

Insulin degludec (Tresiba) and insulin degludec/insulin aspart (Ryzodeg 70/30) – both manufactured by Novo Nordisk – have been shown to improve glucose control in adults with hard-to-regulate type 1 diabetes, and in patients with advanced type 2 diabetes, according to the Food and Drug Administration statement announcing the approvals on Sept. 25.

Insulin degludec is intended to be used as add-on therapy to prandial insulin or oral antidiabetic drugs. Findings from 9 randomized studies comprising almost 4,000 patients supported the approval: three in patients with type 1 disease and six in patients with type 2 disease.

Three trials comprising 1,102 patients with type 1 diabetes examined degludec in combination with prandial insulin or oral therapy. Six trials comprising 2,702 patients with type 2 diabetes also examined the drug in combination with prandial insulin or as an add-on to oral therapy. In all of these studies, degludec was associated with reductions in HbA_1c.

The combination of the long-acting insulin degludec and rapid-acting insulin aspart was evaluated in five studies – one with 362 patients with type 1 diabetes and four comprising 998 patients with type 2 disease.

In the first study, the drug was used with prandial insulin. In the second group of studies, it was administered once or twice a day as the sole treatment.

Both Tresiba and Ryzodeg have been approved in Europe, Mexico, and Japan.

The most common adverse reactions associated with both drugs in clinical trials were hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, itching, rash, edema, and weight gain, according to the FDA.

In 2013, FDA refused to approve either of these drugs, despite a positive recommendation from the review committee. The agency asked for additional cardiovascular risk data, which Novo Nordisk is now acquiring with a 7,600-patient study called DEVOTE. DEVOTE is set to be completed in 2016; it is designed to generate follow-up data for 2 additional years.

In April, the company resubmitted its new drug application based on the study’s interim results, which are not publicly available.

[email protected]

STOCKHOLM – Insulin pump therapy is considerably more expensive than daily insulin injections for patients with type 2 diabetes, but the benefits it confers offset about 30% of the price difference.

A cost-modeling study showed that patients who use the pump gain almost another year of life expectancy and experience a delay in the onset of major complications, such as end-stage renal disease and amputation, Stephane Roze said at the annual meeting of the European Association for the Study of Diabetes.

Pump therapy also conferred a significantly improved quality of life over multiple daily injections, a benefit that carries its own economic value, said Mr. Roze of HEVA-HEOR, a health economics evaluation company in Lyon, France.

“Even though these patients are initiating the pump at an older age than patients with type 1 diabetes, the therapy still looks to be cost effective,” he said. “It’s a good investment for payers.”

Mr. Roze used the CORE Diabetes Model to examine the cost/benefit ratio of insulin pump therapy, compared with multiple daily injections in patients with poorly controlled type 2 diabetes who lived in the Netherlands. The CORE model comprises 14 sub-Markov models that run in parallel; it examines all of the micro- and macrovascular complications related to diabetes. Model input data were the cohort characteristics and 6-month clinical outcomes of the OpT2mise study.

The trial examined glucose variability in 331 patients with type 2 diabetes who were randomized to either pump therapy or daily insulin injections.

It is an excellent study for cost-modeling initiatives, Mr. Roze said. It’s multicenter and multinational, conducted in 36 institutions in the United States, Canada, Europe, Israel, and South Africa. The cohort is large and diverse. Importantly, all of the patients had their treatment optimized with daily insulin analogue injections before being randomized. That initial step lent credence to their baseline glucose control; despite optimization, they still had a mean hemoglobin A_1cof 9%. The OpT2mise patients were a mean of 56 years old, with mean disease duration of 15 years.

At 6 months, the study showed that HbA_1c had decreased significantly more in the pump group than in the injection group (1.1% vs. 0.4%). Patients using the pump also needed significantly lower daily insulin doses (97 unit/kg per day vs. 122 unit/kg per day).

These results were inputted into the CORE model, along with the costs of diabetes-related complications in the Netherlands and the costs of both pump therapy and daily insulin injections. For the first year of treatment, pump therapy more than twice as expensive as daily injections (4,407 euros vs. 1,597 euros). This difference remained when costs were extrapolated to year 2 and beyond (4,365 euros vs. 1,555 euros).

The model, however, determined that pump therapy has the potential to extend life expectancy by almost 1 year, compared with injection therapy, by reducing and/or delaying life-threatening diabetes complications. These clinical benefits translated into an additional 9.38 quality-adjusted life-years (QALY) for patients using the pump, compared with 8.95 QALY for patients using injections.

Over a lifetime of treatment (13 years), pump therapy would cost a total of 58,024 euros, compared with 20,237 euros for injection therapy – a difference of 37,787 euros. Compared with injection therapy, though, pump therapy would save almost 10,000 euros in the cost of renal complications; 625 euros in the cost of ulcer, amputation, and neuropathy complications; 152 euros in the cost of eye complications; and 410 euros in complications due to hypoglycemia. These savings reduced the total cost difference between the two to 27,051 euros, Mr. Roze said.

The benefits held over time, despite the paradox of survivorship, he said. “The longer a patient with chronic disease lives, the more opportunity they have to develop a complication.”

The incremental cost-effectiveness ratio was 62,295 euros/QALY – an amount that falls well within the Netherlands’ “willingness to pay” threshold, which is a measure of what payers or society are generally willing to accept as a good value for health care expenditures.

The newest data from OpT2mise, also released at EASD, bolster Mr. Roze’s modeling. In phase II of the study, patients who had been on injections crossed over to pump therapy. Within 6 months of crossover, these patients experienced a mean HbA_1c decrease of 0.8%. By 12 months from study start, when all patients had been on pump therapy for at least 6 months, the mean HbA_1chad dropped to 7.8% from baseline.

“We were reassured to see the 12-month data, which confirm the sustainability of the effect,” Mr. Roze said. “This is one of the main questions when you do health care modeling.”

Mr. Roze is a co-owner of HEVA-HEOR.

[email protected]

STOCKHOLM – Insulin pump therapy is considerably more expensive than daily insulin injections for patients with type 2 diabetes, but the benefits it confers offset about 30% of the price difference.

A cost-modeling study showed that patients who use the pump gain almost another year of life expectancy and experience a delay in the onset of major complications, such as end-stage renal disease and amputation, Stephane Roze said at the annual meeting of the European Association for the Study of Diabetes.

Pump therapy also conferred a significantly improved quality of life over multiple daily injections, a benefit that carries its own economic value, said Mr. Roze of HEVA-HEOR, a health economics evaluation company in Lyon, France.

“Even though these patients are initiating the pump at an older age than patients with type 1 diabetes, the therapy still looks to be cost effective,” he said. “It’s a good investment for payers.”

Mr. Roze used the CORE Diabetes Model to examine the cost/benefit ratio of insulin pump therapy, compared with multiple daily injections in patients with poorly controlled type 2 diabetes who lived in the Netherlands. The CORE model comprises 14 sub-Markov models that run in parallel; it examines all of the micro- and macrovascular complications related to diabetes. Model input data were the cohort characteristics and 6-month clinical outcomes of the OpT2mise study.

The trial examined glucose variability in 331 patients with type 2 diabetes who were randomized to either pump therapy or daily insulin injections.

It is an excellent study for cost-modeling initiatives, Mr. Roze said. It’s multicenter and multinational, conducted in 36 institutions in the United States, Canada, Europe, Israel, and South Africa. The cohort is large and diverse. Importantly, all of the patients had their treatment optimized with daily insulin analogue injections before being randomized. That initial step lent credence to their baseline glucose control; despite optimization, they still had a mean hemoglobin A_1cof 9%. The OpT2mise patients were a mean of 56 years old, with mean disease duration of 15 years.

At 6 months, the study showed that HbA_1c had decreased significantly more in the pump group than in the injection group (1.1% vs. 0.4%). Patients using the pump also needed significantly lower daily insulin doses (97 unit/kg per day vs. 122 unit/kg per day).

These results were inputted into the CORE model, along with the costs of diabetes-related complications in the Netherlands and the costs of both pump therapy and daily insulin injections. For the first year of treatment, pump therapy more than twice as expensive as daily injections (4,407 euros vs. 1,597 euros). This difference remained when costs were extrapolated to year 2 and beyond (4,365 euros vs. 1,555 euros).

The model, however, determined that pump therapy has the potential to extend life expectancy by almost 1 year, compared with injection therapy, by reducing and/or delaying life-threatening diabetes complications. These clinical benefits translated into an additional 9.38 quality-adjusted life-years (QALY) for patients using the pump, compared with 8.95 QALY for patients using injections.

Over a lifetime of treatment (13 years), pump therapy would cost a total of 58,024 euros, compared with 20,237 euros for injection therapy – a difference of 37,787 euros. Compared with injection therapy, though, pump therapy would save almost 10,000 euros in the cost of renal complications; 625 euros in the cost of ulcer, amputation, and neuropathy complications; 152 euros in the cost of eye complications; and 410 euros in complications due to hypoglycemia. These savings reduced the total cost difference between the two to 27,051 euros, Mr. Roze said.

The benefits held over time, despite the paradox of survivorship, he said. “The longer a patient with chronic disease lives, the more opportunity they have to develop a complication.”

The incremental cost-effectiveness ratio was 62,295 euros/QALY – an amount that falls well within the Netherlands’ “willingness to pay” threshold, which is a measure of what payers or society are generally willing to accept as a good value for health care expenditures.

The newest data from OpT2mise, also released at EASD, bolster Mr. Roze’s modeling. In phase II of the study, patients who had been on injections crossed over to pump therapy. Within 6 months of crossover, these patients experienced a mean HbA_1c decrease of 0.8%. By 12 months from study start, when all patients had been on pump therapy for at least 6 months, the mean HbA_1chad dropped to 7.8% from baseline.

“We were reassured to see the 12-month data, which confirm the sustainability of the effect,” Mr. Roze said. “This is one of the main questions when you do health care modeling.”

Mr. Roze is a co-owner of HEVA-HEOR.

[email protected]

STOCKHOLM – Insulin pump therapy is considerably more expensive than daily insulin injections for patients with type 2 diabetes, but the benefits it confers offset about 30% of the price difference.

A cost-modeling study showed that patients who use the pump gain almost another year of life expectancy and experience a delay in the onset of major complications, such as end-stage renal disease and amputation, Stephane Roze said at the annual meeting of the European Association for the Study of Diabetes.

Pump therapy also conferred a significantly improved quality of life over multiple daily injections, a benefit that carries its own economic value, said Mr. Roze of HEVA-HEOR, a health economics evaluation company in Lyon, France.

“Even though these patients are initiating the pump at an older age than patients with type 1 diabetes, the therapy still looks to be cost effective,” he said. “It’s a good investment for payers.”

Mr. Roze used the CORE Diabetes Model to examine the cost/benefit ratio of insulin pump therapy, compared with multiple daily injections in patients with poorly controlled type 2 diabetes who lived in the Netherlands. The CORE model comprises 14 sub-Markov models that run in parallel; it examines all of the micro- and macrovascular complications related to diabetes. Model input data were the cohort characteristics and 6-month clinical outcomes of the OpT2mise study.

The trial examined glucose variability in 331 patients with type 2 diabetes who were randomized to either pump therapy or daily insulin injections.

It is an excellent study for cost-modeling initiatives, Mr. Roze said. It’s multicenter and multinational, conducted in 36 institutions in the United States, Canada, Europe, Israel, and South Africa. The cohort is large and diverse. Importantly, all of the patients had their treatment optimized with daily insulin analogue injections before being randomized. That initial step lent credence to their baseline glucose control; despite optimization, they still had a mean hemoglobin A_1cof 9%. The OpT2mise patients were a mean of 56 years old, with mean disease duration of 15 years.

At 6 months, the study showed that HbA_1c had decreased significantly more in the pump group than in the injection group (1.1% vs. 0.4%). Patients using the pump also needed significantly lower daily insulin doses (97 unit/kg per day vs. 122 unit/kg per day).

These results were inputted into the CORE model, along with the costs of diabetes-related complications in the Netherlands and the costs of both pump therapy and daily insulin injections. For the first year of treatment, pump therapy more than twice as expensive as daily injections (4,407 euros vs. 1,597 euros). This difference remained when costs were extrapolated to year 2 and beyond (4,365 euros vs. 1,555 euros).

The model, however, determined that pump therapy has the potential to extend life expectancy by almost 1 year, compared with injection therapy, by reducing and/or delaying life-threatening diabetes complications. These clinical benefits translated into an additional 9.38 quality-adjusted life-years (QALY) for patients using the pump, compared with 8.95 QALY for patients using injections.

Over a lifetime of treatment (13 years), pump therapy would cost a total of 58,024 euros, compared with 20,237 euros for injection therapy – a difference of 37,787 euros. Compared with injection therapy, though, pump therapy would save almost 10,000 euros in the cost of renal complications; 625 euros in the cost of ulcer, amputation, and neuropathy complications; 152 euros in the cost of eye complications; and 410 euros in complications due to hypoglycemia. These savings reduced the total cost difference between the two to 27,051 euros, Mr. Roze said.

The benefits held over time, despite the paradox of survivorship, he said. “The longer a patient with chronic disease lives, the more opportunity they have to develop a complication.”

The incremental cost-effectiveness ratio was 62,295 euros/QALY – an amount that falls well within the Netherlands’ “willingness to pay” threshold, which is a measure of what payers or society are generally willing to accept as a good value for health care expenditures.

The newest data from OpT2mise, also released at EASD, bolster Mr. Roze’s modeling. In phase II of the study, patients who had been on injections crossed over to pump therapy. Within 6 months of crossover, these patients experienced a mean HbA_1c decrease of 0.8%. By 12 months from study start, when all patients had been on pump therapy for at least 6 months, the mean HbA_1chad dropped to 7.8% from baseline.

“We were reassured to see the 12-month data, which confirm the sustainability of the effect,” Mr. Roze said. “This is one of the main questions when you do health care modeling.”

Mr. Roze is a co-owner of HEVA-HEOR.

[email protected]

STOCKHOLM – Patients with poorly controlled type 2 diabetes are more likely to hit glycemic targets if their add-on therapy is a GLP-1 receptor agonist.

The GLP-1 drugs seemed slightly more effective than adding a bolus of premixed insulin; data from a recent study show that after receiving a GLP-1 receptor agonist as an add-on drug, patients achieved a mean hemoglobin A_1c of 7.4% within 6 months of treatment intensification, Dr. Reimar W. Thomsen said at the annual meeting of the European Association for the Study of Diabetes. But his Danish database study wasn’t able to control for socioeconomic factors, which may influence whether patients are able to get that more expensive class of drug in Denmark.

Nevertheless, the study provides a “real-world” look at the management of patients who don’t hit therapeutic goals on basal insulin only, said Dr. Thomsen of Aarhus University, Denmark. In the cohort of 7,000 patients, fewer than half were able to reach an HbA_1c of 7.5% or lower on the single treatment.

The patients were drawn from Danish national health care databases, and diagnosed with type 2 diabetes from 2000 to 2012. They were a mean of 64 years old with a mean baseline HbA_1c of 9.2%. Although newly diagnosed, they had probably had the disease for a while – 26% had macrovascular complications and 47%, microvascular disease. All were started on basal insulin monotherapy. Within 6 months, the mean HbA_1c had dropped to 7.6%.

However, just 45% of the group hit the treatment goal of 7.5% or lower, with 29% attaining the 7% HbA_1c target.

A temporal assessment of response showed some improvements over the course of the study, Dr. Thomsen noted. In 2000-2003, about 25% hit the goal on basal insulin only; by 2010-2012, that had increased to 33%. This probably reflects an earlier diagnosis of disease, especially as the mean HbA_1c at diagnosis was lower in the later years (9% vs.9.6%), he said.

In another noteworthy temporal association, choices for add-on therapy changed over the years. In the first few years, premixed insulin was the top choice, accounting for 80% of intensification prescriptions. By 2012, that had dropped to about 22%. Bolus insulin use rose from about 17% in 2000 to 35% in 2012. GLP-1 receptor agonists didn’t arrive on the scene until 2008 but gained rapid acceptance. By 2010-2012 they accounted for 30% of intensification prescriptions.

Patients whose glucose control was intensified with GLP-1 drugs (326) were the youngest (55 years) and healthiest, with only 22% having medical comorbidities. They started the add-on therapy at a mean of 27 months after diagnosis. At that time, the mean HbA_1c was 8.4%; this dropped by 0.8%, landing at a mean of 7.6%.

Those who added bolus insulin (893) were a mean of 59 years old; 30% had comorbidities. They started the new treatment at a mean of 13 months after diagnosis. Their mean HbA_1c at intensification was 8.2%; this dropped 0.4%, landing at 7.8%

Patients who added premixed insulin (1,798) were a mean of 64 years old; 32% had medical comorbidities. They started add-on therapy 11 months after diagnosis. Their HbA_1c was a mean of 8.8% at intensification; it dropped 0.9%, landing at a mean of 7.9%.

Fifty-nine patients were intensified with dual therapy; Dr. Thomsen did not specify what combinations were employed. These patients were a mean of 61 years old; 42% of them had medical comorbidities. They had a mean HbA_1c of 8.9% at the time of intensification. Add-on therapy dropped that measurement by 1.2%, landing this group at a mean HbA_1c of 7.7%.

A multivariate analysis determined the likelihood of attaining the treatment target with the various add-on monotherapies; it adjusted for age, gender, diabetes complications, disease duration, medical comorbidities, and baseline HbA_1c. Compared with premixed insulin, the chance of meeting goal was similar with bolus insulin (relative risk, 1.03) and higher with GLP-1 agonists (RR, 1.56 for less than 7%; RR, 1.27 for less than 7.5%).

Dr. Thomsen had no financial disclosures.

[email protected]

STOCKHOLM – Patients with poorly controlled type 2 diabetes are more likely to hit glycemic targets if their add-on therapy is a GLP-1 receptor agonist.

The GLP-1 drugs seemed slightly more effective than adding a bolus of premixed insulin; data from a recent study show that after receiving a GLP-1 receptor agonist as an add-on drug, patients achieved a mean hemoglobin A_1c of 7.4% within 6 months of treatment intensification, Dr. Reimar W. Thomsen said at the annual meeting of the European Association for the Study of Diabetes. But his Danish database study wasn’t able to control for socioeconomic factors, which may influence whether patients are able to get that more expensive class of drug in Denmark.

Nevertheless, the study provides a “real-world” look at the management of patients who don’t hit therapeutic goals on basal insulin only, said Dr. Thomsen of Aarhus University, Denmark. In the cohort of 7,000 patients, fewer than half were able to reach an HbA_1c of 7.5% or lower on the single treatment.

The patients were drawn from Danish national health care databases, and diagnosed with type 2 diabetes from 2000 to 2012. They were a mean of 64 years old with a mean baseline HbA_1c of 9.2%. Although newly diagnosed, they had probably had the disease for a while – 26% had macrovascular complications and 47%, microvascular disease. All were started on basal insulin monotherapy. Within 6 months, the mean HbA_1c had dropped to 7.6%.

However, just 45% of the group hit the treatment goal of 7.5% or lower, with 29% attaining the 7% HbA_1c target.

A temporal assessment of response showed some improvements over the course of the study, Dr. Thomsen noted. In 2000-2003, about 25% hit the goal on basal insulin only; by 2010-2012, that had increased to 33%. This probably reflects an earlier diagnosis of disease, especially as the mean HbA_1c at diagnosis was lower in the later years (9% vs.9.6%), he said.

In another noteworthy temporal association, choices for add-on therapy changed over the years. In the first few years, premixed insulin was the top choice, accounting for 80% of intensification prescriptions. By 2012, that had dropped to about 22%. Bolus insulin use rose from about 17% in 2000 to 35% in 2012. GLP-1 receptor agonists didn’t arrive on the scene until 2008 but gained rapid acceptance. By 2010-2012 they accounted for 30% of intensification prescriptions.

Patients whose glucose control was intensified with GLP-1 drugs (326) were the youngest (55 years) and healthiest, with only 22% having medical comorbidities. They started the add-on therapy at a mean of 27 months after diagnosis. At that time, the mean HbA_1c was 8.4%; this dropped by 0.8%, landing at a mean of 7.6%.

Those who added bolus insulin (893) were a mean of 59 years old; 30% had comorbidities. They started the new treatment at a mean of 13 months after diagnosis. Their mean HbA_1c at intensification was 8.2%; this dropped 0.4%, landing at 7.8%

Patients who added premixed insulin (1,798) were a mean of 64 years old; 32% had medical comorbidities. They started add-on therapy 11 months after diagnosis. Their HbA_1c was a mean of 8.8% at intensification; it dropped 0.9%, landing at a mean of 7.9%.

Fifty-nine patients were intensified with dual therapy; Dr. Thomsen did not specify what combinations were employed. These patients were a mean of 61 years old; 42% of them had medical comorbidities. They had a mean HbA_1c of 8.9% at the time of intensification. Add-on therapy dropped that measurement by 1.2%, landing this group at a mean HbA_1c of 7.7%.

A multivariate analysis determined the likelihood of attaining the treatment target with the various add-on monotherapies; it adjusted for age, gender, diabetes complications, disease duration, medical comorbidities, and baseline HbA_1c. Compared with premixed insulin, the chance of meeting goal was similar with bolus insulin (relative risk, 1.03) and higher with GLP-1 agonists (RR, 1.56 for less than 7%; RR, 1.27 for less than 7.5%).

Dr. Thomsen had no financial disclosures.

[email protected]

STOCKHOLM – Patients with poorly controlled type 2 diabetes are more likely to hit glycemic targets if their add-on therapy is a GLP-1 receptor agonist.

The GLP-1 drugs seemed slightly more effective than adding a bolus of premixed insulin; data from a recent study show that after receiving a GLP-1 receptor agonist as an add-on drug, patients achieved a mean hemoglobin A_1c of 7.4% within 6 months of treatment intensification, Dr. Reimar W. Thomsen said at the annual meeting of the European Association for the Study of Diabetes. But his Danish database study wasn’t able to control for socioeconomic factors, which may influence whether patients are able to get that more expensive class of drug in Denmark.

Nevertheless, the study provides a “real-world” look at the management of patients who don’t hit therapeutic goals on basal insulin only, said Dr. Thomsen of Aarhus University, Denmark. In the cohort of 7,000 patients, fewer than half were able to reach an HbA_1c of 7.5% or lower on the single treatment.

The patients were drawn from Danish national health care databases, and diagnosed with type 2 diabetes from 2000 to 2012. They were a mean of 64 years old with a mean baseline HbA_1c of 9.2%. Although newly diagnosed, they had probably had the disease for a while – 26% had macrovascular complications and 47%, microvascular disease. All were started on basal insulin monotherapy. Within 6 months, the mean HbA_1c had dropped to 7.6%.

However, just 45% of the group hit the treatment goal of 7.5% or lower, with 29% attaining the 7% HbA_1c target.

A temporal assessment of response showed some improvements over the course of the study, Dr. Thomsen noted. In 2000-2003, about 25% hit the goal on basal insulin only; by 2010-2012, that had increased to 33%. This probably reflects an earlier diagnosis of disease, especially as the mean HbA_1c at diagnosis was lower in the later years (9% vs.9.6%), he said.

In another noteworthy temporal association, choices for add-on therapy changed over the years. In the first few years, premixed insulin was the top choice, accounting for 80% of intensification prescriptions. By 2012, that had dropped to about 22%. Bolus insulin use rose from about 17% in 2000 to 35% in 2012. GLP-1 receptor agonists didn’t arrive on the scene until 2008 but gained rapid acceptance. By 2010-2012 they accounted for 30% of intensification prescriptions.

Patients whose glucose control was intensified with GLP-1 drugs (326) were the youngest (55 years) and healthiest, with only 22% having medical comorbidities. They started the add-on therapy at a mean of 27 months after diagnosis. At that time, the mean HbA_1c was 8.4%; this dropped by 0.8%, landing at a mean of 7.6%.

Those who added bolus insulin (893) were a mean of 59 years old; 30% had comorbidities. They started the new treatment at a mean of 13 months after diagnosis. Their mean HbA_1c at intensification was 8.2%; this dropped 0.4%, landing at 7.8%

Patients who added premixed insulin (1,798) were a mean of 64 years old; 32% had medical comorbidities. They started add-on therapy 11 months after diagnosis. Their HbA_1c was a mean of 8.8% at intensification; it dropped 0.9%, landing at a mean of 7.9%.

Fifty-nine patients were intensified with dual therapy; Dr. Thomsen did not specify what combinations were employed. These patients were a mean of 61 years old; 42% of them had medical comorbidities. They had a mean HbA_1c of 8.9% at the time of intensification. Add-on therapy dropped that measurement by 1.2%, landing this group at a mean HbA_1c of 7.7%.

A multivariate analysis determined the likelihood of attaining the treatment target with the various add-on monotherapies; it adjusted for age, gender, diabetes complications, disease duration, medical comorbidities, and baseline HbA_1c. Compared with premixed insulin, the chance of meeting goal was similar with bolus insulin (relative risk, 1.03) and higher with GLP-1 agonists (RR, 1.56 for less than 7%; RR, 1.27 for less than 7.5%).

Dr. Thomsen had no financial disclosures.

[email protected]

There was no difference in long-term health care cost between conventional treatment and bariatric surgery in patients with diabetes, according to a study published in the Lancet online Sept. 17.

Elevated body mass index is associated with an increased risk of diabetes. However, devising effective lifestyle interventions to reduce weight in the severely obese remains a challenge. Data from the Swedish Obese Subjects (SOS) study have demonstrated prevention and remission of type 2 diabetes after bariatric surgery.

Catherine Keating, Ph.D., of the Deakin Health Economics and Baker IDI Heart and Diabetes Institute in Melbourne, and her associates sought to quantify the health care costs during a 15-year period for obese patients treated with bariatric surgery versus conventional treatment.

Data on prescription drug costs were obtained by questionnaires from participants in the SOS study and the Swedish Prescribed Drug Register. The Swedish National Patient Register was used to obtain data on the outpatient and inpatient visits. The participants were followed for up to 15 years.

The original SOS study was a prospective study that compared treatment outcomes and costs in two groups of obese adults: those who underwent bariatric surgery versus a control cohort who received conventional obesity management. The participants ranged from 37 to 60 years old with BMIs of greater than 34 kg/m² in men and greater than 38 in women. Conventional treatment included behavior modification, lifestyle intervention, or no treatment.

The definition of diabetes was based on a self-report of taking diabetes drugs or a fasting glucose measurement.

After exclusions, 4,030 participants were included; of these, 2,836 were euglycemic, 591 had prediabetes, and 603 were diabetic, the investigators reported (Lancet 2015 Sep 16 [doi: 10.1016/

S2213-8587(15)00290-9]).

©Wavebreakmedia Ltd

Patients in the bariatric surgery groups were on average 6.2 kg heavier (P less than .0001) and 1.5 years younger (P less than .0001) than were the controls. After the 15-year follow-up, weight loss was 16 kg greater in the diabetes subgroup, 18 kg greater in the prediabetes subgroup, and 20 kg greater in the euglycemia subgroup who had bariatric surgery versus conventional treatment (P less than .0001 for all).

After 15 years, the aggregated drug costs were not different between the conventional treatment group and the bariatric surgery group in patients with euglycemia. However, drug costs were lower in the prediabetic participants who had surgery versus conventional treatment (P = .007). Similarly, patients with diabetes who underwent bariatric surgery incurred lower drug costs after 15 years (P less than .0001).

The inpatient hospital costs after 15 years were greater in the surgery group for all glucose levels versus conventional treatment (mean, $51,225 vs. $25,313; P less than .0001).

There were no differences in outpatient costs demonstrated between the glucose subgroups. However, in the diabetes group, there were wide confidence intervals associated with outpatient costs that were thought to be secondary to end-stage renal disease visits.

Finally, the total cost of health care for the euglycemic group was higher in those who underwent surgery versus conventional treatment (P less than .0001). The prediabetic subgroup also incurred a higher total health care cost for surgery versus conventional treatment (P less than .0001). However, there were no differences in total health care cost for patients with diabetes who had surgery versus conventional treatment ($88,572 vs. $79,967, P less than .090).

The total cost was also higher in patients with diabetes for more than 1 year who had surgical intervention versus those who got conventional treatment (P less than .011). However, patients with diabetes for less than 1 year did not show differences in total cost when treated with surgery versus conventional treatments (P less than .476)

“In this study, we show that for obese patients with type 2 diabetes, the upfront costs of bariatric surgery seem to be largely offset by prevention of future health care and drug use,” the authors wrote. In addition, “long-term health care cost results support prioritization of patients with obesity and type 2 diabetes for bariatric surgery.”

This study was supported by a grant from AFA Forsakring. The authors reported multiple disclosures.

There was no difference in long-term health care cost between conventional treatment and bariatric surgery in patients with diabetes, according to a study published in the Lancet online Sept. 17.

Elevated body mass index is associated with an increased risk of diabetes. However, devising effective lifestyle interventions to reduce weight in the severely obese remains a challenge. Data from the Swedish Obese Subjects (SOS) study have demonstrated prevention and remission of type 2 diabetes after bariatric surgery.

Catherine Keating, Ph.D., of the Deakin Health Economics and Baker IDI Heart and Diabetes Institute in Melbourne, and her associates sought to quantify the health care costs during a 15-year period for obese patients treated with bariatric surgery versus conventional treatment.

Data on prescription drug costs were obtained by questionnaires from participants in the SOS study and the Swedish Prescribed Drug Register. The Swedish National Patient Register was used to obtain data on the outpatient and inpatient visits. The participants were followed for up to 15 years.

The original SOS study was a prospective study that compared treatment outcomes and costs in two groups of obese adults: those who underwent bariatric surgery versus a control cohort who received conventional obesity management. The participants ranged from 37 to 60 years old with BMIs of greater than 34 kg/m² in men and greater than 38 in women. Conventional treatment included behavior modification, lifestyle intervention, or no treatment.

The definition of diabetes was based on a self-report of taking diabetes drugs or a fasting glucose measurement.

After exclusions, 4,030 participants were included; of these, 2,836 were euglycemic, 591 had prediabetes, and 603 were diabetic, the investigators reported (Lancet 2015 Sep 16 [doi: 10.1016/

S2213-8587(15)00290-9]).

©Wavebreakmedia Ltd

Patients in the bariatric surgery groups were on average 6.2 kg heavier (P less than .0001) and 1.5 years younger (P less than .0001) than were the controls. After the 15-year follow-up, weight loss was 16 kg greater in the diabetes subgroup, 18 kg greater in the prediabetes subgroup, and 20 kg greater in the euglycemia subgroup who had bariatric surgery versus conventional treatment (P less than .0001 for all).

After 15 years, the aggregated drug costs were not different between the conventional treatment group and the bariatric surgery group in patients with euglycemia. However, drug costs were lower in the prediabetic participants who had surgery versus conventional treatment (P = .007). Similarly, patients with diabetes who underwent bariatric surgery incurred lower drug costs after 15 years (P less than .0001).

The inpatient hospital costs after 15 years were greater in the surgery group for all glucose levels versus conventional treatment (mean, $51,225 vs. $25,313; P less than .0001).

There were no differences in outpatient costs demonstrated between the glucose subgroups. However, in the diabetes group, there were wide confidence intervals associated with outpatient costs that were thought to be secondary to end-stage renal disease visits.

Finally, the total cost of health care for the euglycemic group was higher in those who underwent surgery versus conventional treatment (P less than .0001). The prediabetic subgroup also incurred a higher total health care cost for surgery versus conventional treatment (P less than .0001). However, there were no differences in total health care cost for patients with diabetes who had surgery versus conventional treatment ($88,572 vs. $79,967, P less than .090).

The total cost was also higher in patients with diabetes for more than 1 year who had surgical intervention versus those who got conventional treatment (P less than .011). However, patients with diabetes for less than 1 year did not show differences in total cost when treated with surgery versus conventional treatments (P less than .476)

“In this study, we show that for obese patients with type 2 diabetes, the upfront costs of bariatric surgery seem to be largely offset by prevention of future health care and drug use,” the authors wrote. In addition, “long-term health care cost results support prioritization of patients with obesity and type 2 diabetes for bariatric surgery.”

This study was supported by a grant from AFA Forsakring. The authors reported multiple disclosures.

There was no difference in long-term health care cost between conventional treatment and bariatric surgery in patients with diabetes, according to a study published in the Lancet online Sept. 17.

Elevated body mass index is associated with an increased risk of diabetes. However, devising effective lifestyle interventions to reduce weight in the severely obese remains a challenge. Data from the Swedish Obese Subjects (SOS) study have demonstrated prevention and remission of type 2 diabetes after bariatric surgery.

Catherine Keating, Ph.D., of the Deakin Health Economics and Baker IDI Heart and Diabetes Institute in Melbourne, and her associates sought to quantify the health care costs during a 15-year period for obese patients treated with bariatric surgery versus conventional treatment.

Data on prescription drug costs were obtained by questionnaires from participants in the SOS study and the Swedish Prescribed Drug Register. The Swedish National Patient Register was used to obtain data on the outpatient and inpatient visits. The participants were followed for up to 15 years.

The original SOS study was a prospective study that compared treatment outcomes and costs in two groups of obese adults: those who underwent bariatric surgery versus a control cohort who received conventional obesity management. The participants ranged from 37 to 60 years old with BMIs of greater than 34 kg/m² in men and greater than 38 in women. Conventional treatment included behavior modification, lifestyle intervention, or no treatment.

The definition of diabetes was based on a self-report of taking diabetes drugs or a fasting glucose measurement.

After exclusions, 4,030 participants were included; of these, 2,836 were euglycemic, 591 had prediabetes, and 603 were diabetic, the investigators reported (Lancet 2015 Sep 16 [doi: 10.1016/

S2213-8587(15)00290-9]).

©Wavebreakmedia Ltd

Patients in the bariatric surgery groups were on average 6.2 kg heavier (P less than .0001) and 1.5 years younger (P less than .0001) than were the controls. After the 15-year follow-up, weight loss was 16 kg greater in the diabetes subgroup, 18 kg greater in the prediabetes subgroup, and 20 kg greater in the euglycemia subgroup who had bariatric surgery versus conventional treatment (P less than .0001 for all).

After 15 years, the aggregated drug costs were not different between the conventional treatment group and the bariatric surgery group in patients with euglycemia. However, drug costs were lower in the prediabetic participants who had surgery versus conventional treatment (P = .007). Similarly, patients with diabetes who underwent bariatric surgery incurred lower drug costs after 15 years (P less than .0001).

The inpatient hospital costs after 15 years were greater in the surgery group for all glucose levels versus conventional treatment (mean, $51,225 vs. $25,313; P less than .0001).

There were no differences in outpatient costs demonstrated between the glucose subgroups. However, in the diabetes group, there were wide confidence intervals associated with outpatient costs that were thought to be secondary to end-stage renal disease visits.

Finally, the total cost of health care for the euglycemic group was higher in those who underwent surgery versus conventional treatment (P less than .0001). The prediabetic subgroup also incurred a higher total health care cost for surgery versus conventional treatment (P less than .0001). However, there were no differences in total health care cost for patients with diabetes who had surgery versus conventional treatment ($88,572 vs. $79,967, P less than .090).

The total cost was also higher in patients with diabetes for more than 1 year who had surgical intervention versus those who got conventional treatment (P less than .011). However, patients with diabetes for less than 1 year did not show differences in total cost when treated with surgery versus conventional treatments (P less than .476)

“In this study, we show that for obese patients with type 2 diabetes, the upfront costs of bariatric surgery seem to be largely offset by prevention of future health care and drug use,” the authors wrote. In addition, “long-term health care cost results support prioritization of patients with obesity and type 2 diabetes for bariatric surgery.”

This study was supported by a grant from AFA Forsakring. The authors reported multiple disclosures.

STOCKHOLM – Patients with poorly controlled type 2 diabetes who take the combination of liraglutide and metformin are about four times more likely to hit their glycemic target than those who take lixisenatide and metformin.

After 26 weeks of treatment, hemoglobin A_1cdropped a mean of 1.8% among those on the liraglutide regimen, compared with 1.2% among those taking lixisenatide. The change brought 74% of the liraglutide group into a treatment target of HbA_1c less than 7%; 45% of the lixisenatide group reached that goal (odds ratio, 4.16).

Those taking liraglutide also were almost four times as likely to reach a target of 6.5% or less (55% vs. 26%; OR, 3.6), Dr. Michael A. Nauck said at the annual meeting of the European Association for the Study of Diabetes.

Both of the drugs are glucagon-like peptide-1 receptor agonists, and both are formulated for once-daily injection, but liraglutide’s 13-hour half-life gives it a strong clinical edge.

“Lixisenatide has a 3-hour half-life, so it’s only going to be around for 6 to a maximum of 10 hours after injection,” said Dr. Nauck, head of the Diabeteszentrum in Bad Lauterberg, Germany. “For the most part of the night there’s no exposure to lixisenatide at all, while liraglutide is present 24 hours.”

The study randomized 404 patients with poorly controlled type 2 diabetes to metformin plus either liraglutide 1.8 mg/day or lixisenatide 20 mcg/day, he reported. Patients were a mean of 56 years old, with a mean body mass index of 35 kg/m². Their mean HbA_1c was 8.4%.

At the end of the 26-week study, fasting plasma glucose measurements mirrored the HbA_1c improvements. Both drugs significantly reduced glucose within the first 6 weeks, but liraglutide did so to a significantly greater extent (–2.85 mmol/L vs. –1.7 mmol/L). Each reduction held steady through the end of the trial.

Both drugs effected a similar weight loss by the study’s end – about 4 kg. Both also reduced systolic blood pressure similarly, with a mean drop of about 5 mm Hg for liraglutide and 4 mm Hg for lixisenatide. Liraglutide increased the mean pulse rate from 75 beats per minute (bpm) at baseline to 80 bpm by week 6. The mean decreased to 78 by the end of the study. Pulse declined by 1 bpm from baseline among patients taking lixisenatide.

Liraglutide seemed to exert a beneficial effect on beta cells, as measured by the homeostatic model assessment (HOMA-B). At baseline, mean HOMA-B was 60%. By 26 weeks, it had increased to near 100% among those taking the drug; among those taking lixisenatide, HOMA-B had increased to about 77% – a significant difference.

Liraglutide was associated with a significant increase in lipase, Dr. Nauck said. Baseline lipase was 40 U/L. By 12 weeks, both drugs had increased lipase significantly – lixisenatide to about 50 U/L and liraglutide to about 60 U/L. These levels were constant through the study’s end. There were, however, no cases of pancreatitis or pancreatic cancer in either treatment arm, he noted.

Liraglutide use was associated with significantly more adverse events than lixisenatide (72% vs. 64%), but few of those were serious (6% vs. 3.5%). There were no cases of severe hypoglycemia and no deaths. Less than 5% of patients experienced a treatment-emergent or serious adverse event. The most common of these were nausea (22% in each group), diarrhea (12% liraglutide vs. 10% lixisenatide), vomiting (7% vs. 9%), increased lipase (8% vs. 2.5%), nasopharyngitis (6% vs. 10%), decreased appetite (6% vs. 2.5%), and dyspepsia (5.4% vs. 3%).

Although lixisenatide was outperformed in this analysis, it is still a valuable alternative for some patients, Dr. Bo Ahren said in an interview.

“Its primary action is to reduce postprandial glucose,” said Dr. Ahren, who is dean of the Faculty of Medicine at Lund (Sweden) University. “Therefore, there may be a use for this agent in patients who have controlled fasting glucose, for example, with insulin, but still have high postprandial glucose.”

Although the adverse event data were encouraging, more study is necessary, he added. The current data aren’t enough to hone any patient selection criteria.

“The lipase increases need to be examined in more detail, although it’s true there were no cases of pancreatitis. Also, the heart rate was measured only in the clinic, not as a 24-hour measurement. Therefore it’s too early to base any patient selection on this,” Dr. Ahren said.

Both Dr. Nauck and Dr. Ahren disclosed numerous financial relationships with pharmaceutical companies.

[email protected]

STOCKHOLM – Patients with poorly controlled type 2 diabetes who take the combination of liraglutide and metformin are about four times more likely to hit their glycemic target than those who take lixisenatide and metformin.

After 26 weeks of treatment, hemoglobin A_1cdropped a mean of 1.8% among those on the liraglutide regimen, compared with 1.2% among those taking lixisenatide. The change brought 74% of the liraglutide group into a treatment target of HbA_1c less than 7%; 45% of the lixisenatide group reached that goal (odds ratio, 4.16).

Those taking liraglutide also were almost four times as likely to reach a target of 6.5% or less (55% vs. 26%; OR, 3.6), Dr. Michael A. Nauck said at the annual meeting of the European Association for the Study of Diabetes.

Both of the drugs are glucagon-like peptide-1 receptor agonists, and both are formulated for once-daily injection, but liraglutide’s 13-hour half-life gives it a strong clinical edge.

“Lixisenatide has a 3-hour half-life, so it’s only going to be around for 6 to a maximum of 10 hours after injection,” said Dr. Nauck, head of the Diabeteszentrum in Bad Lauterberg, Germany. “For the most part of the night there’s no exposure to lixisenatide at all, while liraglutide is present 24 hours.”

The study randomized 404 patients with poorly controlled type 2 diabetes to metformin plus either liraglutide 1.8 mg/day or lixisenatide 20 mcg/day, he reported. Patients were a mean of 56 years old, with a mean body mass index of 35 kg/m². Their mean HbA_1c was 8.4%.

At the end of the 26-week study, fasting plasma glucose measurements mirrored the HbA_1c improvements. Both drugs significantly reduced glucose within the first 6 weeks, but liraglutide did so to a significantly greater extent (–2.85 mmol/L vs. –1.7 mmol/L). Each reduction held steady through the end of the trial.

Both drugs effected a similar weight loss by the study’s end – about 4 kg. Both also reduced systolic blood pressure similarly, with a mean drop of about 5 mm Hg for liraglutide and 4 mm Hg for lixisenatide. Liraglutide increased the mean pulse rate from 75 beats per minute (bpm) at baseline to 80 bpm by week 6. The mean decreased to 78 by the end of the study. Pulse declined by 1 bpm from baseline among patients taking lixisenatide.

Liraglutide seemed to exert a beneficial effect on beta cells, as measured by the homeostatic model assessment (HOMA-B). At baseline, mean HOMA-B was 60%. By 26 weeks, it had increased to near 100% among those taking the drug; among those taking lixisenatide, HOMA-B had increased to about 77% – a significant difference.

Liraglutide was associated with a significant increase in lipase, Dr. Nauck said. Baseline lipase was 40 U/L. By 12 weeks, both drugs had increased lipase significantly – lixisenatide to about 50 U/L and liraglutide to about 60 U/L. These levels were constant through the study’s end. There were, however, no cases of pancreatitis or pancreatic cancer in either treatment arm, he noted.

Liraglutide use was associated with significantly more adverse events than lixisenatide (72% vs. 64%), but few of those were serious (6% vs. 3.5%). There were no cases of severe hypoglycemia and no deaths. Less than 5% of patients experienced a treatment-emergent or serious adverse event. The most common of these were nausea (22% in each group), diarrhea (12% liraglutide vs. 10% lixisenatide), vomiting (7% vs. 9%), increased lipase (8% vs. 2.5%), nasopharyngitis (6% vs. 10%), decreased appetite (6% vs. 2.5%), and dyspepsia (5.4% vs. 3%).

Although lixisenatide was outperformed in this analysis, it is still a valuable alternative for some patients, Dr. Bo Ahren said in an interview.

“Its primary action is to reduce postprandial glucose,” said Dr. Ahren, who is dean of the Faculty of Medicine at Lund (Sweden) University. “Therefore, there may be a use for this agent in patients who have controlled fasting glucose, for example, with insulin, but still have high postprandial glucose.”

Although the adverse event data were encouraging, more study is necessary, he added. The current data aren’t enough to hone any patient selection criteria.

“The lipase increases need to be examined in more detail, although it’s true there were no cases of pancreatitis. Also, the heart rate was measured only in the clinic, not as a 24-hour measurement. Therefore it’s too early to base any patient selection on this,” Dr. Ahren said.

Both Dr. Nauck and Dr. Ahren disclosed numerous financial relationships with pharmaceutical companies.

[email protected]

STOCKHOLM – Patients with poorly controlled type 2 diabetes who take the combination of liraglutide and metformin are about four times more likely to hit their glycemic target than those who take lixisenatide and metformin.

After 26 weeks of treatment, hemoglobin A_1cdropped a mean of 1.8% among those on the liraglutide regimen, compared with 1.2% among those taking lixisenatide. The change brought 74% of the liraglutide group into a treatment target of HbA_1c less than 7%; 45% of the lixisenatide group reached that goal (odds ratio, 4.16).

Those taking liraglutide also were almost four times as likely to reach a target of 6.5% or less (55% vs. 26%; OR, 3.6), Dr. Michael A. Nauck said at the annual meeting of the European Association for the Study of Diabetes.

Both of the drugs are glucagon-like peptide-1 receptor agonists, and both are formulated for once-daily injection, but liraglutide’s 13-hour half-life gives it a strong clinical edge.

“Lixisenatide has a 3-hour half-life, so it’s only going to be around for 6 to a maximum of 10 hours after injection,” said Dr. Nauck, head of the Diabeteszentrum in Bad Lauterberg, Germany. “For the most part of the night there’s no exposure to lixisenatide at all, while liraglutide is present 24 hours.”

The study randomized 404 patients with poorly controlled type 2 diabetes to metformin plus either liraglutide 1.8 mg/day or lixisenatide 20 mcg/day, he reported. Patients were a mean of 56 years old, with a mean body mass index of 35 kg/m². Their mean HbA_1c was 8.4%.

At the end of the 26-week study, fasting plasma glucose measurements mirrored the HbA_1c improvements. Both drugs significantly reduced glucose within the first 6 weeks, but liraglutide did so to a significantly greater extent (–2.85 mmol/L vs. –1.7 mmol/L). Each reduction held steady through the end of the trial.

Both drugs effected a similar weight loss by the study’s end – about 4 kg. Both also reduced systolic blood pressure similarly, with a mean drop of about 5 mm Hg for liraglutide and 4 mm Hg for lixisenatide. Liraglutide increased the mean pulse rate from 75 beats per minute (bpm) at baseline to 80 bpm by week 6. The mean decreased to 78 by the end of the study. Pulse declined by 1 bpm from baseline among patients taking lixisenatide.

Liraglutide seemed to exert a beneficial effect on beta cells, as measured by the homeostatic model assessment (HOMA-B). At baseline, mean HOMA-B was 60%. By 26 weeks, it had increased to near 100% among those taking the drug; among those taking lixisenatide, HOMA-B had increased to about 77% – a significant difference.

Liraglutide was associated with a significant increase in lipase, Dr. Nauck said. Baseline lipase was 40 U/L. By 12 weeks, both drugs had increased lipase significantly – lixisenatide to about 50 U/L and liraglutide to about 60 U/L. These levels were constant through the study’s end. There were, however, no cases of pancreatitis or pancreatic cancer in either treatment arm, he noted.

Liraglutide use was associated with significantly more adverse events than lixisenatide (72% vs. 64%), but few of those were serious (6% vs. 3.5%). There were no cases of severe hypoglycemia and no deaths. Less than 5% of patients experienced a treatment-emergent or serious adverse event. The most common of these were nausea (22% in each group), diarrhea (12% liraglutide vs. 10% lixisenatide), vomiting (7% vs. 9%), increased lipase (8% vs. 2.5%), nasopharyngitis (6% vs. 10%), decreased appetite (6% vs. 2.5%), and dyspepsia (5.4% vs. 3%).

Although lixisenatide was outperformed in this analysis, it is still a valuable alternative for some patients, Dr. Bo Ahren said in an interview.

“Its primary action is to reduce postprandial glucose,” said Dr. Ahren, who is dean of the Faculty of Medicine at Lund (Sweden) University. “Therefore, there may be a use for this agent in patients who have controlled fasting glucose, for example, with insulin, but still have high postprandial glucose.”

Although the adverse event data were encouraging, more study is necessary, he added. The current data aren’t enough to hone any patient selection criteria.

“The lipase increases need to be examined in more detail, although it’s true there were no cases of pancreatitis. Also, the heart rate was measured only in the clinic, not as a 24-hour measurement. Therefore it’s too early to base any patient selection on this,” Dr. Ahren said.

Both Dr. Nauck and Dr. Ahren disclosed numerous financial relationships with pharmaceutical companies.

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