Christine Kilgore

WASHINGTON — Insulin resistance is such an integral and dangerous feature of polycystic ovary syndrome that metformin should be favored over oral contraceptive pills for treatment of the syndrome, said physicians in annual scientific sessions of the American Diabetes Association meeting.

While there is a paucity of “good, prospective outcomes data” on cardiovascular disease in PCOS patients—as well as the existence of only limited data on the effect of oral contraceptives (OCs) on insulin resistance—the speakers warned against waiting for definitive data to appear. Current knowledge of the risks of insulin resistance and the potential disadvantages of OCs is too convincing, they said.

“Given everything [we know now], I believe we now must have the goals of preventing glucose intolerance and diabetes, and preventing atherosclerosis and acute coronary events” in addition to addressing the immediate symptoms of PCOS, said Dr. John Nestler, professor of medicine, ob.gyn., pharmacology, and toxicology at the Virginia Commonwealth University, Richmond.

“I will be provocative, because there aren't a lot of studies, but I'm going to argue that there may be disadvantages to using OCs,” said Dr. Nestler, who also chairs the division of endocrinology and metabolism.

OCs may be better for treating symptoms such as acne and hirsutism (studies of metformin have not addressed these problems as primary end points), but studies indicate that OCs worsen insulin resistance and glucose intolerance and that they may increase triglycerides, worsening the risk of diabetes and cardiovascular disease, he said.

Metformin, on the other hand, targets insulin resistance, “what may well be the initiating abnormality in PCOS, and has been shown to normalize or improve the biochemical, clinical, and reproductive abnormalities of PCOS,” said pediatric endocrinologist Dr. Tessa Lebinger.

The drug is effective whether or not insulin resistance can be documented, she said.

In most cases, Dr. Nestler agreed, it won't be documented because insulin resistance is too difficult to accurately measure in a clinical setting. “Most women with PCOS are insulin resistant … so an empiric trial of metformin in any woman with PCOS is reasonable as long as you monitor her and make sure that her menses are improving,” he said.

Dr. Burton Sobel, who directs the Cardiovascular Research Institute at the University of Vermont, said during a symposium on PCOS that from his perspective as a cardiologist, “PCOS is a cardiovascular disease.”

“We know, from so many perspectives, that impaired sensitivity to insulin is a forerunner, and probably a determinant, of premature coronary disease,” Dr. Sobel said. “It may be years before we have prospective data and legitimacy for using insulin sensitizers [in PCOS patients], but if I had a daughter with PCOS, I'd use an insulin sensitizer beginning with my recognition of the problem regardless of whether she had abnormal glucose tolerance. … I wouldn't wait—to me this is a smoking gun.”

The relationship between hyperinsulinemia and hyperandrogenism—in particular, the question of which causes which—is still discussed, but these physicians said they're convinced from available data that insulin resistance leads to hyperandrogenism and is likely a primary cause of PCOS.

Studies have shown that 30%–35% of women with PCOS have impaired glucose tolerance, and that 8%–10% have type 2 diabetes.

On the whole, Dr. Nestler said, 30%–50% of obese women with PCOS develop either impaired glucose tolerance or type 2 diabetes by age 30. Lean women with PCOS, on the other hand, are just as insulin resistant—if not more so—than obese women without PCOS, several speakers said.

Dr. Nestler said that he and his colleagues found in a chart review of 50 consecutive PCOS patients treated with metformin that the incidence of impaired glucose tolerance was “dramatically” reduced.

At baseline, 78% of the 50 patients had normal glucose tolerance (NGT), and 22% had impaired glucose tolerance (IGT). At follow-up (a mean of 43 months for NGT patients, and 29 months for IGT patients), 55% of the IGT patients had converted to normal, with 45% continuing to have IGT. Of the NGT patients, 95% continued to have NGT, and 5% converted to IGT.

“It needs to be verified in a prospective study, but our annual conversion rate to IGT of 1.4% with metformin treatment is a dramatic reduction from the 16%–19% annual conversion rates” reported in women with PCOS who are not treated with metformin, he said.

He and other physicians at the meeting pointed to the Nurses' Health Study as the best of few studies that provides a look at the cardiovascular “outcomes” of PCOS.

In its tracking of over 80,000 women for 14 years, the study found that women with abnormal menstrual cyclicity had a relative risk for cardiovascular disease of 1.5 and a relative risk of fatal MI of 1.9, compared with women with normal menses. (The NHS also found a twofold increased risk, independent of weight, of type 2 diabetes in women with oligomenorrhea.)

Dr. Holley Allen, a pediatric endocrinologist at Baystate Medical Hospital in Springfield, Mass., said that a metaanalysis of case-control studies published in 2005 showed a twofold increased risk of both MI and ischemic stroke in women who took OCs. The risk may be higher in women with PCOS, since they likely start at a higher baseline risk and take OCs for long periods of time, she said.

Still, she said she views the concerns about OCs' impact on insulin resistance and cardiovascular disease as “potential but unproven.”

And the “question is, whether she'll take a pill for the next 30 years that doesn't make her lose weight, doesn't do much for her facial hair or acne, and tastes like dead fish,” she said.

Dr. Lebinger, who spoke with Dr. Allen, acknowledged there are “inadequate data [on metformin use] in adolescents—only small studies and not many [that are] placebo controlled.”

Still, the literature consistently demonstrates either normalization or significant improvements in glucose intolerance, insulin resistance, and menstrual irregularities, said Dr. Lebinger, who practices in New Rochelle, N.Y. Her adolescent patients on metformin also have improvements in their acne and frequently lose weight.

“We're making recommendations based on what we know today. I present all the options—it's the patient's decision,” she said. Regarding OCs and insulin resistance, “most of us observe that if you take a patient with type 1 diabetes and give them OCs, they usually require more insulin,” Dr. Lebinger said.

Dr. Nestler disclosed to the ADA that he is on the speakers' bureau for Sanofi-Aventis and is a stock/shareholder of the Bristol-Myers Squibb Co. and Pfizer Inc.

Metformin OK for Infertile Patients

If time is not critical, metformin is also an appropriate front-line drug for patients with PCOS whose primary concern is infertility, Dr. Nestler said at the annual meeting of the American Diabetes Association.

“If a woman comes to me with PCOS who wants to get pregnant, I usually tell her I'd like to put her on 3–6 months of metformin coupled with diet and exercise. This way we can try first for the singleton pregnancy [without clomiphene],” Dr. Nestler said. “If at the end of 6 months she doesn't become pregnant, I send her to the endocrinologist.”

The authors of a 2003 review by the Cochrane Collaboration concluded that women with PCOS who take metformin are almost four times as likely to achieve ovulation, compared with women receiving placebo, he said.

In a study of 68 infertile women treated at his institution with metformin, Dr. Nestler and his colleagues found that 78% had improvements in menstrual cyclicity and ovulation, with the frequency of cycles increasing threefold. Approximately 44% had normalized cycles—the “optimal” outcome, he said.

Results from a National Institutes of Health-sponsored, multicenter, randomized study of metformin, clomiphene, or both for treating infertility in PCOS patients will be announced in October, he mentioned.

WASHINGTON — Insulin resistance is such an integral and dangerous feature of polycystic ovary syndrome that metformin should be favored over oral contraceptive pills for treatment of the syndrome, said physicians in annual scientific sessions of the American Diabetes Association meeting.

While there is a paucity of “good, prospective outcomes data” on cardiovascular disease in PCOS patients—as well as the existence of only limited data on the effect of oral contraceptives (OCs) on insulin resistance—the speakers warned against waiting for definitive data to appear. Current knowledge of the risks of insulin resistance and the potential disadvantages of OCs is too convincing, they said.

“Given everything [we know now], I believe we now must have the goals of preventing glucose intolerance and diabetes, and preventing atherosclerosis and acute coronary events” in addition to addressing the immediate symptoms of PCOS, said Dr. John Nestler, professor of medicine, ob.gyn., pharmacology, and toxicology at the Virginia Commonwealth University, Richmond.

“I will be provocative, because there aren't a lot of studies, but I'm going to argue that there may be disadvantages to using OCs,” said Dr. Nestler, who also chairs the division of endocrinology and metabolism.

OCs may be better for treating symptoms such as acne and hirsutism (studies of metformin have not addressed these problems as primary end points), but studies indicate that OCs worsen insulin resistance and glucose intolerance and that they may increase triglycerides, worsening the risk of diabetes and cardiovascular disease, he said.

Metformin, on the other hand, targets insulin resistance, “what may well be the initiating abnormality in PCOS, and has been shown to normalize or improve the biochemical, clinical, and reproductive abnormalities of PCOS,” said pediatric endocrinologist Dr. Tessa Lebinger.

The drug is effective whether or not insulin resistance can be documented, she said.

In most cases, Dr. Nestler agreed, it won't be documented because insulin resistance is too difficult to accurately measure in a clinical setting. “Most women with PCOS are insulin resistant … so an empiric trial of metformin in any woman with PCOS is reasonable as long as you monitor her and make sure that her menses are improving,” he said.

Dr. Burton Sobel, who directs the Cardiovascular Research Institute at the University of Vermont, said during a symposium on PCOS that from his perspective as a cardiologist, “PCOS is a cardiovascular disease.”

“We know, from so many perspectives, that impaired sensitivity to insulin is a forerunner, and probably a determinant, of premature coronary disease,” Dr. Sobel said. “It may be years before we have prospective data and legitimacy for using insulin sensitizers [in PCOS patients], but if I had a daughter with PCOS, I'd use an insulin sensitizer beginning with my recognition of the problem regardless of whether she had abnormal glucose tolerance. … I wouldn't wait—to me this is a smoking gun.”

The relationship between hyperinsulinemia and hyperandrogenism—in particular, the question of which causes which—is still discussed, but these physicians said they're convinced from available data that insulin resistance leads to hyperandrogenism and is likely a primary cause of PCOS.

Studies have shown that 30%–35% of women with PCOS have impaired glucose tolerance, and that 8%–10% have type 2 diabetes.

On the whole, Dr. Nestler said, 30%–50% of obese women with PCOS develop either impaired glucose tolerance or type 2 diabetes by age 30. Lean women with PCOS, on the other hand, are just as insulin resistant—if not more so—than obese women without PCOS, several speakers said.

Dr. Nestler said that he and his colleagues found in a chart review of 50 consecutive PCOS patients treated with metformin that the incidence of impaired glucose tolerance was “dramatically” reduced.

At baseline, 78% of the 50 patients had normal glucose tolerance (NGT), and 22% had impaired glucose tolerance (IGT). At follow-up (a mean of 43 months for NGT patients, and 29 months for IGT patients), 55% of the IGT patients had converted to normal, with 45% continuing to have IGT. Of the NGT patients, 95% continued to have NGT, and 5% converted to IGT.

“It needs to be verified in a prospective study, but our annual conversion rate to IGT of 1.4% with metformin treatment is a dramatic reduction from the 16%–19% annual conversion rates” reported in women with PCOS who are not treated with metformin, he said.

He and other physicians at the meeting pointed to the Nurses' Health Study as the best of few studies that provides a look at the cardiovascular “outcomes” of PCOS.

In its tracking of over 80,000 women for 14 years, the study found that women with abnormal menstrual cyclicity had a relative risk for cardiovascular disease of 1.5 and a relative risk of fatal MI of 1.9, compared with women with normal menses. (The NHS also found a twofold increased risk, independent of weight, of type 2 diabetes in women with oligomenorrhea.)

Dr. Holley Allen, a pediatric endocrinologist at Baystate Medical Hospital in Springfield, Mass., said that a metaanalysis of case-control studies published in 2005 showed a twofold increased risk of both MI and ischemic stroke in women who took OCs. The risk may be higher in women with PCOS, since they likely start at a higher baseline risk and take OCs for long periods of time, she said.

Still, she said she views the concerns about OCs' impact on insulin resistance and cardiovascular disease as “potential but unproven.”

And the “question is, whether she'll take a pill for the next 30 years that doesn't make her lose weight, doesn't do much for her facial hair or acne, and tastes like dead fish,” she said.

Dr. Lebinger, who spoke with Dr. Allen, acknowledged there are “inadequate data [on metformin use] in adolescents—only small studies and not many [that are] placebo controlled.”

Still, the literature consistently demonstrates either normalization or significant improvements in glucose intolerance, insulin resistance, and menstrual irregularities, said Dr. Lebinger, who practices in New Rochelle, N.Y. Her adolescent patients on metformin also have improvements in their acne and frequently lose weight.

“We're making recommendations based on what we know today. I present all the options—it's the patient's decision,” she said. Regarding OCs and insulin resistance, “most of us observe that if you take a patient with type 1 diabetes and give them OCs, they usually require more insulin,” Dr. Lebinger said.

Dr. Nestler disclosed to the ADA that he is on the speakers' bureau for Sanofi-Aventis and is a stock/shareholder of the Bristol-Myers Squibb Co. and Pfizer Inc.

Metformin OK for Infertile Patients

If time is not critical, metformin is also an appropriate front-line drug for patients with PCOS whose primary concern is infertility, Dr. Nestler said at the annual meeting of the American Diabetes Association.

“If a woman comes to me with PCOS who wants to get pregnant, I usually tell her I'd like to put her on 3–6 months of metformin coupled with diet and exercise. This way we can try first for the singleton pregnancy [without clomiphene],” Dr. Nestler said. “If at the end of 6 months she doesn't become pregnant, I send her to the endocrinologist.”

The authors of a 2003 review by the Cochrane Collaboration concluded that women with PCOS who take metformin are almost four times as likely to achieve ovulation, compared with women receiving placebo, he said.

In a study of 68 infertile women treated at his institution with metformin, Dr. Nestler and his colleagues found that 78% had improvements in menstrual cyclicity and ovulation, with the frequency of cycles increasing threefold. Approximately 44% had normalized cycles—the “optimal” outcome, he said.

Results from a National Institutes of Health-sponsored, multicenter, randomized study of metformin, clomiphene, or both for treating infertility in PCOS patients will be announced in October, he mentioned.

WASHINGTON — Insulin resistance is such an integral and dangerous feature of polycystic ovary syndrome that metformin should be favored over oral contraceptive pills for treatment of the syndrome, said physicians in annual scientific sessions of the American Diabetes Association meeting.

While there is a paucity of “good, prospective outcomes data” on cardiovascular disease in PCOS patients—as well as the existence of only limited data on the effect of oral contraceptives (OCs) on insulin resistance—the speakers warned against waiting for definitive data to appear. Current knowledge of the risks of insulin resistance and the potential disadvantages of OCs is too convincing, they said.

“Given everything [we know now], I believe we now must have the goals of preventing glucose intolerance and diabetes, and preventing atherosclerosis and acute coronary events” in addition to addressing the immediate symptoms of PCOS, said Dr. John Nestler, professor of medicine, ob.gyn., pharmacology, and toxicology at the Virginia Commonwealth University, Richmond.

“I will be provocative, because there aren't a lot of studies, but I'm going to argue that there may be disadvantages to using OCs,” said Dr. Nestler, who also chairs the division of endocrinology and metabolism.

OCs may be better for treating symptoms such as acne and hirsutism (studies of metformin have not addressed these problems as primary end points), but studies indicate that OCs worsen insulin resistance and glucose intolerance and that they may increase triglycerides, worsening the risk of diabetes and cardiovascular disease, he said.

Metformin, on the other hand, targets insulin resistance, “what may well be the initiating abnormality in PCOS, and has been shown to normalize or improve the biochemical, clinical, and reproductive abnormalities of PCOS,” said pediatric endocrinologist Dr. Tessa Lebinger.

The drug is effective whether or not insulin resistance can be documented, she said.

In most cases, Dr. Nestler agreed, it won't be documented because insulin resistance is too difficult to accurately measure in a clinical setting. “Most women with PCOS are insulin resistant … so an empiric trial of metformin in any woman with PCOS is reasonable as long as you monitor her and make sure that her menses are improving,” he said.

Dr. Burton Sobel, who directs the Cardiovascular Research Institute at the University of Vermont, said during a symposium on PCOS that from his perspective as a cardiologist, “PCOS is a cardiovascular disease.”

“We know, from so many perspectives, that impaired sensitivity to insulin is a forerunner, and probably a determinant, of premature coronary disease,” Dr. Sobel said. “It may be years before we have prospective data and legitimacy for using insulin sensitizers [in PCOS patients], but if I had a daughter with PCOS, I'd use an insulin sensitizer beginning with my recognition of the problem regardless of whether she had abnormal glucose tolerance. … I wouldn't wait—to me this is a smoking gun.”

The relationship between hyperinsulinemia and hyperandrogenism—in particular, the question of which causes which—is still discussed, but these physicians said they're convinced from available data that insulin resistance leads to hyperandrogenism and is likely a primary cause of PCOS.

Studies have shown that 30%–35% of women with PCOS have impaired glucose tolerance, and that 8%–10% have type 2 diabetes.

On the whole, Dr. Nestler said, 30%–50% of obese women with PCOS develop either impaired glucose tolerance or type 2 diabetes by age 30. Lean women with PCOS, on the other hand, are just as insulin resistant—if not more so—than obese women without PCOS, several speakers said.

Dr. Nestler said that he and his colleagues found in a chart review of 50 consecutive PCOS patients treated with metformin that the incidence of impaired glucose tolerance was “dramatically” reduced.

At baseline, 78% of the 50 patients had normal glucose tolerance (NGT), and 22% had impaired glucose tolerance (IGT). At follow-up (a mean of 43 months for NGT patients, and 29 months for IGT patients), 55% of the IGT patients had converted to normal, with 45% continuing to have IGT. Of the NGT patients, 95% continued to have NGT, and 5% converted to IGT.

“It needs to be verified in a prospective study, but our annual conversion rate to IGT of 1.4% with metformin treatment is a dramatic reduction from the 16%–19% annual conversion rates” reported in women with PCOS who are not treated with metformin, he said.

He and other physicians at the meeting pointed to the Nurses' Health Study as the best of few studies that provides a look at the cardiovascular “outcomes” of PCOS.

In its tracking of over 80,000 women for 14 years, the study found that women with abnormal menstrual cyclicity had a relative risk for cardiovascular disease of 1.5 and a relative risk of fatal MI of 1.9, compared with women with normal menses. (The NHS also found a twofold increased risk, independent of weight, of type 2 diabetes in women with oligomenorrhea.)

Dr. Holley Allen, a pediatric endocrinologist at Baystate Medical Hospital in Springfield, Mass., said that a metaanalysis of case-control studies published in 2005 showed a twofold increased risk of both MI and ischemic stroke in women who took OCs. The risk may be higher in women with PCOS, since they likely start at a higher baseline risk and take OCs for long periods of time, she said.

Still, she said she views the concerns about OCs' impact on insulin resistance and cardiovascular disease as “potential but unproven.”

And the “question is, whether she'll take a pill for the next 30 years that doesn't make her lose weight, doesn't do much for her facial hair or acne, and tastes like dead fish,” she said.

Dr. Lebinger, who spoke with Dr. Allen, acknowledged there are “inadequate data [on metformin use] in adolescents—only small studies and not many [that are] placebo controlled.”

Still, the literature consistently demonstrates either normalization or significant improvements in glucose intolerance, insulin resistance, and menstrual irregularities, said Dr. Lebinger, who practices in New Rochelle, N.Y. Her adolescent patients on metformin also have improvements in their acne and frequently lose weight.

“We're making recommendations based on what we know today. I present all the options—it's the patient's decision,” she said. Regarding OCs and insulin resistance, “most of us observe that if you take a patient with type 1 diabetes and give them OCs, they usually require more insulin,” Dr. Lebinger said.

Dr. Nestler disclosed to the ADA that he is on the speakers' bureau for Sanofi-Aventis and is a stock/shareholder of the Bristol-Myers Squibb Co. and Pfizer Inc.

Metformin OK for Infertile Patients

If time is not critical, metformin is also an appropriate front-line drug for patients with PCOS whose primary concern is infertility, Dr. Nestler said at the annual meeting of the American Diabetes Association.

“If a woman comes to me with PCOS who wants to get pregnant, I usually tell her I'd like to put her on 3–6 months of metformin coupled with diet and exercise. This way we can try first for the singleton pregnancy [without clomiphene],” Dr. Nestler said. “If at the end of 6 months she doesn't become pregnant, I send her to the endocrinologist.”

The authors of a 2003 review by the Cochrane Collaboration concluded that women with PCOS who take metformin are almost four times as likely to achieve ovulation, compared with women receiving placebo, he said.

In a study of 68 infertile women treated at his institution with metformin, Dr. Nestler and his colleagues found that 78% had improvements in menstrual cyclicity and ovulation, with the frequency of cycles increasing threefold. Approximately 44% had normalized cycles—the “optimal” outcome, he said.

Results from a National Institutes of Health-sponsored, multicenter, randomized study of metformin, clomiphene, or both for treating infertility in PCOS patients will be announced in October, he mentioned.

WASHINGTON — Patients who regularly skip breakfast have as high a risk of obesity as patients who have a family history of type 2 diabetes, a cross-sectional study of adolescents has shown.

Regularly skipping breakfast has been linked to obesity before, but Alison Okada Wollitzer, Ph.D., who reported the study at the annual scientific sessions of the American Diabetes Association, said she and her colleagues at the Sansum Diabetes Research Institute in Santa Barbara, Calif, wondered about the importance of the link and the reasons for it.

They studied 2,700 high school students in Santa Barbara and found that skipping breakfast doubles the risk of obesity—just as a family history of diabetes does.

Those with both risk factors—breakfast-skipping and a family history—had double the risk of obesity as did adolescents with only one of the risk factors, Dr. Wollitzer reported in a poster presentation at the meeting.

Adolescents at two public high schools who did not have a known diagnosis of diabetes (1,060 males and 1,640 females) participated in a brief physical exam and lifestyle questionnaire, which asked if breakfast was eaten on school days. Only those answering yes or no were included in the analysis.

Obesity was defined as having a body mass index at or above the 95th percentile; diabetes in any first-degree relative constituted a positive family history. About 34% of the students were white and 57% were Hispanic.

Of those who skipped breakfast but had no family history of diabetes, 16% were obese, compared with almost 18% of those who ate breakfast but had a positive family history.

Only 8% of the adolescents with neither risk factor were obese. Of those who skipped breakfast and had a positive family history, 32% were obese, Dr. Wollitzer reported.

Students who ate breakfast regularly were less likely to eat junk food at lunch, more likely to eat fruits and vegetables, and more likely to exercise regularly, she reported.

WASHINGTON — Patients who regularly skip breakfast have as high a risk of obesity as patients who have a family history of type 2 diabetes, a cross-sectional study of adolescents has shown.

Regularly skipping breakfast has been linked to obesity before, but Alison Okada Wollitzer, Ph.D., who reported the study at the annual scientific sessions of the American Diabetes Association, said she and her colleagues at the Sansum Diabetes Research Institute in Santa Barbara, Calif, wondered about the importance of the link and the reasons for it.

They studied 2,700 high school students in Santa Barbara and found that skipping breakfast doubles the risk of obesity—just as a family history of diabetes does.

Those with both risk factors—breakfast-skipping and a family history—had double the risk of obesity as did adolescents with only one of the risk factors, Dr. Wollitzer reported in a poster presentation at the meeting.

Adolescents at two public high schools who did not have a known diagnosis of diabetes (1,060 males and 1,640 females) participated in a brief physical exam and lifestyle questionnaire, which asked if breakfast was eaten on school days. Only those answering yes or no were included in the analysis.

Obesity was defined as having a body mass index at or above the 95th percentile; diabetes in any first-degree relative constituted a positive family history. About 34% of the students were white and 57% were Hispanic.

Of those who skipped breakfast but had no family history of diabetes, 16% were obese, compared with almost 18% of those who ate breakfast but had a positive family history.

Only 8% of the adolescents with neither risk factor were obese. Of those who skipped breakfast and had a positive family history, 32% were obese, Dr. Wollitzer reported.

Students who ate breakfast regularly were less likely to eat junk food at lunch, more likely to eat fruits and vegetables, and more likely to exercise regularly, she reported.

WASHINGTON — Patients who regularly skip breakfast have as high a risk of obesity as patients who have a family history of type 2 diabetes, a cross-sectional study of adolescents has shown.

Regularly skipping breakfast has been linked to obesity before, but Alison Okada Wollitzer, Ph.D., who reported the study at the annual scientific sessions of the American Diabetes Association, said she and her colleagues at the Sansum Diabetes Research Institute in Santa Barbara, Calif, wondered about the importance of the link and the reasons for it.

They studied 2,700 high school students in Santa Barbara and found that skipping breakfast doubles the risk of obesity—just as a family history of diabetes does.

Those with both risk factors—breakfast-skipping and a family history—had double the risk of obesity as did adolescents with only one of the risk factors, Dr. Wollitzer reported in a poster presentation at the meeting.

Adolescents at two public high schools who did not have a known diagnosis of diabetes (1,060 males and 1,640 females) participated in a brief physical exam and lifestyle questionnaire, which asked if breakfast was eaten on school days. Only those answering yes or no were included in the analysis.

Obesity was defined as having a body mass index at or above the 95th percentile; diabetes in any first-degree relative constituted a positive family history. About 34% of the students were white and 57% were Hispanic.

Of those who skipped breakfast but had no family history of diabetes, 16% were obese, compared with almost 18% of those who ate breakfast but had a positive family history.

Only 8% of the adolescents with neither risk factor were obese. Of those who skipped breakfast and had a positive family history, 32% were obese, Dr. Wollitzer reported.

Students who ate breakfast regularly were less likely to eat junk food at lunch, more likely to eat fruits and vegetables, and more likely to exercise regularly, she reported.

WASHINGTON — A preliminary look at the children referred for participation in a large treatment trial of type 2 diabetes in overweight and obese youth shows that the children not only have a high prevalence of hypertension and dyslipidemia, but a high incidence of autoantibody positivity as well, investigators reported at the annual scientific sessions of the American Diabetes Association.

The findings add to those of other studies suggesting that a significant number of children with apparent type 2 diabetes mellitus also may have diabetes autoimmunity consistent with type 1 diabetes, reported Dr. Georgeanna J. Klingensmith, director of pediatric clinics at the Barbara Davis Center for Childhood Diabetes in Aurora, Colo.

Approximately 18% of the 535 children screened for inclusion thus far in the 15-center, National Institutes of Health-sponsored Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study were found to be positive for diabetes autoimmunity. The children, who were racially and ethnically diverse, were considered by their pediatric endocrinologists to have type 2 diabetes.

The number of youth with diabetes autoimmunity in conjunction with characteristics of type 2 diabetes is likely much higher, however, because some potential study participants were locally prescreened for autoantibodies and were not even sent to the TODAY study investigators. The presence of islet cell autoimmunity is an exclusion criterion for the study, Dr. Klingensmith said.

Indeed, other studies have reported higher rates of what some physicians and investigators are now calling “double,” “hybrid,” or “type 3” diabetes.

Investigators of a large British study, for instance, reported almost 10 years ago that 33% of 157 young adults with type 2 diabetes were found to be positive for diabetes-associated antibodies. And, just this year, investigators of a German study reported that 36% of 128 children thought to have type 2 diabetes also had diabetes-associated antibodies, Dr. Klingensmith said.

Dr. Ingrid M. Libman of the Children's Hospital in Pittsburgh said in another presentation that the “spectrum” of diabetes now presenting in youth presents treatment dilemmas.

“If insulin therapy preserves B-cell function, should all patients that phenotypically look like type 2 but have antibodies be treated with insulin?” she asked. “And should patients [with type 1 and obesity] be treated with insulin sensitizers?”

There have been few studies on treatment for “double” diabetes, she continued. Children who are registered in the Allegheny County Registry for diabetes and the Children's Hospital Registry who have characteristics of both type 1 (antibodies and/or ketones and diabetic ketoacidosis, for instance) and type 2 (obesity and/or acanthosis nigricans) are being treated in their communities with either insulin alone or with insulin and an oral agent, mainly metformin, she said.

It is possible that obesity and insulin resistance may accelerate the presentation of type 1 diabetes in patients with type 2, said Dr. Libman.

The children being enrolled in the TODAY study, in addition to having an absence of islet cell autoimmunity, must have had diabetes for 2 years or less, be 10–17 years of age, and have a fasting C-peptide greater than 0.6 ng/mL and a body mass index at the 85th percentile or above. Participants will be randomized to receive metformin alone, metformin and rosiglitazone, or metformin and intensive lifestyle therapy.

Of the 535 children who were screened for inclusion in the TODAY study, approximately 5% had only glutamic acid decarboxylase (GAD) autoantibodies and 6% had only IA-2 autoantibodies. Approximately 7% had both GAD and IA-2 autoantibodies. All told, 18% were positive for one or both of the antibodies measured.

Dr. Klingensmith and her coinvestigators also looked at the number of children who had very high titer antibody levels. They found that 12% of the children screened—and 65% of all antibody-positive children—were either positive for both autoantibodies or had antibody titers that were more than 300% above normal (above the cut-off point for positivity).

They found that there were no differences between the groups in age, gender, or duration of diabetes. Children with both antibodies, however, had lower C-peptide levels, BMI and triglyceride levels, as well as higher HDL cholesterol and HbA_1c levels, and greater insulin use than did children with no antibodies, Dr. Klingensmith said.

According to Dr. Neil H. White, director of the division of pediatric endocrinology and metabolism at St. Louis University who is also a TODAY study investigator, approximately 12% of the children were receiving insulin alone at the time of screening for the study, and almost 50% were receiving metformin only. Approximately 25% were receiving both. The remaining children were receiving other medications or no treatment at all.

In terms of comorbidities, he reported, 26% had hypertension and almost 60% had dyslipidemia.

It remains to be seen whether diabetes autoimmunity will alter the clinical course of the disorder in youth with the clinical features of type 2 diabetes, Dr. Klingensmith said.

When it comes to the risk of conditions and complications traditionally associated with type 1 diabetes, it very well may, Dr. Libman warned.

Current guidelines, for instance, recommend screening for autoimmune thyroid disease in children with type 1 diabetes who, in contrast to those with type 2 diabetes, are known to have an increased frequency of thyroid antibodies and thyroid dysfunction. But a look at a sample of children in the Pittsburgh registries shows that children with “double” diabetes may have the same prevalence of thyroid antibodies as do those with type 1 diabetes.

Twenty percent of 24 children with double diabetes (defined here as obese with diabetes antibodies) were positive for thyroid antibodies, as were 21% of 117 children with type 1 diabetes (lean with diabetes antibodies). The two groups had a similar incidence of hypothyroidism. A sample of 21 children with type 2 diabetes (obese with no diabetes antibodies) had neither problem, Dr. Libman reported.

WASHINGTON — A preliminary look at the children referred for participation in a large treatment trial of type 2 diabetes in overweight and obese youth shows that the children not only have a high prevalence of hypertension and dyslipidemia, but a high incidence of autoantibody positivity as well, investigators reported at the annual scientific sessions of the American Diabetes Association.

The findings add to those of other studies suggesting that a significant number of children with apparent type 2 diabetes mellitus also may have diabetes autoimmunity consistent with type 1 diabetes, reported Dr. Georgeanna J. Klingensmith, director of pediatric clinics at the Barbara Davis Center for Childhood Diabetes in Aurora, Colo.

Approximately 18% of the 535 children screened for inclusion thus far in the 15-center, National Institutes of Health-sponsored Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study were found to be positive for diabetes autoimmunity. The children, who were racially and ethnically diverse, were considered by their pediatric endocrinologists to have type 2 diabetes.

The number of youth with diabetes autoimmunity in conjunction with characteristics of type 2 diabetes is likely much higher, however, because some potential study participants were locally prescreened for autoantibodies and were not even sent to the TODAY study investigators. The presence of islet cell autoimmunity is an exclusion criterion for the study, Dr. Klingensmith said.

Indeed, other studies have reported higher rates of what some physicians and investigators are now calling “double,” “hybrid,” or “type 3” diabetes.

Investigators of a large British study, for instance, reported almost 10 years ago that 33% of 157 young adults with type 2 diabetes were found to be positive for diabetes-associated antibodies. And, just this year, investigators of a German study reported that 36% of 128 children thought to have type 2 diabetes also had diabetes-associated antibodies, Dr. Klingensmith said.

Dr. Ingrid M. Libman of the Children's Hospital in Pittsburgh said in another presentation that the “spectrum” of diabetes now presenting in youth presents treatment dilemmas.

“If insulin therapy preserves B-cell function, should all patients that phenotypically look like type 2 but have antibodies be treated with insulin?” she asked. “And should patients [with type 1 and obesity] be treated with insulin sensitizers?”

There have been few studies on treatment for “double” diabetes, she continued. Children who are registered in the Allegheny County Registry for diabetes and the Children's Hospital Registry who have characteristics of both type 1 (antibodies and/or ketones and diabetic ketoacidosis, for instance) and type 2 (obesity and/or acanthosis nigricans) are being treated in their communities with either insulin alone or with insulin and an oral agent, mainly metformin, she said.

It is possible that obesity and insulin resistance may accelerate the presentation of type 1 diabetes in patients with type 2, said Dr. Libman.

The children being enrolled in the TODAY study, in addition to having an absence of islet cell autoimmunity, must have had diabetes for 2 years or less, be 10–17 years of age, and have a fasting C-peptide greater than 0.6 ng/mL and a body mass index at the 85th percentile or above. Participants will be randomized to receive metformin alone, metformin and rosiglitazone, or metformin and intensive lifestyle therapy.

Of the 535 children who were screened for inclusion in the TODAY study, approximately 5% had only glutamic acid decarboxylase (GAD) autoantibodies and 6% had only IA-2 autoantibodies. Approximately 7% had both GAD and IA-2 autoantibodies. All told, 18% were positive for one or both of the antibodies measured.

Dr. Klingensmith and her coinvestigators also looked at the number of children who had very high titer antibody levels. They found that 12% of the children screened—and 65% of all antibody-positive children—were either positive for both autoantibodies or had antibody titers that were more than 300% above normal (above the cut-off point for positivity).

They found that there were no differences between the groups in age, gender, or duration of diabetes. Children with both antibodies, however, had lower C-peptide levels, BMI and triglyceride levels, as well as higher HDL cholesterol and HbA_1c levels, and greater insulin use than did children with no antibodies, Dr. Klingensmith said.

According to Dr. Neil H. White, director of the division of pediatric endocrinology and metabolism at St. Louis University who is also a TODAY study investigator, approximately 12% of the children were receiving insulin alone at the time of screening for the study, and almost 50% were receiving metformin only. Approximately 25% were receiving both. The remaining children were receiving other medications or no treatment at all.

In terms of comorbidities, he reported, 26% had hypertension and almost 60% had dyslipidemia.

It remains to be seen whether diabetes autoimmunity will alter the clinical course of the disorder in youth with the clinical features of type 2 diabetes, Dr. Klingensmith said.

When it comes to the risk of conditions and complications traditionally associated with type 1 diabetes, it very well may, Dr. Libman warned.

Current guidelines, for instance, recommend screening for autoimmune thyroid disease in children with type 1 diabetes who, in contrast to those with type 2 diabetes, are known to have an increased frequency of thyroid antibodies and thyroid dysfunction. But a look at a sample of children in the Pittsburgh registries shows that children with “double” diabetes may have the same prevalence of thyroid antibodies as do those with type 1 diabetes.

Twenty percent of 24 children with double diabetes (defined here as obese with diabetes antibodies) were positive for thyroid antibodies, as were 21% of 117 children with type 1 diabetes (lean with diabetes antibodies). The two groups had a similar incidence of hypothyroidism. A sample of 21 children with type 2 diabetes (obese with no diabetes antibodies) had neither problem, Dr. Libman reported.

WASHINGTON — A preliminary look at the children referred for participation in a large treatment trial of type 2 diabetes in overweight and obese youth shows that the children not only have a high prevalence of hypertension and dyslipidemia, but a high incidence of autoantibody positivity as well, investigators reported at the annual scientific sessions of the American Diabetes Association.

The findings add to those of other studies suggesting that a significant number of children with apparent type 2 diabetes mellitus also may have diabetes autoimmunity consistent with type 1 diabetes, reported Dr. Georgeanna J. Klingensmith, director of pediatric clinics at the Barbara Davis Center for Childhood Diabetes in Aurora, Colo.

Approximately 18% of the 535 children screened for inclusion thus far in the 15-center, National Institutes of Health-sponsored Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study were found to be positive for diabetes autoimmunity. The children, who were racially and ethnically diverse, were considered by their pediatric endocrinologists to have type 2 diabetes.

The number of youth with diabetes autoimmunity in conjunction with characteristics of type 2 diabetes is likely much higher, however, because some potential study participants were locally prescreened for autoantibodies and were not even sent to the TODAY study investigators. The presence of islet cell autoimmunity is an exclusion criterion for the study, Dr. Klingensmith said.

Indeed, other studies have reported higher rates of what some physicians and investigators are now calling “double,” “hybrid,” or “type 3” diabetes.

Investigators of a large British study, for instance, reported almost 10 years ago that 33% of 157 young adults with type 2 diabetes were found to be positive for diabetes-associated antibodies. And, just this year, investigators of a German study reported that 36% of 128 children thought to have type 2 diabetes also had diabetes-associated antibodies, Dr. Klingensmith said.

Dr. Ingrid M. Libman of the Children's Hospital in Pittsburgh said in another presentation that the “spectrum” of diabetes now presenting in youth presents treatment dilemmas.

“If insulin therapy preserves B-cell function, should all patients that phenotypically look like type 2 but have antibodies be treated with insulin?” she asked. “And should patients [with type 1 and obesity] be treated with insulin sensitizers?”

There have been few studies on treatment for “double” diabetes, she continued. Children who are registered in the Allegheny County Registry for diabetes and the Children's Hospital Registry who have characteristics of both type 1 (antibodies and/or ketones and diabetic ketoacidosis, for instance) and type 2 (obesity and/or acanthosis nigricans) are being treated in their communities with either insulin alone or with insulin and an oral agent, mainly metformin, she said.

It is possible that obesity and insulin resistance may accelerate the presentation of type 1 diabetes in patients with type 2, said Dr. Libman.

The children being enrolled in the TODAY study, in addition to having an absence of islet cell autoimmunity, must have had diabetes for 2 years or less, be 10–17 years of age, and have a fasting C-peptide greater than 0.6 ng/mL and a body mass index at the 85th percentile or above. Participants will be randomized to receive metformin alone, metformin and rosiglitazone, or metformin and intensive lifestyle therapy.

Of the 535 children who were screened for inclusion in the TODAY study, approximately 5% had only glutamic acid decarboxylase (GAD) autoantibodies and 6% had only IA-2 autoantibodies. Approximately 7% had both GAD and IA-2 autoantibodies. All told, 18% were positive for one or both of the antibodies measured.

Dr. Klingensmith and her coinvestigators also looked at the number of children who had very high titer antibody levels. They found that 12% of the children screened—and 65% of all antibody-positive children—were either positive for both autoantibodies or had antibody titers that were more than 300% above normal (above the cut-off point for positivity).

They found that there were no differences between the groups in age, gender, or duration of diabetes. Children with both antibodies, however, had lower C-peptide levels, BMI and triglyceride levels, as well as higher HDL cholesterol and HbA_1c levels, and greater insulin use than did children with no antibodies, Dr. Klingensmith said.

According to Dr. Neil H. White, director of the division of pediatric endocrinology and metabolism at St. Louis University who is also a TODAY study investigator, approximately 12% of the children were receiving insulin alone at the time of screening for the study, and almost 50% were receiving metformin only. Approximately 25% were receiving both. The remaining children were receiving other medications or no treatment at all.

In terms of comorbidities, he reported, 26% had hypertension and almost 60% had dyslipidemia.

It remains to be seen whether diabetes autoimmunity will alter the clinical course of the disorder in youth with the clinical features of type 2 diabetes, Dr. Klingensmith said.

When it comes to the risk of conditions and complications traditionally associated with type 1 diabetes, it very well may, Dr. Libman warned.

Current guidelines, for instance, recommend screening for autoimmune thyroid disease in children with type 1 diabetes who, in contrast to those with type 2 diabetes, are known to have an increased frequency of thyroid antibodies and thyroid dysfunction. But a look at a sample of children in the Pittsburgh registries shows that children with “double” diabetes may have the same prevalence of thyroid antibodies as do those with type 1 diabetes.

Twenty percent of 24 children with double diabetes (defined here as obese with diabetes antibodies) were positive for thyroid antibodies, as were 21% of 117 children with type 1 diabetes (lean with diabetes antibodies). The two groups had a similar incidence of hypothyroidism. A sample of 21 children with type 2 diabetes (obese with no diabetes antibodies) had neither problem, Dr. Libman reported.

WASHINGTON — Early evidence suggests that the health benefits of bariatric surgery offset the risks for severely obese adolescents, according to the results of small studies reported at the annual scientific sessions of the American Diabetes Association.

Significant metabolic improvements and near-complete resolution of type 2 diabetes and obstructive sleep apnea were among the 1-year outcomes of Roux-en-Y gastric bypass surgery performed in 36 morbidly obese adolescents, aged 13–21 years, at three pediatric surgical centers participating in the Pediatric Bariatric Study Group.

Severely obese adolescents are developing serious adultlike comorbidities at an unexpectedly high frequency. Limited success with behavioral and lifestyle interventions has left physicians considering more aggressive interventions. “Children who are obese become obese adults,” said Dr. Carroll M. Harmon, of the Children's Hospital of Alabama, Birmingham.

Teens were eligible for the surgery at Children's Hospital and the other institutions in the Pediatric Bariatric Study Group (the University of Florida in Gainesville and the Cincinnati Children's Hospital Medical Center) if they had a body mass index (BMI) of at least 40 kg/m

The teens in the multicenter cohort had a mean BMI preoperatively of approximately 57. Postoperatively, the mean BMI fell to 36, a 37% reduction.

None of the patients included in the weight loss analysis (9 of the 36 teens in the cohort were excluded because they did not comply with follow-up requirements) attained normal weight in the year of follow-up; BMI values, in fact, still ranged from overweight to severe obesity.

Still, the postoperative weight loss was significant and consistent with outcomes in adults who undergo bariatric surgery, said Dr. Harmon, professor of surgery in the University of Alabama division of pediatric surgery.

Metabolic measures improved as a result of significant changes in triglycerides (−65 mg/dL), total cholesterol (−30 mg/dL), fasting blood glucose (−12 g/dL), and fasting insulin (−21.3 μU/mL). Changes in HDL and LDL cholesterol values were not statistically significant.

Mean hemoglobin A_1c decreased from 7.3% to 5.6% in the 10 patients diagnosed with type 2 diabetes. At 1 year after surgery, 1 of 10 patients remained on diabetic medications; 9 of 10 were on diabetic medications preoperatively, Dr. Harmon reported, adding that the adolescents also scored significantly higher postoperatively on various quality-of-life measures than they did preoperatively.

In a separate poster presentation, Dr. Marc P. Michalsky and Dr. Dara Schuster of Ohio State University, Columbus, reported on what they said are similarly good outcomes in five morbidly obese adolescents (BMI of at least 57) who underwent Roux-en-Y gastric bypass surgery at Columbus Children's Hospital.

Serum hemoglobin A_1c reached normal values within 20 weeks of surgery in each of the four adolescents with type 2 diabetes. Blood pressures reached normal values within 20 weeks in each of four hypertensive patients, and obstructive sleep apnea resolved after surgery in two of three affected patients. Insulin resistance (as determined by calculating the homeostasis model assessment of insulin resistance) also was reduced by a mean of 66% at 12 weeks post surgery.

“These are superobese kids,” and they have the same morbidities as obese adults who qualify for gastric bypass surgery, Dr. Schuster said in an interview. “The question we need to answer is: Do we do them a favor by operating early?”

Long-term follow-up will be necessary to determine the durability of the patients' improvements and the safety of the surger, the physicians said. It remains to be seen whether the patients will experience nutritional malabsorption, they noted.

None of the 5 adolescents treated in Columbus experienced complications during the 20-week follow-up period, but there were complications among the 36 who were followed for a year.

Nine of the 36 patients had minor complications with no long-term sequelae (nausea, wound infection, and food obstruction), and 4 had at least one moderate complication (persistent iron-deficiency anemia or the need for reoperation).

Two patients had severe complications, said Dr. Harmon. One developed severe thiamine deficiency with significant sequelae, and the other, who initially presented with a BMI of 80 and a weight of 630 pounds, died 9 months after surgery due to infectious colitis contracted while undergoing inpatient rehabilitation for osteoarthritis.

The complication profile thus far is similar to that seen in superobese adults who undergo the surgery. “But so far, in adolescents, just as in adults, these risks seem to be offset by the benefits,” he said.

The adjustable gastric banding procedure, which does not involve an intestinal bypass, is getting more attention as a possible “best” operation for adolescents—even though long-term results in adults have not been compared with those of gastric bypass surgery—because it eliminates concerns about nutritional and mineral malabsorption, Dr. Harmon said.

Insurance coverage varies nationwide and is difficult to secure in some locales. “In Ohio, Medicaid has been favorable toward covering these kids so far,” Dr. Michalsky said. “We have a high rate of obesity, so the state may be attuned [to the problem].”

Comorbid Conditions Often Missed

Dr. Schuster said the “most striking thing” about seeing adolescents referred to her hospital's bariatric surgery clinic is how “many of them didn't have their comorbid conditions diagnosed” before their surgical evaluations.

Hypertension, sleep apnea, diabetes, and other obesity-related comorbid conditions “are underdiagnosed and undermanaged” in obese adolescents, Dr. Schuster and her colleagues said in a poster presented at the annual scientific sessions of the American Diabetes Association.

Of 46 patients who were seen at the Columbus Children's Hospital Adolescent Bariatric Surgery Clinic in 2004 and 2005, 42% received a “new diagnosis” of obstructive sleep apnea and 33% learned they were hypothyroid.

During their initial presurgical evaluation, 25% were first told they had type 2 diabetes, 13% learned they had gastroesophageal reflux disease, and 10% received a new diagnosis of hypertension. Not surprisingly, since insulin resistance is hard to diagnose in most clinical settings, 54% learned for the first time that they were insulin resistant.

The prevalence of comorbidities was similar to, or higher than, the rates recorded among morbidly obese adults presenting at other clinics at Ohio State University in Columbus, reported Dr. Schuster and her associates.

WASHINGTON — Early evidence suggests that the health benefits of bariatric surgery offset the risks for severely obese adolescents, according to the results of small studies reported at the annual scientific sessions of the American Diabetes Association.

Significant metabolic improvements and near-complete resolution of type 2 diabetes and obstructive sleep apnea were among the 1-year outcomes of Roux-en-Y gastric bypass surgery performed in 36 morbidly obese adolescents, aged 13–21 years, at three pediatric surgical centers participating in the Pediatric Bariatric Study Group.

Severely obese adolescents are developing serious adultlike comorbidities at an unexpectedly high frequency. Limited success with behavioral and lifestyle interventions has left physicians considering more aggressive interventions. “Children who are obese become obese adults,” said Dr. Carroll M. Harmon, of the Children's Hospital of Alabama, Birmingham.

Teens were eligible for the surgery at Children's Hospital and the other institutions in the Pediatric Bariatric Study Group (the University of Florida in Gainesville and the Cincinnati Children's Hospital Medical Center) if they had a body mass index (BMI) of at least 40 kg/m

The teens in the multicenter cohort had a mean BMI preoperatively of approximately 57. Postoperatively, the mean BMI fell to 36, a 37% reduction.

None of the patients included in the weight loss analysis (9 of the 36 teens in the cohort were excluded because they did not comply with follow-up requirements) attained normal weight in the year of follow-up; BMI values, in fact, still ranged from overweight to severe obesity.

Still, the postoperative weight loss was significant and consistent with outcomes in adults who undergo bariatric surgery, said Dr. Harmon, professor of surgery in the University of Alabama division of pediatric surgery.

Metabolic measures improved as a result of significant changes in triglycerides (−65 mg/dL), total cholesterol (−30 mg/dL), fasting blood glucose (−12 g/dL), and fasting insulin (−21.3 μU/mL). Changes in HDL and LDL cholesterol values were not statistically significant.

Mean hemoglobin A_1c decreased from 7.3% to 5.6% in the 10 patients diagnosed with type 2 diabetes. At 1 year after surgery, 1 of 10 patients remained on diabetic medications; 9 of 10 were on diabetic medications preoperatively, Dr. Harmon reported, adding that the adolescents also scored significantly higher postoperatively on various quality-of-life measures than they did preoperatively.

In a separate poster presentation, Dr. Marc P. Michalsky and Dr. Dara Schuster of Ohio State University, Columbus, reported on what they said are similarly good outcomes in five morbidly obese adolescents (BMI of at least 57) who underwent Roux-en-Y gastric bypass surgery at Columbus Children's Hospital.

Serum hemoglobin A_1c reached normal values within 20 weeks of surgery in each of the four adolescents with type 2 diabetes. Blood pressures reached normal values within 20 weeks in each of four hypertensive patients, and obstructive sleep apnea resolved after surgery in two of three affected patients. Insulin resistance (as determined by calculating the homeostasis model assessment of insulin resistance) also was reduced by a mean of 66% at 12 weeks post surgery.

“These are superobese kids,” and they have the same morbidities as obese adults who qualify for gastric bypass surgery, Dr. Schuster said in an interview. “The question we need to answer is: Do we do them a favor by operating early?”

Long-term follow-up will be necessary to determine the durability of the patients' improvements and the safety of the surger, the physicians said. It remains to be seen whether the patients will experience nutritional malabsorption, they noted.

None of the 5 adolescents treated in Columbus experienced complications during the 20-week follow-up period, but there were complications among the 36 who were followed for a year.

Nine of the 36 patients had minor complications with no long-term sequelae (nausea, wound infection, and food obstruction), and 4 had at least one moderate complication (persistent iron-deficiency anemia or the need for reoperation).

Two patients had severe complications, said Dr. Harmon. One developed severe thiamine deficiency with significant sequelae, and the other, who initially presented with a BMI of 80 and a weight of 630 pounds, died 9 months after surgery due to infectious colitis contracted while undergoing inpatient rehabilitation for osteoarthritis.

The complication profile thus far is similar to that seen in superobese adults who undergo the surgery. “But so far, in adolescents, just as in adults, these risks seem to be offset by the benefits,” he said.

The adjustable gastric banding procedure, which does not involve an intestinal bypass, is getting more attention as a possible “best” operation for adolescents—even though long-term results in adults have not been compared with those of gastric bypass surgery—because it eliminates concerns about nutritional and mineral malabsorption, Dr. Harmon said.

Insurance coverage varies nationwide and is difficult to secure in some locales. “In Ohio, Medicaid has been favorable toward covering these kids so far,” Dr. Michalsky said. “We have a high rate of obesity, so the state may be attuned [to the problem].”

Comorbid Conditions Often Missed

Dr. Schuster said the “most striking thing” about seeing adolescents referred to her hospital's bariatric surgery clinic is how “many of them didn't have their comorbid conditions diagnosed” before their surgical evaluations.

Hypertension, sleep apnea, diabetes, and other obesity-related comorbid conditions “are underdiagnosed and undermanaged” in obese adolescents, Dr. Schuster and her colleagues said in a poster presented at the annual scientific sessions of the American Diabetes Association.

Of 46 patients who were seen at the Columbus Children's Hospital Adolescent Bariatric Surgery Clinic in 2004 and 2005, 42% received a “new diagnosis” of obstructive sleep apnea and 33% learned they were hypothyroid.

During their initial presurgical evaluation, 25% were first told they had type 2 diabetes, 13% learned they had gastroesophageal reflux disease, and 10% received a new diagnosis of hypertension. Not surprisingly, since insulin resistance is hard to diagnose in most clinical settings, 54% learned for the first time that they were insulin resistant.

The prevalence of comorbidities was similar to, or higher than, the rates recorded among morbidly obese adults presenting at other clinics at Ohio State University in Columbus, reported Dr. Schuster and her associates.

WASHINGTON — Early evidence suggests that the health benefits of bariatric surgery offset the risks for severely obese adolescents, according to the results of small studies reported at the annual scientific sessions of the American Diabetes Association.

Significant metabolic improvements and near-complete resolution of type 2 diabetes and obstructive sleep apnea were among the 1-year outcomes of Roux-en-Y gastric bypass surgery performed in 36 morbidly obese adolescents, aged 13–21 years, at three pediatric surgical centers participating in the Pediatric Bariatric Study Group.

Severely obese adolescents are developing serious adultlike comorbidities at an unexpectedly high frequency. Limited success with behavioral and lifestyle interventions has left physicians considering more aggressive interventions. “Children who are obese become obese adults,” said Dr. Carroll M. Harmon, of the Children's Hospital of Alabama, Birmingham.

Teens were eligible for the surgery at Children's Hospital and the other institutions in the Pediatric Bariatric Study Group (the University of Florida in Gainesville and the Cincinnati Children's Hospital Medical Center) if they had a body mass index (BMI) of at least 40 kg/m

The teens in the multicenter cohort had a mean BMI preoperatively of approximately 57. Postoperatively, the mean BMI fell to 36, a 37% reduction.

None of the patients included in the weight loss analysis (9 of the 36 teens in the cohort were excluded because they did not comply with follow-up requirements) attained normal weight in the year of follow-up; BMI values, in fact, still ranged from overweight to severe obesity.

Still, the postoperative weight loss was significant and consistent with outcomes in adults who undergo bariatric surgery, said Dr. Harmon, professor of surgery in the University of Alabama division of pediatric surgery.

Metabolic measures improved as a result of significant changes in triglycerides (−65 mg/dL), total cholesterol (−30 mg/dL), fasting blood glucose (−12 g/dL), and fasting insulin (−21.3 μU/mL). Changes in HDL and LDL cholesterol values were not statistically significant.

Mean hemoglobin A_1c decreased from 7.3% to 5.6% in the 10 patients diagnosed with type 2 diabetes. At 1 year after surgery, 1 of 10 patients remained on diabetic medications; 9 of 10 were on diabetic medications preoperatively, Dr. Harmon reported, adding that the adolescents also scored significantly higher postoperatively on various quality-of-life measures than they did preoperatively.

In a separate poster presentation, Dr. Marc P. Michalsky and Dr. Dara Schuster of Ohio State University, Columbus, reported on what they said are similarly good outcomes in five morbidly obese adolescents (BMI of at least 57) who underwent Roux-en-Y gastric bypass surgery at Columbus Children's Hospital.

Serum hemoglobin A_1c reached normal values within 20 weeks of surgery in each of the four adolescents with type 2 diabetes. Blood pressures reached normal values within 20 weeks in each of four hypertensive patients, and obstructive sleep apnea resolved after surgery in two of three affected patients. Insulin resistance (as determined by calculating the homeostasis model assessment of insulin resistance) also was reduced by a mean of 66% at 12 weeks post surgery.

“These are superobese kids,” and they have the same morbidities as obese adults who qualify for gastric bypass surgery, Dr. Schuster said in an interview. “The question we need to answer is: Do we do them a favor by operating early?”

Long-term follow-up will be necessary to determine the durability of the patients' improvements and the safety of the surger, the physicians said. It remains to be seen whether the patients will experience nutritional malabsorption, they noted.

None of the 5 adolescents treated in Columbus experienced complications during the 20-week follow-up period, but there were complications among the 36 who were followed for a year.

Nine of the 36 patients had minor complications with no long-term sequelae (nausea, wound infection, and food obstruction), and 4 had at least one moderate complication (persistent iron-deficiency anemia or the need for reoperation).

Two patients had severe complications, said Dr. Harmon. One developed severe thiamine deficiency with significant sequelae, and the other, who initially presented with a BMI of 80 and a weight of 630 pounds, died 9 months after surgery due to infectious colitis contracted while undergoing inpatient rehabilitation for osteoarthritis.

The complication profile thus far is similar to that seen in superobese adults who undergo the surgery. “But so far, in adolescents, just as in adults, these risks seem to be offset by the benefits,” he said.

The adjustable gastric banding procedure, which does not involve an intestinal bypass, is getting more attention as a possible “best” operation for adolescents—even though long-term results in adults have not been compared with those of gastric bypass surgery—because it eliminates concerns about nutritional and mineral malabsorption, Dr. Harmon said.

Insurance coverage varies nationwide and is difficult to secure in some locales. “In Ohio, Medicaid has been favorable toward covering these kids so far,” Dr. Michalsky said. “We have a high rate of obesity, so the state may be attuned [to the problem].”

Comorbid Conditions Often Missed

Dr. Schuster said the “most striking thing” about seeing adolescents referred to her hospital's bariatric surgery clinic is how “many of them didn't have their comorbid conditions diagnosed” before their surgical evaluations.

Hypertension, sleep apnea, diabetes, and other obesity-related comorbid conditions “are underdiagnosed and undermanaged” in obese adolescents, Dr. Schuster and her colleagues said in a poster presented at the annual scientific sessions of the American Diabetes Association.

Of 46 patients who were seen at the Columbus Children's Hospital Adolescent Bariatric Surgery Clinic in 2004 and 2005, 42% received a “new diagnosis” of obstructive sleep apnea and 33% learned they were hypothyroid.

During their initial presurgical evaluation, 25% were first told they had type 2 diabetes, 13% learned they had gastroesophageal reflux disease, and 10% received a new diagnosis of hypertension. Not surprisingly, since insulin resistance is hard to diagnose in most clinical settings, 54% learned for the first time that they were insulin resistant.

The prevalence of comorbidities was similar to, or higher than, the rates recorded among morbidly obese adults presenting at other clinics at Ohio State University in Columbus, reported Dr. Schuster and her associates.

WASHINGTON — Insulin resistance is such an integral and dangerous feature of polycystic ovary syndrome that metformin should be favored over oral contraceptive pills for treatment of the syndrome, said physicians in annual scientific sessions of the American Diabetes Association meeting.

Although there is a paucity of “good, prospective outcomes data” on cardiovascular disease in patients with polycystic ovary syndrome (PCOS)—as well as the existence of only limited data on oral contraceptives' (OCs) effect on insulin resistance—the speakers warned against waiting for definitive data to appear. Current knowledge of the risks of insulin resistance and the potential disadvantages of OCs is too convincing, they argued.

“Given everything [we know now], I believe we now must have the goals of preventing glucose intolerance and diabetes, and preventing atherosclerosis and acute coronary events” in addition to addressing the immediate symptoms of PCOS, said Dr. John Nestler, professor of medicine, ob.gyn., pharmacology, and toxicology at the Virginia Commonwealth University, Richmond.

“I will be provocative, because there aren't a lot of studies, but I'm going to argue that there may be disadvantages to using OCs,” said Dr. Nestler, who also chairs the division of endocrinology and metabolism.

OCs may be better for treating symptoms such as acne and hirsutism (studies of metformin have not addressed these problems as primary end points), but studies indicate that OCs worsen insulin resistance and glucose intolerance and that they may increase triglycerides, worsening the risk of diabetes and cardiovascular disease, he said.

Metformin, on the other hand, targets insulin resistance, “what may well be the initiating abnormality in PCOS, and has been shown to normalize or improve the biochemical, clinical, and reproductive abnormalities of PCOS,” said Dr. Tessa Lebinger, a pediatric endocrinologist. The drug is effective whether or not insulin resistance can be documented, she added.

In most cases, Dr. Nestler agreed, it won't be documented because insulin resistance is too difficult to accurately measure in a clinical setting. “Most women with PCOS are insulin resistant … so an empiric trial of metformin in any woman with PCOS is reasonable as you long as you monitor her and make sure that her menses are improving,” he said.

Dr. Burton Sobel, who directs the Cardiovascular Research Institute at the University of Vermont, said during a symposium on PCOS that from his perspective as a cardiologist, “PCOS is a cardiovascular disease.”

“We know, from so many perspectives, that impaired sensitivity to insulin is a forerunner, and probably a determinant, of premature coronary disease,” Dr. Sobel said. “It may be years before we have prospective data and legitimacy for using insulin sensitizers [in PCOS patients], but if I had a daughter with PCOS, I'd use an insulin sensitizer beginning with my recognition of the problem regardless of whether she had abnormal glucose tolerance. … I wouldn't wait—to me this is a smoking gun.”

The relationship between hyperinsulinemia and hyperandrogenism—in particular, the question of which causes which—is still discussed, but these physicians said they're convinced from available data that insulin resistance leads to hyperandrogenism and is likely a primary cause of PCOS.

Study results have shown that 30%–35% of women with PCOS have impaired glucose tolerance, and that 8%–10% have type 2 diabetes.

On the whole, Dr. Nestler said, 30%–50% of obese women with PCOS develop either impaired glucose tolerance or type 2 diabetes by age 30. Lean women with PCOS, on the other hand, are just as insulin resistant—if not more so—than obese women without PCOS, several speakers said.

Dr. Nestler said he and his colleagues found in a chart review of 50 consecutive PCOS patients treated with metformin that the incidence of impaired glucose tolerance was “dramatically” reduced.

At baseline, 78% of the 50 patients had normal glucose tolerance (NGT), and 22% had impaired glucose tolerance (IGT). At follow-up (a mean of 43 months for NGT patients, and 29 months for IGT patients), 55% of the IGT patients had converted to normal, with 45% continuing to have IGT. Of the NGT patients, 95% continued to have NGT, and 5% converted to IGT.

“It needs to be verified in a prospective study, but our annual conversion rate to IGT of 1.4% with metformin treatment is a dramatic reduction from the 16%–19% annual conversion rates” reported in women with PCOS who are not treated with metformin, he said.

He and other physicians at the meeting pointed to the Nurses' Health Study as the best of few studies that provides a look at the cardiovascular “outcomes” of PCOS.

In its tracking of over 80,000 women for 14 years, the study found that women with abnormal menstrual cyclicity had a relative risk for cardiovascular disease of 1.5 and a relative risk of fatal MI of 1.9, compared with women with normal menses. (The NHS also found a twofold increased risk, independent of weight, of type 2 diabetes in women with oligomenorrhea.)

Dr. Holley Allen, a pediatric endocrinologist at Baystate Medical Hospital in Springfield, Mass., said that a metaanalysis of case-control studies published in 2005 showed a twofold increased risk of both MI and ischemic stroke in women who took OCs.

The risk may be higher in women with PCOS, because they likely start at a higher baseline risk and take OCs for long periods of time, she said.

Still, she said she views the concerns about OCs' impact on insulin resistance and cardiovascular disease as “potential but unproven.”

And the “question is, whether she'll take a pill for the next 30 years that does not make her lose weight, doesn't do much for her facial hair or acne, and tastes like dead fish,” she said.

Dr. Lebinger, who spoke with Dr. Allen, acknowledged there are “inadequate data [on metformin use] in adolescents—only small studies and not many [that are] placebo controlled.”

Still, the literature consistently demonstrates either normalization or significant improvements in glucose intolerance, insulin resistance, and menstrual irregularities, said Dr. Lebinger, who practices in New Rochelle, N.Y.

Her adolescent patients on metformin also have improvements in their acne and frequently lose weight. “We're making recommendations based on what we know today. I present all the options—it's the patient's decision,” she said.

Regarding OCs and insulin resistance, “most of us observe that if you take a patient with type 1 diabetes and give them OCs, they usually require more insulin,” Dr. Lebinger said.

Dr. Nestler disclosed to the ADA that he is on the speakers' bureau for Sanofi-Aventis and that he is a stock/shareholder of the Bristol-Myers Squibb Co. and of Pfizer Inc.

Okay for Use in Infertile Patients

If time is not critical, metformin is also an appropriate front-line drug for patients with PCOS whose primary concern is infertility, Dr. Nestler said at the annual meeting of the American Diabetes Association.

“If a woman comes to me with PCOS and wants to get pregnant, I will usually tell her I'd like to put her on 3–6 months of metformin coupled with diet and exercise. In that way, we can try first for the singleton pregnancy [without clomiphene],” Dr. Nestler said. “If, at the end of 6 months, she doesn't become pregnant, I will send her to the endocrinologist.”

The authors of a 2003 review by the Cochrane Collaboration concluded that women with PCOS who take metformin are almost four times as likely to achieve ovulation, compared with women receiving placebo, he said.

In a study of 68 infertile women treated at his institution with metformin, Dr. Nestler and his colleagues found that 78% had improvements in menstrual cyclicity and ovulation, with the frequency of cycles increasing threefold. Approximately 44% had normalized cycles—the “optimal” outcome, he said.

Results from a National Institutes of Health-sponsored, multicenter, randomized study of metformin, clomiphene, or both for treating infertility in PCOS patients will be announced in October, he mentioned.

WASHINGTON — Insulin resistance is such an integral and dangerous feature of polycystic ovary syndrome that metformin should be favored over oral contraceptive pills for treatment of the syndrome, said physicians in annual scientific sessions of the American Diabetes Association meeting.

Although there is a paucity of “good, prospective outcomes data” on cardiovascular disease in patients with polycystic ovary syndrome (PCOS)—as well as the existence of only limited data on oral contraceptives' (OCs) effect on insulin resistance—the speakers warned against waiting for definitive data to appear. Current knowledge of the risks of insulin resistance and the potential disadvantages of OCs is too convincing, they argued.

“Given everything [we know now], I believe we now must have the goals of preventing glucose intolerance and diabetes, and preventing atherosclerosis and acute coronary events” in addition to addressing the immediate symptoms of PCOS, said Dr. John Nestler, professor of medicine, ob.gyn., pharmacology, and toxicology at the Virginia Commonwealth University, Richmond.

“I will be provocative, because there aren't a lot of studies, but I'm going to argue that there may be disadvantages to using OCs,” said Dr. Nestler, who also chairs the division of endocrinology and metabolism.

OCs may be better for treating symptoms such as acne and hirsutism (studies of metformin have not addressed these problems as primary end points), but studies indicate that OCs worsen insulin resistance and glucose intolerance and that they may increase triglycerides, worsening the risk of diabetes and cardiovascular disease, he said.

Metformin, on the other hand, targets insulin resistance, “what may well be the initiating abnormality in PCOS, and has been shown to normalize or improve the biochemical, clinical, and reproductive abnormalities of PCOS,” said Dr. Tessa Lebinger, a pediatric endocrinologist. The drug is effective whether or not insulin resistance can be documented, she added.

In most cases, Dr. Nestler agreed, it won't be documented because insulin resistance is too difficult to accurately measure in a clinical setting. “Most women with PCOS are insulin resistant … so an empiric trial of metformin in any woman with PCOS is reasonable as you long as you monitor her and make sure that her menses are improving,” he said.

Dr. Burton Sobel, who directs the Cardiovascular Research Institute at the University of Vermont, said during a symposium on PCOS that from his perspective as a cardiologist, “PCOS is a cardiovascular disease.”

“We know, from so many perspectives, that impaired sensitivity to insulin is a forerunner, and probably a determinant, of premature coronary disease,” Dr. Sobel said. “It may be years before we have prospective data and legitimacy for using insulin sensitizers [in PCOS patients], but if I had a daughter with PCOS, I'd use an insulin sensitizer beginning with my recognition of the problem regardless of whether she had abnormal glucose tolerance. … I wouldn't wait—to me this is a smoking gun.”

The relationship between hyperinsulinemia and hyperandrogenism—in particular, the question of which causes which—is still discussed, but these physicians said they're convinced from available data that insulin resistance leads to hyperandrogenism and is likely a primary cause of PCOS.

Study results have shown that 30%–35% of women with PCOS have impaired glucose tolerance, and that 8%–10% have type 2 diabetes.

On the whole, Dr. Nestler said, 30%–50% of obese women with PCOS develop either impaired glucose tolerance or type 2 diabetes by age 30. Lean women with PCOS, on the other hand, are just as insulin resistant—if not more so—than obese women without PCOS, several speakers said.

Dr. Nestler said he and his colleagues found in a chart review of 50 consecutive PCOS patients treated with metformin that the incidence of impaired glucose tolerance was “dramatically” reduced.

At baseline, 78% of the 50 patients had normal glucose tolerance (NGT), and 22% had impaired glucose tolerance (IGT). At follow-up (a mean of 43 months for NGT patients, and 29 months for IGT patients), 55% of the IGT patients had converted to normal, with 45% continuing to have IGT. Of the NGT patients, 95% continued to have NGT, and 5% converted to IGT.

“It needs to be verified in a prospective study, but our annual conversion rate to IGT of 1.4% with metformin treatment is a dramatic reduction from the 16%–19% annual conversion rates” reported in women with PCOS who are not treated with metformin, he said.

He and other physicians at the meeting pointed to the Nurses' Health Study as the best of few studies that provides a look at the cardiovascular “outcomes” of PCOS.

In its tracking of over 80,000 women for 14 years, the study found that women with abnormal menstrual cyclicity had a relative risk for cardiovascular disease of 1.5 and a relative risk of fatal MI of 1.9, compared with women with normal menses. (The NHS also found a twofold increased risk, independent of weight, of type 2 diabetes in women with oligomenorrhea.)

Dr. Holley Allen, a pediatric endocrinologist at Baystate Medical Hospital in Springfield, Mass., said that a metaanalysis of case-control studies published in 2005 showed a twofold increased risk of both MI and ischemic stroke in women who took OCs.

The risk may be higher in women with PCOS, because they likely start at a higher baseline risk and take OCs for long periods of time, she said.

Still, she said she views the concerns about OCs' impact on insulin resistance and cardiovascular disease as “potential but unproven.”

And the “question is, whether she'll take a pill for the next 30 years that does not make her lose weight, doesn't do much for her facial hair or acne, and tastes like dead fish,” she said.

Dr. Lebinger, who spoke with Dr. Allen, acknowledged there are “inadequate data [on metformin use] in adolescents—only small studies and not many [that are] placebo controlled.”

Still, the literature consistently demonstrates either normalization or significant improvements in glucose intolerance, insulin resistance, and menstrual irregularities, said Dr. Lebinger, who practices in New Rochelle, N.Y.

Her adolescent patients on metformin also have improvements in their acne and frequently lose weight. “We're making recommendations based on what we know today. I present all the options—it's the patient's decision,” she said.

Regarding OCs and insulin resistance, “most of us observe that if you take a patient with type 1 diabetes and give them OCs, they usually require more insulin,” Dr. Lebinger said.

Dr. Nestler disclosed to the ADA that he is on the speakers' bureau for Sanofi-Aventis and that he is a stock/shareholder of the Bristol-Myers Squibb Co. and of Pfizer Inc.

Okay for Use in Infertile Patients

If time is not critical, metformin is also an appropriate front-line drug for patients with PCOS whose primary concern is infertility, Dr. Nestler said at the annual meeting of the American Diabetes Association.

“If a woman comes to me with PCOS and wants to get pregnant, I will usually tell her I'd like to put her on 3–6 months of metformin coupled with diet and exercise. In that way, we can try first for the singleton pregnancy [without clomiphene],” Dr. Nestler said. “If, at the end of 6 months, she doesn't become pregnant, I will send her to the endocrinologist.”

The authors of a 2003 review by the Cochrane Collaboration concluded that women with PCOS who take metformin are almost four times as likely to achieve ovulation, compared with women receiving placebo, he said.

In a study of 68 infertile women treated at his institution with metformin, Dr. Nestler and his colleagues found that 78% had improvements in menstrual cyclicity and ovulation, with the frequency of cycles increasing threefold. Approximately 44% had normalized cycles—the “optimal” outcome, he said.

Results from a National Institutes of Health-sponsored, multicenter, randomized study of metformin, clomiphene, or both for treating infertility in PCOS patients will be announced in October, he mentioned.

WASHINGTON — Insulin resistance is such an integral and dangerous feature of polycystic ovary syndrome that metformin should be favored over oral contraceptive pills for treatment of the syndrome, said physicians in annual scientific sessions of the American Diabetes Association meeting.

Although there is a paucity of “good, prospective outcomes data” on cardiovascular disease in patients with polycystic ovary syndrome (PCOS)—as well as the existence of only limited data on oral contraceptives' (OCs) effect on insulin resistance—the speakers warned against waiting for definitive data to appear. Current knowledge of the risks of insulin resistance and the potential disadvantages of OCs is too convincing, they argued.

“Given everything [we know now], I believe we now must have the goals of preventing glucose intolerance and diabetes, and preventing atherosclerosis and acute coronary events” in addition to addressing the immediate symptoms of PCOS, said Dr. John Nestler, professor of medicine, ob.gyn., pharmacology, and toxicology at the Virginia Commonwealth University, Richmond.

“I will be provocative, because there aren't a lot of studies, but I'm going to argue that there may be disadvantages to using OCs,” said Dr. Nestler, who also chairs the division of endocrinology and metabolism.

OCs may be better for treating symptoms such as acne and hirsutism (studies of metformin have not addressed these problems as primary end points), but studies indicate that OCs worsen insulin resistance and glucose intolerance and that they may increase triglycerides, worsening the risk of diabetes and cardiovascular disease, he said.

Metformin, on the other hand, targets insulin resistance, “what may well be the initiating abnormality in PCOS, and has been shown to normalize or improve the biochemical, clinical, and reproductive abnormalities of PCOS,” said Dr. Tessa Lebinger, a pediatric endocrinologist. The drug is effective whether or not insulin resistance can be documented, she added.

In most cases, Dr. Nestler agreed, it won't be documented because insulin resistance is too difficult to accurately measure in a clinical setting. “Most women with PCOS are insulin resistant … so an empiric trial of metformin in any woman with PCOS is reasonable as you long as you monitor her and make sure that her menses are improving,” he said.

Dr. Burton Sobel, who directs the Cardiovascular Research Institute at the University of Vermont, said during a symposium on PCOS that from his perspective as a cardiologist, “PCOS is a cardiovascular disease.”

“We know, from so many perspectives, that impaired sensitivity to insulin is a forerunner, and probably a determinant, of premature coronary disease,” Dr. Sobel said. “It may be years before we have prospective data and legitimacy for using insulin sensitizers [in PCOS patients], but if I had a daughter with PCOS, I'd use an insulin sensitizer beginning with my recognition of the problem regardless of whether she had abnormal glucose tolerance. … I wouldn't wait—to me this is a smoking gun.”

The relationship between hyperinsulinemia and hyperandrogenism—in particular, the question of which causes which—is still discussed, but these physicians said they're convinced from available data that insulin resistance leads to hyperandrogenism and is likely a primary cause of PCOS.

Study results have shown that 30%–35% of women with PCOS have impaired glucose tolerance, and that 8%–10% have type 2 diabetes.

On the whole, Dr. Nestler said, 30%–50% of obese women with PCOS develop either impaired glucose tolerance or type 2 diabetes by age 30. Lean women with PCOS, on the other hand, are just as insulin resistant—if not more so—than obese women without PCOS, several speakers said.

Dr. Nestler said he and his colleagues found in a chart review of 50 consecutive PCOS patients treated with metformin that the incidence of impaired glucose tolerance was “dramatically” reduced.

At baseline, 78% of the 50 patients had normal glucose tolerance (NGT), and 22% had impaired glucose tolerance (IGT). At follow-up (a mean of 43 months for NGT patients, and 29 months for IGT patients), 55% of the IGT patients had converted to normal, with 45% continuing to have IGT. Of the NGT patients, 95% continued to have NGT, and 5% converted to IGT.

“It needs to be verified in a prospective study, but our annual conversion rate to IGT of 1.4% with metformin treatment is a dramatic reduction from the 16%–19% annual conversion rates” reported in women with PCOS who are not treated with metformin, he said.

He and other physicians at the meeting pointed to the Nurses' Health Study as the best of few studies that provides a look at the cardiovascular “outcomes” of PCOS.

In its tracking of over 80,000 women for 14 years, the study found that women with abnormal menstrual cyclicity had a relative risk for cardiovascular disease of 1.5 and a relative risk of fatal MI of 1.9, compared with women with normal menses. (The NHS also found a twofold increased risk, independent of weight, of type 2 diabetes in women with oligomenorrhea.)

Dr. Holley Allen, a pediatric endocrinologist at Baystate Medical Hospital in Springfield, Mass., said that a metaanalysis of case-control studies published in 2005 showed a twofold increased risk of both MI and ischemic stroke in women who took OCs.

The risk may be higher in women with PCOS, because they likely start at a higher baseline risk and take OCs for long periods of time, she said.

Still, she said she views the concerns about OCs' impact on insulin resistance and cardiovascular disease as “potential but unproven.”

And the “question is, whether she'll take a pill for the next 30 years that does not make her lose weight, doesn't do much for her facial hair or acne, and tastes like dead fish,” she said.

Dr. Lebinger, who spoke with Dr. Allen, acknowledged there are “inadequate data [on metformin use] in adolescents—only small studies and not many [that are] placebo controlled.”

Still, the literature consistently demonstrates either normalization or significant improvements in glucose intolerance, insulin resistance, and menstrual irregularities, said Dr. Lebinger, who practices in New Rochelle, N.Y.

Her adolescent patients on metformin also have improvements in their acne and frequently lose weight. “We're making recommendations based on what we know today. I present all the options—it's the patient's decision,” she said.

Regarding OCs and insulin resistance, “most of us observe that if you take a patient with type 1 diabetes and give them OCs, they usually require more insulin,” Dr. Lebinger said.

Dr. Nestler disclosed to the ADA that he is on the speakers' bureau for Sanofi-Aventis and that he is a stock/shareholder of the Bristol-Myers Squibb Co. and of Pfizer Inc.

Okay for Use in Infertile Patients

If time is not critical, metformin is also an appropriate front-line drug for patients with PCOS whose primary concern is infertility, Dr. Nestler said at the annual meeting of the American Diabetes Association.

“If a woman comes to me with PCOS and wants to get pregnant, I will usually tell her I'd like to put her on 3–6 months of metformin coupled with diet and exercise. In that way, we can try first for the singleton pregnancy [without clomiphene],” Dr. Nestler said. “If, at the end of 6 months, she doesn't become pregnant, I will send her to the endocrinologist.”

The authors of a 2003 review by the Cochrane Collaboration concluded that women with PCOS who take metformin are almost four times as likely to achieve ovulation, compared with women receiving placebo, he said.

In a study of 68 infertile women treated at his institution with metformin, Dr. Nestler and his colleagues found that 78% had improvements in menstrual cyclicity and ovulation, with the frequency of cycles increasing threefold. Approximately 44% had normalized cycles—the “optimal” outcome, he said.

Results from a National Institutes of Health-sponsored, multicenter, randomized study of metformin, clomiphene, or both for treating infertility in PCOS patients will be announced in October, he mentioned.

Patients with early-stage rheumatoid arthritis who are treated with methotrexate plus infliximab are more likely to remain employed or able to work than are patients treated with methotrexate alone, according to findings from another new analysis of the ASPIRE trial data.

Physical function deteriorates so rapidly in rheumatoid arthritis (RA) that 20% of employed patients have to quit their jobs within 2 years of disease onset, and approximately half of RA patients face work disability within 10 years, reported Dr. Josef S. Smolen of the Medical University of Vienna, and his colleagues in Europe and the United States (Arthritis Rheum. 2006;54:716–22).

Patients in the ASPIRE (Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset) trial—which compared methotrexate alone with methotrexate plus infliximab—were asked at each visit whether they were currently employed and if not, whether they felt well enough to work if a job were available.

The new analysis, which covered approximately 850 patients aged 65 years or younger, found that rapid disease control in early-stage RA reduced patients work disability and improved their employability, reported Dr. Smolen and colleagues.

While the actual employment rate did not differ significantly between the two treatment groups, the patients treated with both drugs were more likely to maintain their employability or to feel able to work throughout the 54-week study.

The proportion of patients whose status changed from employable at baseline to unemployable at week 54 was smaller in the methotrexate-plus-infliximab group than in the methotrexate-only group (8% vs. 14%, respectively). Similarly, the proportion of employed patients who lost more than 10 workdays was smaller in the combination group, when compared with the methotrexate-only group (10% vs. 17%, respectively), the investigators reported.

Patients with early-stage rheumatoid arthritis who are treated with methotrexate plus infliximab are more likely to remain employed or able to work than are patients treated with methotrexate alone, according to findings from another new analysis of the ASPIRE trial data.

Physical function deteriorates so rapidly in rheumatoid arthritis (RA) that 20% of employed patients have to quit their jobs within 2 years of disease onset, and approximately half of RA patients face work disability within 10 years, reported Dr. Josef S. Smolen of the Medical University of Vienna, and his colleagues in Europe and the United States (Arthritis Rheum. 2006;54:716–22).

Patients in the ASPIRE (Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset) trial—which compared methotrexate alone with methotrexate plus infliximab—were asked at each visit whether they were currently employed and if not, whether they felt well enough to work if a job were available.

The new analysis, which covered approximately 850 patients aged 65 years or younger, found that rapid disease control in early-stage RA reduced patients work disability and improved their employability, reported Dr. Smolen and colleagues.

While the actual employment rate did not differ significantly between the two treatment groups, the patients treated with both drugs were more likely to maintain their employability or to feel able to work throughout the 54-week study.

The proportion of patients whose status changed from employable at baseline to unemployable at week 54 was smaller in the methotrexate-plus-infliximab group than in the methotrexate-only group (8% vs. 14%, respectively). Similarly, the proportion of employed patients who lost more than 10 workdays was smaller in the combination group, when compared with the methotrexate-only group (10% vs. 17%, respectively), the investigators reported.

Patients with early-stage rheumatoid arthritis who are treated with methotrexate plus infliximab are more likely to remain employed or able to work than are patients treated with methotrexate alone, according to findings from another new analysis of the ASPIRE trial data.

Physical function deteriorates so rapidly in rheumatoid arthritis (RA) that 20% of employed patients have to quit their jobs within 2 years of disease onset, and approximately half of RA patients face work disability within 10 years, reported Dr. Josef S. Smolen of the Medical University of Vienna, and his colleagues in Europe and the United States (Arthritis Rheum. 2006;54:716–22).

Patients in the ASPIRE (Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset) trial—which compared methotrexate alone with methotrexate plus infliximab—were asked at each visit whether they were currently employed and if not, whether they felt well enough to work if a job were available.

The new analysis, which covered approximately 850 patients aged 65 years or younger, found that rapid disease control in early-stage RA reduced patients work disability and improved their employability, reported Dr. Smolen and colleagues.

While the actual employment rate did not differ significantly between the two treatment groups, the patients treated with both drugs were more likely to maintain their employability or to feel able to work throughout the 54-week study.

The proportion of patients whose status changed from employable at baseline to unemployable at week 54 was smaller in the methotrexate-plus-infliximab group than in the methotrexate-only group (8% vs. 14%, respectively). Similarly, the proportion of employed patients who lost more than 10 workdays was smaller in the combination group, when compared with the methotrexate-only group (10% vs. 17%, respectively), the investigators reported.

With a new carotid registry on both carotid artery stenting and endarterectomy about to open, the American College of Cardiology is at the forefront of an intensifying national focus on the use of patient registries for measuring effectiveness of new treatments.

Officials at the Agency for Healthcare Research and Quality (AHRQ), the National Committee for Quality Assurance (NCQA), the Centers for Medicare and Medicaid Services (CMS), and other organizations increasingly view patient registries as a key component of outcomes research, benchmarking, and payment policy, including future pay-for-performance initiatives.

They also view carotid artery stenting (CAS) as a perfect example of a complex, high-risk procedure involving different specialists that must be systematically studied and analyzed after it has been unveiled in clinical practice—and one for which registries may be an ideal tool.

The collection of outcomes data on high-risk patients who undergo CAS is now a requirement for Medicare payment. When CMS expanded coverage of CAS a year ago to high-risk, symptomatic patients with carotid artery stenosis of at least 70% (treated outside the context of clinical trials), it stipulated that facilities must be certified by CMS to perform carotid stenting and that facilities must also collect data on all CAS procedures.

Data must be analyzed at least every 6 months and made available to CMS “upon request” and as part of the CMS process of recredentialing facilities. According to the CMS Web site, more than 800 hospitals are now certified and collecting data.

The ACC's carotid registry is expected to open officially this month or next. The Society for Vascular Surgery (SVS) has already opened a similar registry. Both registries will make it easier for facilities and physicians of all specialties to comply with CMS's payment requirements for CAS, leaders at the organizations say.

The registries also will allow them to collect long-term outcomes data on both CAS and carotid artery endarterectomy (CAE) and to benchmark their outcomes against those of other institutions.

The ACC's CAS registry has been in the works for some time, but the decision to include CAE was a more recent consideration, after it became evident that including it would make the registry an attractive option for surgeons as well as interventional cardiologists, said Dr. Kenneth Rosenfield, who led development of the registry.

Having a registry that is as multispecialty as possible has always been a goal of the ACC, Dr. Rosenfield said. “We're talking about optimizing patient safety across the board. We owe it to patients to collaborate.”

The ACC and SVS registries have their origins in a broader “Clinical Competence Statement on Carotid Stenting” that was published jointly by vascular surgery and interventional cardiology organizations last year.

The statement endorsed the creation of a national multispecialty carotid registry “for reporting of outcomes and assessment of institutional and individual operator competence.” It was issued by SVS, the Society for Cardiovascular Angiography and Interventions (SCAI), and the Society for Vascular Medicine and Biology, and endorsed by the ACC.

Officials at ACC and SVS said that despite efforts to welcome all specialties, the two organizations decided to develop separate registries. However, officials at both organizations have also said in interviews that they are fully committed to sharing data elements and definitions.

“Both of our societies are committed to a process that will enable us to compare apples with apples,” said Dr. Rosenfield, director of the cardiac and vascular invasive service at Massachusetts General Hospital, Boston.

Officials at NCQA and AHRQ, in the meantime, are trying to anticipate and prepare for challenges in coordinating and analyzing data on carotid procedures from multiple patient registries.

The issue was discussed at a conference held late last year by NCQA and SCAI with funding from AHRQ, when experts discussed registries as evaluation tools and focused on CAS as a case study.

CMS, which anticipated and has supported the development of more than one carotid registry, also has told societies there should be as many common data elements as possible among the registries, that they should have “full transparency,” and that the registries should be accessible to the public.

ACC is adding the carotid registry to its larger Web-based National Cardiovascular Data Registry (NCDR), which houses two other registries—the CathPCI Registry, used by about 750 hospitals, and the ICD [implantable cardioverter defibrillator] Registry, which, starting this month, is the required registry for hospitals to receive Medicare coverage for the use of implantable cardioverter defibrillators for primary prevention of sudden cardiac death. (CMS contracted last fall with the ACC's NCDR to collect data on ICDs used for this indication. By this month, all hospitals must have transferred their current ICD data reporting activities to the ICD Registry.)

For carotid procedures, registry-level data are not enough, and randomized trials of CAS and CAE “need to be completed,” said Dr. Steve Phurrough, director of the Coverage and Analysis Group at CMS, in an interview. “With ICDs, we had lots of good-quality, high-volume data—with CAS we don't.”

Still, he said, registries are an important part of it all, especially because “comparing [and] risk-adjusting are better done in larger databases.”

The collection of data as a condition of coverage “will become more and more prevalent, especially [in light of recent cases in which] the risks of drugs and devices weren't known until a few years out,” he said.

Dr. Rosenfield said he believed the ACC registry is “a bit more robust” than the SVS registry, particularly with respect to preprocedural history, including neurologic history, and neurologic end points.

Dr. Ralph G. Brindis, chairman and chief medical officer of the ACC-NCDR, said the new registry would benefit from the NCDR's multifaceted strategy for auditing registry data to ensure it is complete and accurate.

“The biggest Achilles' heel [for registries] is the ability of [outsiders] to feel comfortable with the validity of the data,” he said.

With a new carotid registry on both carotid artery stenting and endarterectomy about to open, the American College of Cardiology is at the forefront of an intensifying national focus on the use of patient registries for measuring effectiveness of new treatments.

Officials at the Agency for Healthcare Research and Quality (AHRQ), the National Committee for Quality Assurance (NCQA), the Centers for Medicare and Medicaid Services (CMS), and other organizations increasingly view patient registries as a key component of outcomes research, benchmarking, and payment policy, including future pay-for-performance initiatives.

They also view carotid artery stenting (CAS) as a perfect example of a complex, high-risk procedure involving different specialists that must be systematically studied and analyzed after it has been unveiled in clinical practice—and one for which registries may be an ideal tool.

The collection of outcomes data on high-risk patients who undergo CAS is now a requirement for Medicare payment. When CMS expanded coverage of CAS a year ago to high-risk, symptomatic patients with carotid artery stenosis of at least 70% (treated outside the context of clinical trials), it stipulated that facilities must be certified by CMS to perform carotid stenting and that facilities must also collect data on all CAS procedures.

Data must be analyzed at least every 6 months and made available to CMS “upon request” and as part of the CMS process of recredentialing facilities. According to the CMS Web site, more than 800 hospitals are now certified and collecting data.

The ACC's carotid registry is expected to open officially this month or next. The Society for Vascular Surgery (SVS) has already opened a similar registry. Both registries will make it easier for facilities and physicians of all specialties to comply with CMS's payment requirements for CAS, leaders at the organizations say.

The registries also will allow them to collect long-term outcomes data on both CAS and carotid artery endarterectomy (CAE) and to benchmark their outcomes against those of other institutions.

The ACC's CAS registry has been in the works for some time, but the decision to include CAE was a more recent consideration, after it became evident that including it would make the registry an attractive option for surgeons as well as interventional cardiologists, said Dr. Kenneth Rosenfield, who led development of the registry.

Having a registry that is as multispecialty as possible has always been a goal of the ACC, Dr. Rosenfield said. “We're talking about optimizing patient safety across the board. We owe it to patients to collaborate.”

The ACC and SVS registries have their origins in a broader “Clinical Competence Statement on Carotid Stenting” that was published jointly by vascular surgery and interventional cardiology organizations last year.

The statement endorsed the creation of a national multispecialty carotid registry “for reporting of outcomes and assessment of institutional and individual operator competence.” It was issued by SVS, the Society for Cardiovascular Angiography and Interventions (SCAI), and the Society for Vascular Medicine and Biology, and endorsed by the ACC.

Officials at ACC and SVS said that despite efforts to welcome all specialties, the two organizations decided to develop separate registries. However, officials at both organizations have also said in interviews that they are fully committed to sharing data elements and definitions.

“Both of our societies are committed to a process that will enable us to compare apples with apples,” said Dr. Rosenfield, director of the cardiac and vascular invasive service at Massachusetts General Hospital, Boston.

Officials at NCQA and AHRQ, in the meantime, are trying to anticipate and prepare for challenges in coordinating and analyzing data on carotid procedures from multiple patient registries.

The issue was discussed at a conference held late last year by NCQA and SCAI with funding from AHRQ, when experts discussed registries as evaluation tools and focused on CAS as a case study.

CMS, which anticipated and has supported the development of more than one carotid registry, also has told societies there should be as many common data elements as possible among the registries, that they should have “full transparency,” and that the registries should be accessible to the public.

ACC is adding the carotid registry to its larger Web-based National Cardiovascular Data Registry (NCDR), which houses two other registries—the CathPCI Registry, used by about 750 hospitals, and the ICD [implantable cardioverter defibrillator] Registry, which, starting this month, is the required registry for hospitals to receive Medicare coverage for the use of implantable cardioverter defibrillators for primary prevention of sudden cardiac death. (CMS contracted last fall with the ACC's NCDR to collect data on ICDs used for this indication. By this month, all hospitals must have transferred their current ICD data reporting activities to the ICD Registry.)

For carotid procedures, registry-level data are not enough, and randomized trials of CAS and CAE “need to be completed,” said Dr. Steve Phurrough, director of the Coverage and Analysis Group at CMS, in an interview. “With ICDs, we had lots of good-quality, high-volume data—with CAS we don't.”

Still, he said, registries are an important part of it all, especially because “comparing [and] risk-adjusting are better done in larger databases.”

The collection of data as a condition of coverage “will become more and more prevalent, especially [in light of recent cases in which] the risks of drugs and devices weren't known until a few years out,” he said.

Dr. Rosenfield said he believed the ACC registry is “a bit more robust” than the SVS registry, particularly with respect to preprocedural history, including neurologic history, and neurologic end points.

Dr. Ralph G. Brindis, chairman and chief medical officer of the ACC-NCDR, said the new registry would benefit from the NCDR's multifaceted strategy for auditing registry data to ensure it is complete and accurate.

“The biggest Achilles' heel [for registries] is the ability of [outsiders] to feel comfortable with the validity of the data,” he said.

With a new carotid registry on both carotid artery stenting and endarterectomy about to open, the American College of Cardiology is at the forefront of an intensifying national focus on the use of patient registries for measuring effectiveness of new treatments.

Officials at the Agency for Healthcare Research and Quality (AHRQ), the National Committee for Quality Assurance (NCQA), the Centers for Medicare and Medicaid Services (CMS), and other organizations increasingly view patient registries as a key component of outcomes research, benchmarking, and payment policy, including future pay-for-performance initiatives.

They also view carotid artery stenting (CAS) as a perfect example of a complex, high-risk procedure involving different specialists that must be systematically studied and analyzed after it has been unveiled in clinical practice—and one for which registries may be an ideal tool.

The collection of outcomes data on high-risk patients who undergo CAS is now a requirement for Medicare payment. When CMS expanded coverage of CAS a year ago to high-risk, symptomatic patients with carotid artery stenosis of at least 70% (treated outside the context of clinical trials), it stipulated that facilities must be certified by CMS to perform carotid stenting and that facilities must also collect data on all CAS procedures.

Data must be analyzed at least every 6 months and made available to CMS “upon request” and as part of the CMS process of recredentialing facilities. According to the CMS Web site, more than 800 hospitals are now certified and collecting data.

The ACC's carotid registry is expected to open officially this month or next. The Society for Vascular Surgery (SVS) has already opened a similar registry. Both registries will make it easier for facilities and physicians of all specialties to comply with CMS's payment requirements for CAS, leaders at the organizations say.

The registries also will allow them to collect long-term outcomes data on both CAS and carotid artery endarterectomy (CAE) and to benchmark their outcomes against those of other institutions.

The ACC's CAS registry has been in the works for some time, but the decision to include CAE was a more recent consideration, after it became evident that including it would make the registry an attractive option for surgeons as well as interventional cardiologists, said Dr. Kenneth Rosenfield, who led development of the registry.

Having a registry that is as multispecialty as possible has always been a goal of the ACC, Dr. Rosenfield said. “We're talking about optimizing patient safety across the board. We owe it to patients to collaborate.”

The ACC and SVS registries have their origins in a broader “Clinical Competence Statement on Carotid Stenting” that was published jointly by vascular surgery and interventional cardiology organizations last year.

The statement endorsed the creation of a national multispecialty carotid registry “for reporting of outcomes and assessment of institutional and individual operator competence.” It was issued by SVS, the Society for Cardiovascular Angiography and Interventions (SCAI), and the Society for Vascular Medicine and Biology, and endorsed by the ACC.

Officials at ACC and SVS said that despite efforts to welcome all specialties, the two organizations decided to develop separate registries. However, officials at both organizations have also said in interviews that they are fully committed to sharing data elements and definitions.

“Both of our societies are committed to a process that will enable us to compare apples with apples,” said Dr. Rosenfield, director of the cardiac and vascular invasive service at Massachusetts General Hospital, Boston.

Officials at NCQA and AHRQ, in the meantime, are trying to anticipate and prepare for challenges in coordinating and analyzing data on carotid procedures from multiple patient registries.

The issue was discussed at a conference held late last year by NCQA and SCAI with funding from AHRQ, when experts discussed registries as evaluation tools and focused on CAS as a case study.

CMS, which anticipated and has supported the development of more than one carotid registry, also has told societies there should be as many common data elements as possible among the registries, that they should have “full transparency,” and that the registries should be accessible to the public.

ACC is adding the carotid registry to its larger Web-based National Cardiovascular Data Registry (NCDR), which houses two other registries—the CathPCI Registry, used by about 750 hospitals, and the ICD [implantable cardioverter defibrillator] Registry, which, starting this month, is the required registry for hospitals to receive Medicare coverage for the use of implantable cardioverter defibrillators for primary prevention of sudden cardiac death. (CMS contracted last fall with the ACC's NCDR to collect data on ICDs used for this indication. By this month, all hospitals must have transferred their current ICD data reporting activities to the ICD Registry.)

For carotid procedures, registry-level data are not enough, and randomized trials of CAS and CAE “need to be completed,” said Dr. Steve Phurrough, director of the Coverage and Analysis Group at CMS, in an interview. “With ICDs, we had lots of good-quality, high-volume data—with CAS we don't.”

Still, he said, registries are an important part of it all, especially because “comparing [and] risk-adjusting are better done in larger databases.”

The collection of data as a condition of coverage “will become more and more prevalent, especially [in light of recent cases in which] the risks of drugs and devices weren't known until a few years out,” he said.

Dr. Rosenfield said he believed the ACC registry is “a bit more robust” than the SVS registry, particularly with respect to preprocedural history, including neurologic history, and neurologic end points.

Dr. Ralph G. Brindis, chairman and chief medical officer of the ACC-NCDR, said the new registry would benefit from the NCDR's multifaceted strategy for auditing registry data to ensure it is complete and accurate.

“The biggest Achilles' heel [for registries] is the ability of [outsiders] to feel comfortable with the validity of the data,” he said.

Patients with early rheumatoid arthritis who are most likely to benefit from immediate introduction of infliximab plus high-dose methotrexate are those with high C-reactive protein levels, a high erythrocyte sedimentation rate, or persistent disease activity, as well as greater initial joint damage, according to a new analysis of trial data reported Dr. Josef S. Smolen, and his associates in Europe and the United States.

The 54-week trial showed that overall, combination therapy with methotrexate and infliximab provided greater clinical, radiographic, and functional benefits than treatment with methotrexate alone for patients with active, early-stage RA (Arthritis Rheum. 2006;54:702–10).

The new findings build on results from the ASPIRE study (Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset), the investigators reported.

Patients in the trial had RA for no longer than 3 years; the 1,049 patients were randomized to receive titrating doses of methotrexate up to 20 mg/wk plus placebo or infliximab at weeks 0, 2, and 6, and then every 8 weeks through week 46, Dr. Smolen, of the Medical University of Vienna, and his colleagues reported.

In the new analysis, the investigators looked for predictors of radiographic joint damage in order to identify subgroups of patients who would likely improve with methotrexate alone and those who would most benefit from the more expensive and potentially toxic combination therapy.

To do so, Dr. Smolen and his colleagues looked at the relationship between disease activity measures taken at baseline and at week 14, as well as those averaged over time, with changes in radiographic joint damage.

Radiographs were obtained within 4 weeks of the start of treatment and at weeks 30 and 54. Joint damage was assessed by changes in modified Sharp/van der Heijde scores (SHS).

The investigators found that methotrexate alone failed to prevent the progression of joint damage among patients with the highest C-reactive protein (CRP) levels, erythrocyte sedimentation rate (ESR), and swollen joint counts, as well as the highest levels of joint damage at baseline.

Infliximab in combination with methotrexate, on the other hand, inhibited radiographic progression regardless of baseline and early disease activity or joint damage.

Patients in the highest baseline tertile of CRP (3 mg/dL or greater) and ESR (52 mm/hour or greater) who were treated only with methotrexate had mean increases in the SHS for joint damage of 5.62 and 5.89, respectively, from baseline to week 54. In patients who were treated with methotrexate plus infliximab, these changes were 0.73 and 1.12, respectively.

Also, patients receiving methotrexate alone who had persistently active disease—higher disease activity scores (DAS28)—at week 14 showed greater progression of joint damage from baseline to week 54 than those with lower DAS28 scores. Combination treatment led to significantly less joint damage regardless of disease activity at this time.

“This finding is of particular importance, since physicians generally prescribe [methotrexate] as initial [disease modifying-antirheumatic drug therapy] and then assess the adequacy of response [some] 3–6 months later,” the investigators said. The results “suggest that continuation of [methotrexate] alone in patients with a DAS28 of [greater than] 4.02 (or a simplified Disease Activity Index of [greater than] 23.8) at week 14 carries with it a significant risk of progressive joint damage.”

Overall, they said, the new analysis shows that “it is especially important to identify patients whose disease is rapidly advancing and who have the greatest potential to benefit from more intensive therapy.”

Patients with early rheumatoid arthritis who are most likely to benefit from immediate introduction of infliximab plus high-dose methotrexate are those with high C-reactive protein levels, a high erythrocyte sedimentation rate, or persistent disease activity, as well as greater initial joint damage, according to a new analysis of trial data reported Dr. Josef S. Smolen, and his associates in Europe and the United States.

The 54-week trial showed that overall, combination therapy with methotrexate and infliximab provided greater clinical, radiographic, and functional benefits than treatment with methotrexate alone for patients with active, early-stage RA (Arthritis Rheum. 2006;54:702–10).

The new findings build on results from the ASPIRE study (Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset), the investigators reported.

Patients in the trial had RA for no longer than 3 years; the 1,049 patients were randomized to receive titrating doses of methotrexate up to 20 mg/wk plus placebo or infliximab at weeks 0, 2, and 6, and then every 8 weeks through week 46, Dr. Smolen, of the Medical University of Vienna, and his colleagues reported.

In the new analysis, the investigators looked for predictors of radiographic joint damage in order to identify subgroups of patients who would likely improve with methotrexate alone and those who would most benefit from the more expensive and potentially toxic combination therapy.

To do so, Dr. Smolen and his colleagues looked at the relationship between disease activity measures taken at baseline and at week 14, as well as those averaged over time, with changes in radiographic joint damage.

Radiographs were obtained within 4 weeks of the start of treatment and at weeks 30 and 54. Joint damage was assessed by changes in modified Sharp/van der Heijde scores (SHS).

The investigators found that methotrexate alone failed to prevent the progression of joint damage among patients with the highest C-reactive protein (CRP) levels, erythrocyte sedimentation rate (ESR), and swollen joint counts, as well as the highest levels of joint damage at baseline.

Infliximab in combination with methotrexate, on the other hand, inhibited radiographic progression regardless of baseline and early disease activity or joint damage.

Patients in the highest baseline tertile of CRP (3 mg/dL or greater) and ESR (52 mm/hour or greater) who were treated only with methotrexate had mean increases in the SHS for joint damage of 5.62 and 5.89, respectively, from baseline to week 54. In patients who were treated with methotrexate plus infliximab, these changes were 0.73 and 1.12, respectively.

Also, patients receiving methotrexate alone who had persistently active disease—higher disease activity scores (DAS28)—at week 14 showed greater progression of joint damage from baseline to week 54 than those with lower DAS28 scores. Combination treatment led to significantly less joint damage regardless of disease activity at this time.

“This finding is of particular importance, since physicians generally prescribe [methotrexate] as initial [disease modifying-antirheumatic drug therapy] and then assess the adequacy of response [some] 3–6 months later,” the investigators said. The results “suggest that continuation of [methotrexate] alone in patients with a DAS28 of [greater than] 4.02 (or a simplified Disease Activity Index of [greater than] 23.8) at week 14 carries with it a significant risk of progressive joint damage.”

Overall, they said, the new analysis shows that “it is especially important to identify patients whose disease is rapidly advancing and who have the greatest potential to benefit from more intensive therapy.”

Patients with early rheumatoid arthritis who are most likely to benefit from immediate introduction of infliximab plus high-dose methotrexate are those with high C-reactive protein levels, a high erythrocyte sedimentation rate, or persistent disease activity, as well as greater initial joint damage, according to a new analysis of trial data reported Dr. Josef S. Smolen, and his associates in Europe and the United States.

The 54-week trial showed that overall, combination therapy with methotrexate and infliximab provided greater clinical, radiographic, and functional benefits than treatment with methotrexate alone for patients with active, early-stage RA (Arthritis Rheum. 2006;54:702–10).

The new findings build on results from the ASPIRE study (Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset), the investigators reported.

Patients in the trial had RA for no longer than 3 years; the 1,049 patients were randomized to receive titrating doses of methotrexate up to 20 mg/wk plus placebo or infliximab at weeks 0, 2, and 6, and then every 8 weeks through week 46, Dr. Smolen, of the Medical University of Vienna, and his colleagues reported.

In the new analysis, the investigators looked for predictors of radiographic joint damage in order to identify subgroups of patients who would likely improve with methotrexate alone and those who would most benefit from the more expensive and potentially toxic combination therapy.

To do so, Dr. Smolen and his colleagues looked at the relationship between disease activity measures taken at baseline and at week 14, as well as those averaged over time, with changes in radiographic joint damage.

Radiographs were obtained within 4 weeks of the start of treatment and at weeks 30 and 54. Joint damage was assessed by changes in modified Sharp/van der Heijde scores (SHS).

The investigators found that methotrexate alone failed to prevent the progression of joint damage among patients with the highest C-reactive protein (CRP) levels, erythrocyte sedimentation rate (ESR), and swollen joint counts, as well as the highest levels of joint damage at baseline.

Infliximab in combination with methotrexate, on the other hand, inhibited radiographic progression regardless of baseline and early disease activity or joint damage.

Patients in the highest baseline tertile of CRP (3 mg/dL or greater) and ESR (52 mm/hour or greater) who were treated only with methotrexate had mean increases in the SHS for joint damage of 5.62 and 5.89, respectively, from baseline to week 54. In patients who were treated with methotrexate plus infliximab, these changes were 0.73 and 1.12, respectively.

Also, patients receiving methotrexate alone who had persistently active disease—higher disease activity scores (DAS28)—at week 14 showed greater progression of joint damage from baseline to week 54 than those with lower DAS28 scores. Combination treatment led to significantly less joint damage regardless of disease activity at this time.

“This finding is of particular importance, since physicians generally prescribe [methotrexate] as initial [disease modifying-antirheumatic drug therapy] and then assess the adequacy of response [some] 3–6 months later,” the investigators said. The results “suggest that continuation of [methotrexate] alone in patients with a DAS28 of [greater than] 4.02 (or a simplified Disease Activity Index of [greater than] 23.8) at week 14 carries with it a significant risk of progressive joint damage.”

Overall, they said, the new analysis shows that “it is especially important to identify patients whose disease is rapidly advancing and who have the greatest potential to benefit from more intensive therapy.”

Protein and energy supplementation can increase survival and reduce complications for hospitalized elderly patients who are undernourished at admission, but there is little or no evidence that it helps well-nourished patients who are hospitalized or older people who live in other settings, according to a review of 55 randomized controlled trials.

“Although the evidence is limited and generally of poor quality, we suggest that routine supplements should be considered” for undernourished elderly patients in the hospital, said Anne C. Milne, research fellow at the University of Aberdeen, Scotland, and her colleagues.

They used the methods of the international Cochrane Collaboration, an organization that evaluates medical research and draws evidence-based conclusions about medical practice, to conduct a metaanalysis of randomized or “quasirandomized trials” of oral protein and energy supplementation lasting at least 1 week in people older than 65 years. Supplementation included various commercial nutritional supplements, milk-based supplements, and fortification of normal food sources, but not special immunomodulatory supplements or supplements of specific amino acids.

The effects of supplementation on mortality and morbidity were statistically significant only in hospitalized patients who were deemed undernourished—and even then, the results were “borderline statistically significant,” the investigators said. Hospital stay was not reduced in patients who received supplements.

Supplementation may improve mortality in older patients in long-term care, but there's no evidence to suggest improvement in mortality and morbidity for older people at home or well-nourished older patients in any setting, they said (Ann. Intern. Med. 2006;144:37–48).

Protein and energy supplementation can increase survival and reduce complications for hospitalized elderly patients who are undernourished at admission, but there is little or no evidence that it helps well-nourished patients who are hospitalized or older people who live in other settings, according to a review of 55 randomized controlled trials.

“Although the evidence is limited and generally of poor quality, we suggest that routine supplements should be considered” for undernourished elderly patients in the hospital, said Anne C. Milne, research fellow at the University of Aberdeen, Scotland, and her colleagues.

They used the methods of the international Cochrane Collaboration, an organization that evaluates medical research and draws evidence-based conclusions about medical practice, to conduct a metaanalysis of randomized or “quasirandomized trials” of oral protein and energy supplementation lasting at least 1 week in people older than 65 years. Supplementation included various commercial nutritional supplements, milk-based supplements, and fortification of normal food sources, but not special immunomodulatory supplements or supplements of specific amino acids.

The effects of supplementation on mortality and morbidity were statistically significant only in hospitalized patients who were deemed undernourished—and even then, the results were “borderline statistically significant,” the investigators said. Hospital stay was not reduced in patients who received supplements.

Supplementation may improve mortality in older patients in long-term care, but there's no evidence to suggest improvement in mortality and morbidity for older people at home or well-nourished older patients in any setting, they said (Ann. Intern. Med. 2006;144:37–48).

Protein and energy supplementation can increase survival and reduce complications for hospitalized elderly patients who are undernourished at admission, but there is little or no evidence that it helps well-nourished patients who are hospitalized or older people who live in other settings, according to a review of 55 randomized controlled trials.

“Although the evidence is limited and generally of poor quality, we suggest that routine supplements should be considered” for undernourished elderly patients in the hospital, said Anne C. Milne, research fellow at the University of Aberdeen, Scotland, and her colleagues.

They used the methods of the international Cochrane Collaboration, an organization that evaluates medical research and draws evidence-based conclusions about medical practice, to conduct a metaanalysis of randomized or “quasirandomized trials” of oral protein and energy supplementation lasting at least 1 week in people older than 65 years. Supplementation included various commercial nutritional supplements, milk-based supplements, and fortification of normal food sources, but not special immunomodulatory supplements or supplements of specific amino acids.

The effects of supplementation on mortality and morbidity were statistically significant only in hospitalized patients who were deemed undernourished—and even then, the results were “borderline statistically significant,” the investigators said. Hospital stay was not reduced in patients who received supplements.

Supplementation may improve mortality in older patients in long-term care, but there's no evidence to suggest improvement in mortality and morbidity for older people at home or well-nourished older patients in any setting, they said (Ann. Intern. Med. 2006;144:37–48).

A new scientific statement from the cardiology community on the evaluation of syncope could either win nods of acceptance or raise eyebrows with its support for echocardiograms and stress tests and its caution against tilt table testing.

The American Heart Association/American College of Cardiology Foundation Scientific Statement on the Evaluation of Syncope—the first such statement on syncope issued by the organizations—reiterates some well-established findings, chiefly that most cases of the often-vexing problem have a cardiovascular cause. It emphasizes the importance of promptly ruling out structural heart disease and ischemia, as well as less common causes associated with sudden death.

The statement lays out a diminished role, however, for tilt table testing, saying that “serious questions about the sensitivity, specificity, diagnostic yield, and day-to-day reproducibility of tilt table testing exist.”

Tilt table testing has traditionally been used as an aid in establishing the diagnosis of neurocardiogenic syncope, and according to lead author Dr. S. Adam Strickberger, “some … may feel the tilt table test was devalued” in the new statement.

“But in general, I think there are a lot fewer tilt table tests ordered by electrophysiologists today … and it's fair to say there is a smaller role for the tests than there would have been 10–15 years ago,” Dr. Strickberger said in an interview.

The 11-page statement, which the AHA and ACC Foundation issued in collaboration with the Heart Rhythm Society and which was endorsed by the American Autonomic Society, was published in February (J. Am. Coll. Cardiol. 2006;47:473–84).

Although the document does not offer guidelines per se, it features a simple flowchart for the “diagnostic approach” to patients with syncope and comments on the role of various tests.

Its creation was driven by the recognition that syncope “can herald life-threatening diseases” and that “there are patients who are not managed appropriately,” said Dr. Strickberger, director of arrhythmia research and professor of medicine at Georgetown University, Washington. “We wanted a practical document.”

Most important, the statement says, the evaluation of syncope should include a front-line assessment for structural heart disease and ischemia. Less common causes that are associated with sudden death, including Wolff-Parkinson-White syndrome and inherited cardiac ion channel abnormalities, should be excluded early. “The primary purpose of the evaluation … is to determine whether the patient is at increased risk for death,” the statement says.

In most patients, the cause of syncope can be determined “with great accuracy” from a careful history, physical exam, and ECG. Echocardiograms, exercise tests, and ischemic evaluations fall on the next tier.

The statement says that “an echocardiogram is a helpful screening test if the history, physical examination, and ECG do not provide a diagnosis or if underlying heart disease is suspected.”

“Most of the people on the writing group have a fairly low threshold for the echocardiogram and stress test, which may represent some shift (in thinking),” Dr. Strickberger said.

The statement includes a section on the elderly, mentioning that up to 30% of falls in this population may be due to syncope, and that orthostatic hypotension is the cause of falls in up to a third of elderly patients.

Carotid sinus hypersensitivity is an underrecognized cause of syncope in the elderly, the statement says, and “neurally mediated causes remain a frequent mechanism of syncope in the elderly and may be underestimated because of an atypical presentation.”

The statement says that “particular emphasis (in the elderly) should be given to the impact of polypharmacy, orthostatic intolerance, autonomic dysfunction, and carotid sinus hypersensitivity.”

The greatest challenges with syncope evaluation can lie with the patient, of any age, who has a normal general work-up and cardiac examination. Here, Dr. Strickberger said, the key lies in determining the “malignancy” of the episode and adjusting the intensity of the evaluation accordingly.

Episodes that occur with little or no warning and that result in a significant injury may warrant other tests, such as electrophysiologic testing—which has a low yield and is not routinely recommended—and the tilt table test, Dr. Strickberger said.

In general, however, the tilt table test provides little useful information, the statement points out. In patients who have no evidence of ischemia and a structurally normal heart, “the pretest probability that the diagnosis is neurocardiogenic syncope is high, so heads-up tilt table testing contributes little to establishing the diagnosis.”

In a patient who has an otherwise normal evaluation, the statement explains, “the most likely diagnosis” after a negative tilt table test “is still neurocardiogenic syncope.”

A new scientific statement from the cardiology community on the evaluation of syncope could either win nods of acceptance or raise eyebrows with its support for echocardiograms and stress tests and its caution against tilt table testing.

The American Heart Association/American College of Cardiology Foundation Scientific Statement on the Evaluation of Syncope—the first such statement on syncope issued by the organizations—reiterates some well-established findings, chiefly that most cases of the often-vexing problem have a cardiovascular cause. It emphasizes the importance of promptly ruling out structural heart disease and ischemia, as well as less common causes associated with sudden death.

The statement lays out a diminished role, however, for tilt table testing, saying that “serious questions about the sensitivity, specificity, diagnostic yield, and day-to-day reproducibility of tilt table testing exist.”

Tilt table testing has traditionally been used as an aid in establishing the diagnosis of neurocardiogenic syncope, and according to lead author Dr. S. Adam Strickberger, “some … may feel the tilt table test was devalued” in the new statement.

“But in general, I think there are a lot fewer tilt table tests ordered by electrophysiologists today … and it's fair to say there is a smaller role for the tests than there would have been 10–15 years ago,” Dr. Strickberger said in an interview.

The 11-page statement, which the AHA and ACC Foundation issued in collaboration with the Heart Rhythm Society and which was endorsed by the American Autonomic Society, was published in February (J. Am. Coll. Cardiol. 2006;47:473–84).

Although the document does not offer guidelines per se, it features a simple flowchart for the “diagnostic approach” to patients with syncope and comments on the role of various tests.

Its creation was driven by the recognition that syncope “can herald life-threatening diseases” and that “there are patients who are not managed appropriately,” said Dr. Strickberger, director of arrhythmia research and professor of medicine at Georgetown University, Washington. “We wanted a practical document.”

Most important, the statement says, the evaluation of syncope should include a front-line assessment for structural heart disease and ischemia. Less common causes that are associated with sudden death, including Wolff-Parkinson-White syndrome and inherited cardiac ion channel abnormalities, should be excluded early. “The primary purpose of the evaluation … is to determine whether the patient is at increased risk for death,” the statement says.

In most patients, the cause of syncope can be determined “with great accuracy” from a careful history, physical exam, and ECG. Echocardiograms, exercise tests, and ischemic evaluations fall on the next tier.

The statement says that “an echocardiogram is a helpful screening test if the history, physical examination, and ECG do not provide a diagnosis or if underlying heart disease is suspected.”

“Most of the people on the writing group have a fairly low threshold for the echocardiogram and stress test, which may represent some shift (in thinking),” Dr. Strickberger said.

The statement includes a section on the elderly, mentioning that up to 30% of falls in this population may be due to syncope, and that orthostatic hypotension is the cause of falls in up to a third of elderly patients.

Carotid sinus hypersensitivity is an underrecognized cause of syncope in the elderly, the statement says, and “neurally mediated causes remain a frequent mechanism of syncope in the elderly and may be underestimated because of an atypical presentation.”

The statement says that “particular emphasis (in the elderly) should be given to the impact of polypharmacy, orthostatic intolerance, autonomic dysfunction, and carotid sinus hypersensitivity.”

The greatest challenges with syncope evaluation can lie with the patient, of any age, who has a normal general work-up and cardiac examination. Here, Dr. Strickberger said, the key lies in determining the “malignancy” of the episode and adjusting the intensity of the evaluation accordingly.

Episodes that occur with little or no warning and that result in a significant injury may warrant other tests, such as electrophysiologic testing—which has a low yield and is not routinely recommended—and the tilt table test, Dr. Strickberger said.

In general, however, the tilt table test provides little useful information, the statement points out. In patients who have no evidence of ischemia and a structurally normal heart, “the pretest probability that the diagnosis is neurocardiogenic syncope is high, so heads-up tilt table testing contributes little to establishing the diagnosis.”

In a patient who has an otherwise normal evaluation, the statement explains, “the most likely diagnosis” after a negative tilt table test “is still neurocardiogenic syncope.”

A new scientific statement from the cardiology community on the evaluation of syncope could either win nods of acceptance or raise eyebrows with its support for echocardiograms and stress tests and its caution against tilt table testing.

The American Heart Association/American College of Cardiology Foundation Scientific Statement on the Evaluation of Syncope—the first such statement on syncope issued by the organizations—reiterates some well-established findings, chiefly that most cases of the often-vexing problem have a cardiovascular cause. It emphasizes the importance of promptly ruling out structural heart disease and ischemia, as well as less common causes associated with sudden death.

The statement lays out a diminished role, however, for tilt table testing, saying that “serious questions about the sensitivity, specificity, diagnostic yield, and day-to-day reproducibility of tilt table testing exist.”

Tilt table testing has traditionally been used as an aid in establishing the diagnosis of neurocardiogenic syncope, and according to lead author Dr. S. Adam Strickberger, “some … may feel the tilt table test was devalued” in the new statement.

“But in general, I think there are a lot fewer tilt table tests ordered by electrophysiologists today … and it's fair to say there is a smaller role for the tests than there would have been 10–15 years ago,” Dr. Strickberger said in an interview.

The 11-page statement, which the AHA and ACC Foundation issued in collaboration with the Heart Rhythm Society and which was endorsed by the American Autonomic Society, was published in February (J. Am. Coll. Cardiol. 2006;47:473–84).

Although the document does not offer guidelines per se, it features a simple flowchart for the “diagnostic approach” to patients with syncope and comments on the role of various tests.

Its creation was driven by the recognition that syncope “can herald life-threatening diseases” and that “there are patients who are not managed appropriately,” said Dr. Strickberger, director of arrhythmia research and professor of medicine at Georgetown University, Washington. “We wanted a practical document.”

Most important, the statement says, the evaluation of syncope should include a front-line assessment for structural heart disease and ischemia. Less common causes that are associated with sudden death, including Wolff-Parkinson-White syndrome and inherited cardiac ion channel abnormalities, should be excluded early. “The primary purpose of the evaluation … is to determine whether the patient is at increased risk for death,” the statement says.

In most patients, the cause of syncope can be determined “with great accuracy” from a careful history, physical exam, and ECG. Echocardiograms, exercise tests, and ischemic evaluations fall on the next tier.

The statement says that “an echocardiogram is a helpful screening test if the history, physical examination, and ECG do not provide a diagnosis or if underlying heart disease is suspected.”

“Most of the people on the writing group have a fairly low threshold for the echocardiogram and stress test, which may represent some shift (in thinking),” Dr. Strickberger said.

The statement includes a section on the elderly, mentioning that up to 30% of falls in this population may be due to syncope, and that orthostatic hypotension is the cause of falls in up to a third of elderly patients.

Carotid sinus hypersensitivity is an underrecognized cause of syncope in the elderly, the statement says, and “neurally mediated causes remain a frequent mechanism of syncope in the elderly and may be underestimated because of an atypical presentation.”

The statement says that “particular emphasis (in the elderly) should be given to the impact of polypharmacy, orthostatic intolerance, autonomic dysfunction, and carotid sinus hypersensitivity.”

The greatest challenges with syncope evaluation can lie with the patient, of any age, who has a normal general work-up and cardiac examination. Here, Dr. Strickberger said, the key lies in determining the “malignancy” of the episode and adjusting the intensity of the evaluation accordingly.

Episodes that occur with little or no warning and that result in a significant injury may warrant other tests, such as electrophysiologic testing—which has a low yield and is not routinely recommended—and the tilt table test, Dr. Strickberger said.

In general, however, the tilt table test provides little useful information, the statement points out. In patients who have no evidence of ischemia and a structurally normal heart, “the pretest probability that the diagnosis is neurocardiogenic syncope is high, so heads-up tilt table testing contributes little to establishing the diagnosis.”

In a patient who has an otherwise normal evaluation, the statement explains, “the most likely diagnosis” after a negative tilt table test “is still neurocardiogenic syncope.”