Here are 5 articles in the October issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Autism Follow-up Screening by PCPs Yields High Accuracy

To take the posttest, go to: http://bit.ly/2bTLhFS
Expires August 19, 2017

VITALS

Key clinical point:

Primary care providers can conduct the M-CHAT/F following a positive M-CHAT screening for autism spectrum disorders.

Major finding:

Primary care providers and trained interviewers agreed 86.6% of the time on the screening results of the M-CHAT/F for ASDs.

Data source:

A cohort study of 5,071 children, mean age 23 months, screened with the M-CHAT, and a subsequent 197 children screened with the M-CHAT/F in 22 Maryland primary care practices.

Disclosures:

The National Institutes of Mental Health funded the research. Dr. Sturner is director of Total Child Health (TCH), a for-profit subsidiary of the Center for Promotion of Child Development through Primary Care, which conducted the study. Barbara Howard, MD, is president of TCH. Tanya Morrel, PhD, is an employee of and stockholder in TCH, and Paul Bergmann has consulted for the company. The remaining authors had no relevant disclosures.

2. Gallstone Disease Boosts Heart Risk

To take the posttest, go to: http://bit.ly/2c7TP7D
Expires August 18, 2017

VITALS

Key clinical point:

Gallstone disease is associated with an increased risk for coronary heart disease; preventing the former can help mitigate chances of developing the latter.

Major finding:

A meta-analysis revealed a 23% increased chance of CHD in gallstone disease patients.

Data source:

A meta-analysis of seven studies involving 842,553 subjects, and a prospective cohort study of 269,142 participants in three separate studies that took place from 1980 to 2011.

Disclosures:

Funding provided by NIH, Boston Obesity Nutrition Research Center, and United States-Israel Binational Science Foundation. The authors had no relevant financial disclosures.

3. New HER2-testing Guidelines Result in More Women Eligible for Directed Treatment

To take the posttest, go to: http://bit.ly/2cd9llO
Expires July 25, 2017

VITALS

Key clinical point:

New IHC and FISH pathology guidelines categorize more breast cancers as "equivocal" regarding HER2 positivity and ultimately lead to identifying more of them as HER2 positive.

Major finding:

By using 2013 guidelines, 358 additional tumors were interpreted as positive, compared with the 2007 guidelines and 298 additional tumors were considered positive, compared with the FDA criteria.

Data source:

A cohort study involving 2,851 breast cancer samples analyzed according to three different pathology guidelines during a 1-year period.

Disclosures:

This study was supported by the Mayo Clinic. Dr. Shah reported having no relevant financial disclosures; his associates reported ties to Merck, Hospira, Ariad Pharmaceuticals, Abbott Molecular, and Genome Diagnostics.

4. Extreme Alcohol Use Worsens HIV Disease

To take the posttest, go to: http://bit.ly/2coIzG3
Expires August 14, 2017

VITALS

Key clinical point:

A pattern of heavy alcohol use over time in HIV-infected patients was associated with accelerated HIV disease progression.

Major finding:

Long-term heavy alcohol use by middle-aged, HIV-infected military veterans was associated with a 1.83-fold increased likelihood of also being in the highest-risk group for accelerated progression of HIV disease.

Data source:

This study included 3,539 U.S. military veterans receiving care for HIV infection at eight VA centers. The impact of their long-term pattern of alcohol use on HIV disease progression was assessed over an 8-year period by annual assessments using validated instruments.

Disclosures:

The presenter reported having no financial conflicts of interest regarding the study, funded by the National Institute on Alcohol Abuse and Alcoholism and the National Institute of Allergy and Infectious Diseases.

5. Weight Loss Boosts TNFis' Psoriatic Arthritis Efficacy

To take the posttest, go to: http://bit.ly/2chD4M1
Expires July 23, 2017

Here are 5 articles in the October issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Autism Follow-up Screening by PCPs Yields High Accuracy

To take the posttest, go to: http://bit.ly/2bTLhFS
Expires August 19, 2017

VITALS

Key clinical point:

Primary care providers can conduct the M-CHAT/F following a positive M-CHAT screening for autism spectrum disorders.

Major finding:

Primary care providers and trained interviewers agreed 86.6% of the time on the screening results of the M-CHAT/F for ASDs.

Data source:

A cohort study of 5,071 children, mean age 23 months, screened with the M-CHAT, and a subsequent 197 children screened with the M-CHAT/F in 22 Maryland primary care practices.

Disclosures:

The National Institutes of Mental Health funded the research. Dr. Sturner is director of Total Child Health (TCH), a for-profit subsidiary of the Center for Promotion of Child Development through Primary Care, which conducted the study. Barbara Howard, MD, is president of TCH. Tanya Morrel, PhD, is an employee of and stockholder in TCH, and Paul Bergmann has consulted for the company. The remaining authors had no relevant disclosures.

2. Gallstone Disease Boosts Heart Risk

To take the posttest, go to: http://bit.ly/2c7TP7D
Expires August 18, 2017

VITALS

Key clinical point:

Gallstone disease is associated with an increased risk for coronary heart disease; preventing the former can help mitigate chances of developing the latter.

Major finding:

A meta-analysis revealed a 23% increased chance of CHD in gallstone disease patients.

Data source:

A meta-analysis of seven studies involving 842,553 subjects, and a prospective cohort study of 269,142 participants in three separate studies that took place from 1980 to 2011.

Disclosures:

Funding provided by NIH, Boston Obesity Nutrition Research Center, and United States-Israel Binational Science Foundation. The authors had no relevant financial disclosures.

3. New HER2-testing Guidelines Result in More Women Eligible for Directed Treatment

To take the posttest, go to: http://bit.ly/2cd9llO
Expires July 25, 2017

VITALS

Key clinical point:

New IHC and FISH pathology guidelines categorize more breast cancers as "equivocal" regarding HER2 positivity and ultimately lead to identifying more of them as HER2 positive.

Major finding:

By using 2013 guidelines, 358 additional tumors were interpreted as positive, compared with the 2007 guidelines and 298 additional tumors were considered positive, compared with the FDA criteria.

Data source:

A cohort study involving 2,851 breast cancer samples analyzed according to three different pathology guidelines during a 1-year period.

Disclosures:

This study was supported by the Mayo Clinic. Dr. Shah reported having no relevant financial disclosures; his associates reported ties to Merck, Hospira, Ariad Pharmaceuticals, Abbott Molecular, and Genome Diagnostics.

4. Extreme Alcohol Use Worsens HIV Disease

To take the posttest, go to: http://bit.ly/2coIzG3
Expires August 14, 2017

VITALS

Key clinical point:

A pattern of heavy alcohol use over time in HIV-infected patients was associated with accelerated HIV disease progression.

Major finding:

Long-term heavy alcohol use by middle-aged, HIV-infected military veterans was associated with a 1.83-fold increased likelihood of also being in the highest-risk group for accelerated progression of HIV disease.

Data source:

This study included 3,539 U.S. military veterans receiving care for HIV infection at eight VA centers. The impact of their long-term pattern of alcohol use on HIV disease progression was assessed over an 8-year period by annual assessments using validated instruments.

Disclosures:

The presenter reported having no financial conflicts of interest regarding the study, funded by the National Institute on Alcohol Abuse and Alcoholism and the National Institute of Allergy and Infectious Diseases.

5. Weight Loss Boosts TNFis' Psoriatic Arthritis Efficacy

To take the posttest, go to: http://bit.ly/2chD4M1
Expires July 23, 2017

Here are 5 articles in the October issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Autism Follow-up Screening by PCPs Yields High Accuracy

To take the posttest, go to: http://bit.ly/2bTLhFS
Expires August 19, 2017

VITALS

Key clinical point:

Primary care providers can conduct the M-CHAT/F following a positive M-CHAT screening for autism spectrum disorders.

Major finding:

Primary care providers and trained interviewers agreed 86.6% of the time on the screening results of the M-CHAT/F for ASDs.

Data source:

A cohort study of 5,071 children, mean age 23 months, screened with the M-CHAT, and a subsequent 197 children screened with the M-CHAT/F in 22 Maryland primary care practices.

Disclosures:

The National Institutes of Mental Health funded the research. Dr. Sturner is director of Total Child Health (TCH), a for-profit subsidiary of the Center for Promotion of Child Development through Primary Care, which conducted the study. Barbara Howard, MD, is president of TCH. Tanya Morrel, PhD, is an employee of and stockholder in TCH, and Paul Bergmann has consulted for the company. The remaining authors had no relevant disclosures.

2. Gallstone Disease Boosts Heart Risk

To take the posttest, go to: http://bit.ly/2c7TP7D
Expires August 18, 2017

VITALS

Key clinical point:

Gallstone disease is associated with an increased risk for coronary heart disease; preventing the former can help mitigate chances of developing the latter.

Major finding:

A meta-analysis revealed a 23% increased chance of CHD in gallstone disease patients.

Data source:

A meta-analysis of seven studies involving 842,553 subjects, and a prospective cohort study of 269,142 participants in three separate studies that took place from 1980 to 2011.

Disclosures:

Funding provided by NIH, Boston Obesity Nutrition Research Center, and United States-Israel Binational Science Foundation. The authors had no relevant financial disclosures.

3. New HER2-testing Guidelines Result in More Women Eligible for Directed Treatment

To take the posttest, go to: http://bit.ly/2cd9llO
Expires July 25, 2017

VITALS

Key clinical point:

New IHC and FISH pathology guidelines categorize more breast cancers as "equivocal" regarding HER2 positivity and ultimately lead to identifying more of them as HER2 positive.

Major finding:

By using 2013 guidelines, 358 additional tumors were interpreted as positive, compared with the 2007 guidelines and 298 additional tumors were considered positive, compared with the FDA criteria.

Data source:

A cohort study involving 2,851 breast cancer samples analyzed according to three different pathology guidelines during a 1-year period.

Disclosures:

This study was supported by the Mayo Clinic. Dr. Shah reported having no relevant financial disclosures; his associates reported ties to Merck, Hospira, Ariad Pharmaceuticals, Abbott Molecular, and Genome Diagnostics.

4. Extreme Alcohol Use Worsens HIV Disease

To take the posttest, go to: http://bit.ly/2coIzG3
Expires August 14, 2017

VITALS

Key clinical point:

A pattern of heavy alcohol use over time in HIV-infected patients was associated with accelerated HIV disease progression.

Major finding:

Long-term heavy alcohol use by middle-aged, HIV-infected military veterans was associated with a 1.83-fold increased likelihood of also being in the highest-risk group for accelerated progression of HIV disease.

Data source:

This study included 3,539 U.S. military veterans receiving care for HIV infection at eight VA centers. The impact of their long-term pattern of alcohol use on HIV disease progression was assessed over an 8-year period by annual assessments using validated instruments.

Disclosures:

The presenter reported having no financial conflicts of interest regarding the study, funded by the National Institute on Alcohol Abuse and Alcoholism and the National Institute of Allergy and Infectious Diseases.

5. Weight Loss Boosts TNFis' Psoriatic Arthritis Efficacy

To take the posttest, go to: http://bit.ly/2chD4M1
Expires July 23, 2017

• Be comfortable taking a sexual history from their patients.
• Understand the prevalence of HSDD.
• Understand how to diagnose HSDD and distinguish it from other sexual complaints.
• Understand data from trials involving pharmacologic agents both approved and not approved in attempts to treat HSDD.
• Employ multidisciplinary communication strategies to improve quality of life in patients with PDP

This CME supplement entitles the reader to 1 free CME credit.

Click here to read supplement.

After reading the supplement, click here to access the CME posttest 

• Be comfortable taking a sexual history from their patients.
• Understand the prevalence of HSDD.
• Understand how to diagnose HSDD and distinguish it from other sexual complaints.
• Understand data from trials involving pharmacologic agents both approved and not approved in attempts to treat HSDD.
• Employ multidisciplinary communication strategies to improve quality of life in patients with PDP

This CME supplement entitles the reader to 1 free CME credit.

Click here to read supplement.

After reading the supplement, click here to access the CME posttest 

• Be comfortable taking a sexual history from their patients.
• Understand the prevalence of HSDD.
• Understand how to diagnose HSDD and distinguish it from other sexual complaints.
• Understand data from trials involving pharmacologic agents both approved and not approved in attempts to treat HSDD.
• Employ multidisciplinary communication strategies to improve quality of life in patients with PDP

This CME supplement entitles the reader to 1 free CME credit.

Click here to read supplement.

After reading the supplement, click here to access the CME posttest 

Achieving the glycemic target—a key goal of diabetes management—remains elusive despite pharmacological and technological advances in insulin delivery and glucose monitoring

FACULTY

Davida F. Kruger, MSN, APN-BC, BC-ADM

Certified Nurse Practitioner

Henry Ford Medical Group

Division of Endocrinology, Diabetes, Bone, and Mineral

Disease

Detroit, Michigan

DISCLOSURES

Davida Kruger discloses that she is on the advisory boards for Abbott; Eli Lilly and Company; Janssen Pharmaceuticals, Inc.; Novo Nordisk; and sanofi-aventis U.S. LLC; and on the speakers’ bureaus for Animas Corporation, AstraZeneca; Boehringer Ingelheim/Eli Lilly and Company; Dexcom, Inc.; Janssen Pharmaceuticals, Inc.; Novo Nordisk; and Valeritas, Inc. She owns stock in Dexcom, Inc.

Stephen Brunton, MD, discloses that he is on the advisory boards and speakers’ bureaus for AstraZeneca; Boehringer Ingelheim; Becton, Dickinson and Company; Eli Lilly and Company; Janssen Pharmaceuticals, Inc.; and Novo Nordisk. He is also on the advisory board for Abbott Diabetes.

Click here to read the supplement.

To receive CME credit, please read the article and on completion, go to www.pcmg-us.org/agpCME to complete the online evaluation and receive your certificate of completion.

Achieving the glycemic target—a key goal of diabetes management—remains elusive despite pharmacological and technological advances in insulin delivery and glucose monitoring

FACULTY

Davida F. Kruger, MSN, APN-BC, BC-ADM

Certified Nurse Practitioner

Henry Ford Medical Group

Division of Endocrinology, Diabetes, Bone, and Mineral

Disease

Detroit, Michigan

DISCLOSURES

Davida Kruger discloses that she is on the advisory boards for Abbott; Eli Lilly and Company; Janssen Pharmaceuticals, Inc.; Novo Nordisk; and sanofi-aventis U.S. LLC; and on the speakers’ bureaus for Animas Corporation, AstraZeneca; Boehringer Ingelheim/Eli Lilly and Company; Dexcom, Inc.; Janssen Pharmaceuticals, Inc.; Novo Nordisk; and Valeritas, Inc. She owns stock in Dexcom, Inc.

Stephen Brunton, MD, discloses that he is on the advisory boards and speakers’ bureaus for AstraZeneca; Boehringer Ingelheim; Becton, Dickinson and Company; Eli Lilly and Company; Janssen Pharmaceuticals, Inc.; and Novo Nordisk. He is also on the advisory board for Abbott Diabetes.

Click here to read the supplement.

To receive CME credit, please read the article and on completion, go to www.pcmg-us.org/agpCME to complete the online evaluation and receive your certificate of completion.

Achieving the glycemic target—a key goal of diabetes management—remains elusive despite pharmacological and technological advances in insulin delivery and glucose monitoring

FACULTY

Davida F. Kruger, MSN, APN-BC, BC-ADM

Certified Nurse Practitioner

Henry Ford Medical Group

Division of Endocrinology, Diabetes, Bone, and Mineral

Disease

Detroit, Michigan

DISCLOSURES

Davida Kruger discloses that she is on the advisory boards for Abbott; Eli Lilly and Company; Janssen Pharmaceuticals, Inc.; Novo Nordisk; and sanofi-aventis U.S. LLC; and on the speakers’ bureaus for Animas Corporation, AstraZeneca; Boehringer Ingelheim/Eli Lilly and Company; Dexcom, Inc.; Janssen Pharmaceuticals, Inc.; Novo Nordisk; and Valeritas, Inc. She owns stock in Dexcom, Inc.

Stephen Brunton, MD, discloses that he is on the advisory boards and speakers’ bureaus for AstraZeneca; Boehringer Ingelheim; Becton, Dickinson and Company; Eli Lilly and Company; Janssen Pharmaceuticals, Inc.; and Novo Nordisk. He is also on the advisory board for Abbott Diabetes.

Click here to read the supplement.

To receive CME credit, please read the article and on completion, go to www.pcmg-us.org/agpCME to complete the online evaluation and receive your certificate of completion.

Self-administration of an inhalable formulation of levodopa rapidly improves motor function and significantly reduces off time in people with Parkinson’s disease, according to data published in the September issue of Movement Disorders. The drug may fill an unmet need for a well-tolerated and noninvasive intervention, according to the authors.

Over time, many patients with Parkinson’s disease lose a predictable and sustained response to levodopa. Irregular intestinal absorption of oral levodopa formulations may be one cause of this reduced response. Among currently available therapies, apomorphine acts rapidly and effectively aborts off episodes. The drug is ineffective if taken orally, however, and subcutaneous injection often requires premedication with an antiemetic.

CVT-301 is an inhalable formulation of levodopa designed for pulmonary absorption. The drug is administered using a passive, breath-actuated delivery system and it improved motor function in a phase IIa dose-finding study. Peter A. LeWitt, MD, MMSc, a neurologist at Henry Ford West Bloomfield Hospital in Michigan, and colleagues conducted a phase IIb trial to evaluate the efficacy and safety of self-administered CVT-301 among patients with Parkinson’s disease in a clinical setting and at home during off episodes.

Investigators Evaluated Two Doses

Dr. LeWitt’s group conducted a randomized, double-blind, controlled trial that lasted for four weeks. Eligible participants were between ages 30 and 80, had typical clinical features of Parkinson’s disease, took oral levodopa at least four times daily, and had predictable off episodes totaling two or more hours per day. People with a history of chronic respiratory disease within the previous five years or a Mini-Mental State Examination score lower than 25 were excluded.

After learning how to use the inhaler system, patients were randomized to CVT-301 or placebo (an inhalation-grade lactose monohydrate) for four weeks to treat as many as three off episodes per day. During the first two weeks, the dose of CVT-301 was 35 mg. During the second two weeks, the dose of CVT-301 was 50 mg, and the dose of placebo was increased.

The researchers assessed participants with the Unified Parkinson’s Disease Rating Scale (UPDRS) Part III at screening and at the end of weeks 1, 2, and 4. During the latter three visits, investigators blinded to treatment assignments obtained UPDRS Part III scores for the predose off state and at 10, 20, 30, and 60 minutes post dose. Patients were rated subjectively as achieving or not achieving an on state during the 60-minute observation period. Patients also responded to the Patient Global Impression of Change scale at the end of weeks 2 and 4.

Drug Improved Motor Scores

Dr. LeWitt and colleagues enrolled 89 patients in the study. Of these participants, 86 used at least one dose of study drug, and 75 completed the study. Average age was approximately 62, and participants had received a diagnosis of Parkinson’s disease an average of nine years before study initiation. Mean off time was approximately six hours per day.

As measured in clinic by UPDRS Part III score, motor function improved significantly during off episodes after administration of CVT-301. At the end of week 1, the least-squares mean change in UPDRS Part III score was –9.9 points for 35 mg of CVT-301, compared with –5.3 points for placebo. One week later, the mean change was –10.2 points for the first 50-mg dose of CVT-301, compared with –3.5 points for placebo. At the end of week 4, the mean change was –10.0 points for 50 mg of CVT-301 versus –3.1 points for placebo.

Post hoc analyses indicated that onset of action was evident at 10 minutes for both doses of CVT-301. The mean improvement in motor scores remained significant versus placebo through the 60-minute final assessment. At 60 minutes, the week 4 treatment effect (ie, 50 mg vs placebo) exceeded the week 1 treatment effect (ie, 35 mg vs placebo) by 4.3 points.

Approximately 47% of the active group and 33% of the placebo group reported treatment-emergent adverse events. Adverse events with an incidence of 5.0% or greater in the CVT-301 group were dizziness, cough, and nausea, each of which was reported in three patients. Dyskinesia was reported in one patient in each treatment group. Two patients, both in the placebo group, experienced severe adverse events: drop attack and dyskinesia.

Results May Reflect Treatment Duration

Inhaled CVT-301 “provided rapid amelioration of off episodes,” said Dr. LeWitt. “The average improvement in motor function was similar for both dose levels. However, the average difference from placebo was numerically greater after the 50-mg dose, at least partly because of a decrease in placebo response in weeks 2 and 4, compared with week 1.” The average improvement associated with active treatment greatly exceeded the reported minimum values for a clinically relevant change in Part III scores, he added.

Cough is a particular concern for inhaled drugs, but all reported instances of cough were mild, and none led to dose reduction or discontinuation. No patient reported dyspnea, wheezing, or bronchospasm.

A potential limitation of the study is that patients were not allowed to take the study drug more than three times daily, even though they had an average reported baseline frequency of 3.6 off episodes per day. In addition, the study assessed 35- and 50-mg doses of CVT-301 as sequential treatments. Overall differences between the doses thus might reflect treatment duration rather than dose strength. Nevertheless, “the study’s findings support continued investigation of CVT-301 for rapid treatment of off episodes,” Dr. LeWitt concluded.

—Erik Greb

Suggested Reading

LeWitt PA, Hauser RA, Grosset DG, et al. A randomized trial of inhaled levodopa (CVT-301) for motor fluctuations in Parkinson’s disease. Mov Disord. 2016;31(9):1356-1365.

Self-administration of an inhalable formulation of levodopa rapidly improves motor function and significantly reduces off time in people with Parkinson’s disease, according to data published in the September issue of Movement Disorders. The drug may fill an unmet need for a well-tolerated and noninvasive intervention, according to the authors.

Over time, many patients with Parkinson’s disease lose a predictable and sustained response to levodopa. Irregular intestinal absorption of oral levodopa formulations may be one cause of this reduced response. Among currently available therapies, apomorphine acts rapidly and effectively aborts off episodes. The drug is ineffective if taken orally, however, and subcutaneous injection often requires premedication with an antiemetic.

CVT-301 is an inhalable formulation of levodopa designed for pulmonary absorption. The drug is administered using a passive, breath-actuated delivery system and it improved motor function in a phase IIa dose-finding study. Peter A. LeWitt, MD, MMSc, a neurologist at Henry Ford West Bloomfield Hospital in Michigan, and colleagues conducted a phase IIb trial to evaluate the efficacy and safety of self-administered CVT-301 among patients with Parkinson’s disease in a clinical setting and at home during off episodes.

Investigators Evaluated Two Doses

Dr. LeWitt’s group conducted a randomized, double-blind, controlled trial that lasted for four weeks. Eligible participants were between ages 30 and 80, had typical clinical features of Parkinson’s disease, took oral levodopa at least four times daily, and had predictable off episodes totaling two or more hours per day. People with a history of chronic respiratory disease within the previous five years or a Mini-Mental State Examination score lower than 25 were excluded.

After learning how to use the inhaler system, patients were randomized to CVT-301 or placebo (an inhalation-grade lactose monohydrate) for four weeks to treat as many as three off episodes per day. During the first two weeks, the dose of CVT-301 was 35 mg. During the second two weeks, the dose of CVT-301 was 50 mg, and the dose of placebo was increased.

The researchers assessed participants with the Unified Parkinson’s Disease Rating Scale (UPDRS) Part III at screening and at the end of weeks 1, 2, and 4. During the latter three visits, investigators blinded to treatment assignments obtained UPDRS Part III scores for the predose off state and at 10, 20, 30, and 60 minutes post dose. Patients were rated subjectively as achieving or not achieving an on state during the 60-minute observation period. Patients also responded to the Patient Global Impression of Change scale at the end of weeks 2 and 4.

Drug Improved Motor Scores

Dr. LeWitt and colleagues enrolled 89 patients in the study. Of these participants, 86 used at least one dose of study drug, and 75 completed the study. Average age was approximately 62, and participants had received a diagnosis of Parkinson’s disease an average of nine years before study initiation. Mean off time was approximately six hours per day.

As measured in clinic by UPDRS Part III score, motor function improved significantly during off episodes after administration of CVT-301. At the end of week 1, the least-squares mean change in UPDRS Part III score was –9.9 points for 35 mg of CVT-301, compared with –5.3 points for placebo. One week later, the mean change was –10.2 points for the first 50-mg dose of CVT-301, compared with –3.5 points for placebo. At the end of week 4, the mean change was –10.0 points for 50 mg of CVT-301 versus –3.1 points for placebo.

Post hoc analyses indicated that onset of action was evident at 10 minutes for both doses of CVT-301. The mean improvement in motor scores remained significant versus placebo through the 60-minute final assessment. At 60 minutes, the week 4 treatment effect (ie, 50 mg vs placebo) exceeded the week 1 treatment effect (ie, 35 mg vs placebo) by 4.3 points.

Approximately 47% of the active group and 33% of the placebo group reported treatment-emergent adverse events. Adverse events with an incidence of 5.0% or greater in the CVT-301 group were dizziness, cough, and nausea, each of which was reported in three patients. Dyskinesia was reported in one patient in each treatment group. Two patients, both in the placebo group, experienced severe adverse events: drop attack and dyskinesia.

Results May Reflect Treatment Duration

Inhaled CVT-301 “provided rapid amelioration of off episodes,” said Dr. LeWitt. “The average improvement in motor function was similar for both dose levels. However, the average difference from placebo was numerically greater after the 50-mg dose, at least partly because of a decrease in placebo response in weeks 2 and 4, compared with week 1.” The average improvement associated with active treatment greatly exceeded the reported minimum values for a clinically relevant change in Part III scores, he added.

Cough is a particular concern for inhaled drugs, but all reported instances of cough were mild, and none led to dose reduction or discontinuation. No patient reported dyspnea, wheezing, or bronchospasm.

A potential limitation of the study is that patients were not allowed to take the study drug more than three times daily, even though they had an average reported baseline frequency of 3.6 off episodes per day. In addition, the study assessed 35- and 50-mg doses of CVT-301 as sequential treatments. Overall differences between the doses thus might reflect treatment duration rather than dose strength. Nevertheless, “the study’s findings support continued investigation of CVT-301 for rapid treatment of off episodes,” Dr. LeWitt concluded.

—Erik Greb

Suggested Reading

LeWitt PA, Hauser RA, Grosset DG, et al. A randomized trial of inhaled levodopa (CVT-301) for motor fluctuations in Parkinson’s disease. Mov Disord. 2016;31(9):1356-1365.

Self-administration of an inhalable formulation of levodopa rapidly improves motor function and significantly reduces off time in people with Parkinson’s disease, according to data published in the September issue of Movement Disorders. The drug may fill an unmet need for a well-tolerated and noninvasive intervention, according to the authors.

Over time, many patients with Parkinson’s disease lose a predictable and sustained response to levodopa. Irregular intestinal absorption of oral levodopa formulations may be one cause of this reduced response. Among currently available therapies, apomorphine acts rapidly and effectively aborts off episodes. The drug is ineffective if taken orally, however, and subcutaneous injection often requires premedication with an antiemetic.

CVT-301 is an inhalable formulation of levodopa designed for pulmonary absorption. The drug is administered using a passive, breath-actuated delivery system and it improved motor function in a phase IIa dose-finding study. Peter A. LeWitt, MD, MMSc, a neurologist at Henry Ford West Bloomfield Hospital in Michigan, and colleagues conducted a phase IIb trial to evaluate the efficacy and safety of self-administered CVT-301 among patients with Parkinson’s disease in a clinical setting and at home during off episodes.

Investigators Evaluated Two Doses

Dr. LeWitt’s group conducted a randomized, double-blind, controlled trial that lasted for four weeks. Eligible participants were between ages 30 and 80, had typical clinical features of Parkinson’s disease, took oral levodopa at least four times daily, and had predictable off episodes totaling two or more hours per day. People with a history of chronic respiratory disease within the previous five years or a Mini-Mental State Examination score lower than 25 were excluded.

After learning how to use the inhaler system, patients were randomized to CVT-301 or placebo (an inhalation-grade lactose monohydrate) for four weeks to treat as many as three off episodes per day. During the first two weeks, the dose of CVT-301 was 35 mg. During the second two weeks, the dose of CVT-301 was 50 mg, and the dose of placebo was increased.

The researchers assessed participants with the Unified Parkinson’s Disease Rating Scale (UPDRS) Part III at screening and at the end of weeks 1, 2, and 4. During the latter three visits, investigators blinded to treatment assignments obtained UPDRS Part III scores for the predose off state and at 10, 20, 30, and 60 minutes post dose. Patients were rated subjectively as achieving or not achieving an on state during the 60-minute observation period. Patients also responded to the Patient Global Impression of Change scale at the end of weeks 2 and 4.

Drug Improved Motor Scores

Dr. LeWitt and colleagues enrolled 89 patients in the study. Of these participants, 86 used at least one dose of study drug, and 75 completed the study. Average age was approximately 62, and participants had received a diagnosis of Parkinson’s disease an average of nine years before study initiation. Mean off time was approximately six hours per day.

As measured in clinic by UPDRS Part III score, motor function improved significantly during off episodes after administration of CVT-301. At the end of week 1, the least-squares mean change in UPDRS Part III score was –9.9 points for 35 mg of CVT-301, compared with –5.3 points for placebo. One week later, the mean change was –10.2 points for the first 50-mg dose of CVT-301, compared with –3.5 points for placebo. At the end of week 4, the mean change was –10.0 points for 50 mg of CVT-301 versus –3.1 points for placebo.

Post hoc analyses indicated that onset of action was evident at 10 minutes for both doses of CVT-301. The mean improvement in motor scores remained significant versus placebo through the 60-minute final assessment. At 60 minutes, the week 4 treatment effect (ie, 50 mg vs placebo) exceeded the week 1 treatment effect (ie, 35 mg vs placebo) by 4.3 points.

Approximately 47% of the active group and 33% of the placebo group reported treatment-emergent adverse events. Adverse events with an incidence of 5.0% or greater in the CVT-301 group were dizziness, cough, and nausea, each of which was reported in three patients. Dyskinesia was reported in one patient in each treatment group. Two patients, both in the placebo group, experienced severe adverse events: drop attack and dyskinesia.

Results May Reflect Treatment Duration

Inhaled CVT-301 “provided rapid amelioration of off episodes,” said Dr. LeWitt. “The average improvement in motor function was similar for both dose levels. However, the average difference from placebo was numerically greater after the 50-mg dose, at least partly because of a decrease in placebo response in weeks 2 and 4, compared with week 1.” The average improvement associated with active treatment greatly exceeded the reported minimum values for a clinically relevant change in Part III scores, he added.

Cough is a particular concern for inhaled drugs, but all reported instances of cough were mild, and none led to dose reduction or discontinuation. No patient reported dyspnea, wheezing, or bronchospasm.

A potential limitation of the study is that patients were not allowed to take the study drug more than three times daily, even though they had an average reported baseline frequency of 3.6 off episodes per day. In addition, the study assessed 35- and 50-mg doses of CVT-301 as sequential treatments. Overall differences between the doses thus might reflect treatment duration rather than dose strength. Nevertheless, “the study’s findings support continued investigation of CVT-301 for rapid treatment of off episodes,” Dr. LeWitt concluded.

—Erik Greb

Suggested Reading

LeWitt PA, Hauser RA, Grosset DG, et al. A randomized trial of inhaled levodopa (CVT-301) for motor fluctuations in Parkinson’s disease. Mov Disord. 2016;31(9):1356-1365.

LONDON—As has been previously shown with brain atrophy and lesion volume, retinal measures can have predictive value for medium-term disability in multiple sclerosis (MS), according to research presented at the 32nd Congress of the European Committee for Treatment and Research in MS (ECTRIMS). “Our preliminary findings support the utility of optical coherence tomography (OCT) as a tool to predict neurodegeneration and disease progression over time in patients with MS,” said Alissa M. Rothman, MD, a post-doctoral research coordinator at the Johns Hopkins MS Center in Baltimore.

Measures of retinal layer thickness obtained with OCT have been shown to correlate with visual function, grey matter volume, and Expanded Disability Status Scale (EDSS) scores in MS. However, the prognostic value of retinal measurements for predicting long-term disability in patients with MS is still being evaluated. In the present study, Dr. Rothman and colleagues sought to determine whether retinal thickness, as assessed by OCT, predicts disability in MS 10 years later.

A total of 89 patients with MS were scanned on Stratus OCT between 2006 and 2007. During 2015 and 2016, these patients underwent formal, blinded EDSS determination. Average peripapillary retinal nerve fiber layer (RNFL) thickness and total macular volume (TMV) were assessed by calculating the mean value of these measures for both eyes in each subject. Patients were categorized by baseline diagnosis as relapsing remitting (RRMS), secondary progressive (SPMS), or primary progressive MS (PPMS). Mixed effects linear regression models were used to investigate whether average TMV and RNFL thickness at baseline predict EDSS score after 10 years.

The final analysis included 75 patients with RRMS, nine patients with SPMS, and five patients with PPMS. Fourteen of the 75 patients with a baseline diagnosis of RRMS transitioned to SPMS during the follow-up period. Baseline analyses revealed that the RRMS cohort was significantly younger than the SPMS and PPMS cohorts (mean difference = 21.5 years and 11.7 years, respectively) and that patients with SPMS had a longer disease duration than patients with RRMS and PPMS (mean difference = 14.2 years and 13.2 years, respectively). A history of optic neuritis (ON) was observed in the RRMS and SPMS cohorts (41% and 44%, respectively), but not in the PPMS cohorts. Adjusting for age, sex, and a history of ON, the mean TMV values at baseline predicted EDSS scores after a median follow-up of 9.3 years. On average, a 1 mm3 lower TMV value at baseline predicted a mean decrease of 2 in EDSS at follow-up. Mean baseline RNFL values did not significantly predict EDSS scores.

—Glenn S. Williams

LONDON—As has been previously shown with brain atrophy and lesion volume, retinal measures can have predictive value for medium-term disability in multiple sclerosis (MS), according to research presented at the 32nd Congress of the European Committee for Treatment and Research in MS (ECTRIMS). “Our preliminary findings support the utility of optical coherence tomography (OCT) as a tool to predict neurodegeneration and disease progression over time in patients with MS,” said Alissa M. Rothman, MD, a post-doctoral research coordinator at the Johns Hopkins MS Center in Baltimore.

Measures of retinal layer thickness obtained with OCT have been shown to correlate with visual function, grey matter volume, and Expanded Disability Status Scale (EDSS) scores in MS. However, the prognostic value of retinal measurements for predicting long-term disability in patients with MS is still being evaluated. In the present study, Dr. Rothman and colleagues sought to determine whether retinal thickness, as assessed by OCT, predicts disability in MS 10 years later.

A total of 89 patients with MS were scanned on Stratus OCT between 2006 and 2007. During 2015 and 2016, these patients underwent formal, blinded EDSS determination. Average peripapillary retinal nerve fiber layer (RNFL) thickness and total macular volume (TMV) were assessed by calculating the mean value of these measures for both eyes in each subject. Patients were categorized by baseline diagnosis as relapsing remitting (RRMS), secondary progressive (SPMS), or primary progressive MS (PPMS). Mixed effects linear regression models were used to investigate whether average TMV and RNFL thickness at baseline predict EDSS score after 10 years.

The final analysis included 75 patients with RRMS, nine patients with SPMS, and five patients with PPMS. Fourteen of the 75 patients with a baseline diagnosis of RRMS transitioned to SPMS during the follow-up period. Baseline analyses revealed that the RRMS cohort was significantly younger than the SPMS and PPMS cohorts (mean difference = 21.5 years and 11.7 years, respectively) and that patients with SPMS had a longer disease duration than patients with RRMS and PPMS (mean difference = 14.2 years and 13.2 years, respectively). A history of optic neuritis (ON) was observed in the RRMS and SPMS cohorts (41% and 44%, respectively), but not in the PPMS cohorts. Adjusting for age, sex, and a history of ON, the mean TMV values at baseline predicted EDSS scores after a median follow-up of 9.3 years. On average, a 1 mm3 lower TMV value at baseline predicted a mean decrease of 2 in EDSS at follow-up. Mean baseline RNFL values did not significantly predict EDSS scores.

—Glenn S. Williams

LONDON—As has been previously shown with brain atrophy and lesion volume, retinal measures can have predictive value for medium-term disability in multiple sclerosis (MS), according to research presented at the 32nd Congress of the European Committee for Treatment and Research in MS (ECTRIMS). “Our preliminary findings support the utility of optical coherence tomography (OCT) as a tool to predict neurodegeneration and disease progression over time in patients with MS,” said Alissa M. Rothman, MD, a post-doctoral research coordinator at the Johns Hopkins MS Center in Baltimore.

Measures of retinal layer thickness obtained with OCT have been shown to correlate with visual function, grey matter volume, and Expanded Disability Status Scale (EDSS) scores in MS. However, the prognostic value of retinal measurements for predicting long-term disability in patients with MS is still being evaluated. In the present study, Dr. Rothman and colleagues sought to determine whether retinal thickness, as assessed by OCT, predicts disability in MS 10 years later.

A total of 89 patients with MS were scanned on Stratus OCT between 2006 and 2007. During 2015 and 2016, these patients underwent formal, blinded EDSS determination. Average peripapillary retinal nerve fiber layer (RNFL) thickness and total macular volume (TMV) were assessed by calculating the mean value of these measures for both eyes in each subject. Patients were categorized by baseline diagnosis as relapsing remitting (RRMS), secondary progressive (SPMS), or primary progressive MS (PPMS). Mixed effects linear regression models were used to investigate whether average TMV and RNFL thickness at baseline predict EDSS score after 10 years.

The final analysis included 75 patients with RRMS, nine patients with SPMS, and five patients with PPMS. Fourteen of the 75 patients with a baseline diagnosis of RRMS transitioned to SPMS during the follow-up period. Baseline analyses revealed that the RRMS cohort was significantly younger than the SPMS and PPMS cohorts (mean difference = 21.5 years and 11.7 years, respectively) and that patients with SPMS had a longer disease duration than patients with RRMS and PPMS (mean difference = 14.2 years and 13.2 years, respectively). A history of optic neuritis (ON) was observed in the RRMS and SPMS cohorts (41% and 44%, respectively), but not in the PPMS cohorts. Adjusting for age, sex, and a history of ON, the mean TMV values at baseline predicted EDSS scores after a median follow-up of 9.3 years. On average, a 1 mm3 lower TMV value at baseline predicted a mean decrease of 2 in EDSS at follow-up. Mean baseline RNFL values did not significantly predict EDSS scores.

—Glenn S. Williams

LONDON—A dynamic model based on long-term observations and a statistical modeling approach can help neurologists predict the future disability trajectory of a new patient with primary progressive multiple sclerosis (MS), according to a study presented at the 32nd Congress of the European Committee for Treatment and Research in MS (ECTRIMS). The existence of heterogeneous classes of patients should be considered in the design of future clinical trials in primary progressive MS that have time-to-reach-disability milestones as their primary end points, said the researchers.

Several natural history studies of patients with primary progressive MS have been reported from international registries over the past decades. This population had a consistently heterogeneous rate of disability accumulation. Time to reach the milestone of an Expanded Disability Status Scale (EDSS) score of 6 ranged between seven and 14 years from disease onset.

Alessio Signori, PhD, postdoctoral researcher in biostatistics at the University of Genoa, Italy, and colleagues sought to identify subgroups of patients with primary progressive MS who had similar longitudinal EDSS trajectories over time. The investigators included in their analysis all patients with primary progressive MS in the MSBase international registry who had their first EDSS assessment within five years of disease onset. Longitudinal EDSS scores were modeled by a latent class mixed model (LCMM) using a nonlinear function of time from onset. LCMM is an advanced statistical approach that models heterogeneity between patients by classifying them into unobserved groups (ie, latent classes) that have similar characteristics.

A total of 853 participants with primary progressive MS (51.7% female) from 24 countries with a mean age at onset of 42.4, a median baseline EDSS score of 4, and 2.4 years of disease duration were included. LCMM detected three distinct subgroups of patients with a mild (n = 143; 16.8%), a moderate (n = 378; 44.3%), and a severe (n = 332; 38.9%) disability trajectory, respectively. Time from disease onset to diagnosis was shortest for the severe group. Median time to an EDSS score of 4 was 14, five, and 3.7 years for the three groups, respectively. The probability of reaching an EDSS score of 6 at 10 years was 0%, 46.5%, and 83.1%, respectively. Increasing severity of the disability time course was related to a decreasing frequency of patients with at least one relapse during follow-up (ie, from 47.6% to 36.5%).

“Using this modeling approach, it is possible to predict the future disease course of a subject with primary progressive MS using early EDSS assessments,” said Dr. Signori. “By using only one year of EDSS monitoring, 73% of patients are correctly classified in their disability trajectory group (mild, moderate, or severe). After three years, this proportion is 87%, and after five years, it is 92%.”

LONDON—A dynamic model based on long-term observations and a statistical modeling approach can help neurologists predict the future disability trajectory of a new patient with primary progressive multiple sclerosis (MS), according to a study presented at the 32nd Congress of the European Committee for Treatment and Research in MS (ECTRIMS). The existence of heterogeneous classes of patients should be considered in the design of future clinical trials in primary progressive MS that have time-to-reach-disability milestones as their primary end points, said the researchers.

Several natural history studies of patients with primary progressive MS have been reported from international registries over the past decades. This population had a consistently heterogeneous rate of disability accumulation. Time to reach the milestone of an Expanded Disability Status Scale (EDSS) score of 6 ranged between seven and 14 years from disease onset.

Alessio Signori, PhD, postdoctoral researcher in biostatistics at the University of Genoa, Italy, and colleagues sought to identify subgroups of patients with primary progressive MS who had similar longitudinal EDSS trajectories over time. The investigators included in their analysis all patients with primary progressive MS in the MSBase international registry who had their first EDSS assessment within five years of disease onset. Longitudinal EDSS scores were modeled by a latent class mixed model (LCMM) using a nonlinear function of time from onset. LCMM is an advanced statistical approach that models heterogeneity between patients by classifying them into unobserved groups (ie, latent classes) that have similar characteristics.

A total of 853 participants with primary progressive MS (51.7% female) from 24 countries with a mean age at onset of 42.4, a median baseline EDSS score of 4, and 2.4 years of disease duration were included. LCMM detected three distinct subgroups of patients with a mild (n = 143; 16.8%), a moderate (n = 378; 44.3%), and a severe (n = 332; 38.9%) disability trajectory, respectively. Time from disease onset to diagnosis was shortest for the severe group. Median time to an EDSS score of 4 was 14, five, and 3.7 years for the three groups, respectively. The probability of reaching an EDSS score of 6 at 10 years was 0%, 46.5%, and 83.1%, respectively. Increasing severity of the disability time course was related to a decreasing frequency of patients with at least one relapse during follow-up (ie, from 47.6% to 36.5%).

“Using this modeling approach, it is possible to predict the future disease course of a subject with primary progressive MS using early EDSS assessments,” said Dr. Signori. “By using only one year of EDSS monitoring, 73% of patients are correctly classified in their disability trajectory group (mild, moderate, or severe). After three years, this proportion is 87%, and after five years, it is 92%.”

LONDON—A dynamic model based on long-term observations and a statistical modeling approach can help neurologists predict the future disability trajectory of a new patient with primary progressive multiple sclerosis (MS), according to a study presented at the 32nd Congress of the European Committee for Treatment and Research in MS (ECTRIMS). The existence of heterogeneous classes of patients should be considered in the design of future clinical trials in primary progressive MS that have time-to-reach-disability milestones as their primary end points, said the researchers.

Several natural history studies of patients with primary progressive MS have been reported from international registries over the past decades. This population had a consistently heterogeneous rate of disability accumulation. Time to reach the milestone of an Expanded Disability Status Scale (EDSS) score of 6 ranged between seven and 14 years from disease onset.

Alessio Signori, PhD, postdoctoral researcher in biostatistics at the University of Genoa, Italy, and colleagues sought to identify subgroups of patients with primary progressive MS who had similar longitudinal EDSS trajectories over time. The investigators included in their analysis all patients with primary progressive MS in the MSBase international registry who had their first EDSS assessment within five years of disease onset. Longitudinal EDSS scores were modeled by a latent class mixed model (LCMM) using a nonlinear function of time from onset. LCMM is an advanced statistical approach that models heterogeneity between patients by classifying them into unobserved groups (ie, latent classes) that have similar characteristics.

A total of 853 participants with primary progressive MS (51.7% female) from 24 countries with a mean age at onset of 42.4, a median baseline EDSS score of 4, and 2.4 years of disease duration were included. LCMM detected three distinct subgroups of patients with a mild (n = 143; 16.8%), a moderate (n = 378; 44.3%), and a severe (n = 332; 38.9%) disability trajectory, respectively. Time from disease onset to diagnosis was shortest for the severe group. Median time to an EDSS score of 4 was 14, five, and 3.7 years for the three groups, respectively. The probability of reaching an EDSS score of 6 at 10 years was 0%, 46.5%, and 83.1%, respectively. Increasing severity of the disability time course was related to a decreasing frequency of patients with at least one relapse during follow-up (ie, from 47.6% to 36.5%).

“Using this modeling approach, it is possible to predict the future disease course of a subject with primary progressive MS using early EDSS assessments,” said Dr. Signori. “By using only one year of EDSS monitoring, 73% of patients are correctly classified in their disability trajectory group (mild, moderate, or severe). After three years, this proportion is 87%, and after five years, it is 92%.”

A new way to track the progression of Parkinson’s disease could help evaluate experimental treatments aimed at slowing or stopping the disease’s progression. “We provide evidence using task-based functional MRI (fMRI) for cortical and striatal functional deterioration in Parkinson’s disease over a one-year period,” researchers reported in the August 16 issue of Neurology.

Study results also describe unique patterns of functional changes in patients with multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) that are more widespread, compared with those in Parkinson’s disease, suggesting that distinctive rates of disease progression in parkinsonian disorders may assist in future clinical studies of disease-modifying therapies.

While current treatments focus on controlling symptoms, biomarkers provide a quantifiable way to measure how medications address not just symptoms, but the neurologic changes behind them. Previous studies have used imaging techniques that require the injection of a drug that crosses the blood–brain barrier. “Our technique does not rely upon the injection of a drug. Not only is it noninvasive, it is much less expensive,” said senior study author David Vaillancourt, PhD, a Professor in the Department of Applied Physiology and Kinesiology at the University of Florida, Gainesville.

A total of 112 individuals were scanned at baseline and at one year while preforming a unimanual grip force task. The study cohort included 46 patients with Parkinson’s disease, 13 patients with MSA, 19 patients with PSP, and 34 healthy controls. The outcome measure was percent signal change in the prespecified brain regions.

A year after the baseline study, the 46 patients with Parkinson’s disease showed declining function in the primary motor cortex and putamen, compared with controls. Changes after one year in patients with MSA were exclusively extrastriatal and included a reduction in functional activity in the primary motor cortex, supplementary motor area, and superior cerebellum. In patients with PSP, all regions of interest were less active at one year, compared with baseline. Functional activity of the brain regions in the control group did not change during the study.

“Collectively, these findings point to disease-specific noninvasive progression markers of sensorimotor brain regions in parkinsonian disorders,” the researchers said.

The present findings build on two 2015 studies that used fMRI to document progressive deterioration from Parkinson’s disease, MSA, and PSP.

Suggested Reading

Burciu RG, Chung JW, Shukla P, et al. Functional MRI of disease progression in Parkinson disease and atypical parksonian syndromes. Neurology. 2016;87(7):709-717.

Burciu RG, Ofori E, Shukla P, et al. Distinct patters of brain activity in progressive supranuclear palsy and Parkinson’s disease. Mov Disord. 2015;30(9):1248-1258.

Oh M, Kim JS, Kim JY, et al. Subregional patterns of preferential striatal dopamine transporter loss differ in Parkinson disease, progressive supranuclear palsy, and multiple system atrophy. J Nucl Med. 2012;53(3):399-406.

Planetta PJ, Kurani AS, Shukla P, et al. Distinct functional and macrostructural brain changes in Parkinson’s disease and multiple system atrophy. Human Brain Mapp. 2015;36(3):1165-1179.

A new way to track the progression of Parkinson’s disease could help evaluate experimental treatments aimed at slowing or stopping the disease’s progression. “We provide evidence using task-based functional MRI (fMRI) for cortical and striatal functional deterioration in Parkinson’s disease over a one-year period,” researchers reported in the August 16 issue of Neurology.

Study results also describe unique patterns of functional changes in patients with multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) that are more widespread, compared with those in Parkinson’s disease, suggesting that distinctive rates of disease progression in parkinsonian disorders may assist in future clinical studies of disease-modifying therapies.

While current treatments focus on controlling symptoms, biomarkers provide a quantifiable way to measure how medications address not just symptoms, but the neurologic changes behind them. Previous studies have used imaging techniques that require the injection of a drug that crosses the blood–brain barrier. “Our technique does not rely upon the injection of a drug. Not only is it noninvasive, it is much less expensive,” said senior study author David Vaillancourt, PhD, a Professor in the Department of Applied Physiology and Kinesiology at the University of Florida, Gainesville.

A total of 112 individuals were scanned at baseline and at one year while preforming a unimanual grip force task. The study cohort included 46 patients with Parkinson’s disease, 13 patients with MSA, 19 patients with PSP, and 34 healthy controls. The outcome measure was percent signal change in the prespecified brain regions.

A year after the baseline study, the 46 patients with Parkinson’s disease showed declining function in the primary motor cortex and putamen, compared with controls. Changes after one year in patients with MSA were exclusively extrastriatal and included a reduction in functional activity in the primary motor cortex, supplementary motor area, and superior cerebellum. In patients with PSP, all regions of interest were less active at one year, compared with baseline. Functional activity of the brain regions in the control group did not change during the study.

“Collectively, these findings point to disease-specific noninvasive progression markers of sensorimotor brain regions in parkinsonian disorders,” the researchers said.

The present findings build on two 2015 studies that used fMRI to document progressive deterioration from Parkinson’s disease, MSA, and PSP.

Suggested Reading

Burciu RG, Chung JW, Shukla P, et al. Functional MRI of disease progression in Parkinson disease and atypical parksonian syndromes. Neurology. 2016;87(7):709-717.

Burciu RG, Ofori E, Shukla P, et al. Distinct patters of brain activity in progressive supranuclear palsy and Parkinson’s disease. Mov Disord. 2015;30(9):1248-1258.

Oh M, Kim JS, Kim JY, et al. Subregional patterns of preferential striatal dopamine transporter loss differ in Parkinson disease, progressive supranuclear palsy, and multiple system atrophy. J Nucl Med. 2012;53(3):399-406.

Planetta PJ, Kurani AS, Shukla P, et al. Distinct functional and macrostructural brain changes in Parkinson’s disease and multiple system atrophy. Human Brain Mapp. 2015;36(3):1165-1179.

A new way to track the progression of Parkinson’s disease could help evaluate experimental treatments aimed at slowing or stopping the disease’s progression. “We provide evidence using task-based functional MRI (fMRI) for cortical and striatal functional deterioration in Parkinson’s disease over a one-year period,” researchers reported in the August 16 issue of Neurology.

Study results also describe unique patterns of functional changes in patients with multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) that are more widespread, compared with those in Parkinson’s disease, suggesting that distinctive rates of disease progression in parkinsonian disorders may assist in future clinical studies of disease-modifying therapies.

While current treatments focus on controlling symptoms, biomarkers provide a quantifiable way to measure how medications address not just symptoms, but the neurologic changes behind them. Previous studies have used imaging techniques that require the injection of a drug that crosses the blood–brain barrier. “Our technique does not rely upon the injection of a drug. Not only is it noninvasive, it is much less expensive,” said senior study author David Vaillancourt, PhD, a Professor in the Department of Applied Physiology and Kinesiology at the University of Florida, Gainesville.

A total of 112 individuals were scanned at baseline and at one year while preforming a unimanual grip force task. The study cohort included 46 patients with Parkinson’s disease, 13 patients with MSA, 19 patients with PSP, and 34 healthy controls. The outcome measure was percent signal change in the prespecified brain regions.

A year after the baseline study, the 46 patients with Parkinson’s disease showed declining function in the primary motor cortex and putamen, compared with controls. Changes after one year in patients with MSA were exclusively extrastriatal and included a reduction in functional activity in the primary motor cortex, supplementary motor area, and superior cerebellum. In patients with PSP, all regions of interest were less active at one year, compared with baseline. Functional activity of the brain regions in the control group did not change during the study.

“Collectively, these findings point to disease-specific noninvasive progression markers of sensorimotor brain regions in parkinsonian disorders,” the researchers said.

The present findings build on two 2015 studies that used fMRI to document progressive deterioration from Parkinson’s disease, MSA, and PSP.

Suggested Reading

Burciu RG, Chung JW, Shukla P, et al. Functional MRI of disease progression in Parkinson disease and atypical parksonian syndromes. Neurology. 2016;87(7):709-717.

Burciu RG, Ofori E, Shukla P, et al. Distinct patters of brain activity in progressive supranuclear palsy and Parkinson’s disease. Mov Disord. 2015;30(9):1248-1258.

Oh M, Kim JS, Kim JY, et al. Subregional patterns of preferential striatal dopamine transporter loss differ in Parkinson disease, progressive supranuclear palsy, and multiple system atrophy. J Nucl Med. 2012;53(3):399-406.

Planetta PJ, Kurani AS, Shukla P, et al. Distinct functional and macrostructural brain changes in Parkinson’s disease and multiple system atrophy. Human Brain Mapp. 2015;36(3):1165-1179.

SAN DIEGO—A behavioral intervention for comorbid insomnia in people with chronic migraine may reduce headache frequency by approximately 50%, according to research presented at the 58th Annual Scientific Meeting of the American Headache Society. Improvements in headache frequency and sleep efficiency continue after the intervention ends, as is the case with many behavioral therapies.

More than 38% of migraineurs sleep less than six hours per night, compared with about 10% of the general population. In addition, the prevalence of insomnia is much higher among individuals with headache than among the general population. “Most people who present for treatment of migraine have insomnia, and that’s true even of episodic migraineurs,” said Todd Smitherman, PhD, Associate Professor of Clinical Psychology at the University of Mississippi in Oxford.

Treatment Included Stimulus Control

Dr. Smitherman and colleagues conducted a randomized controlled pilot trial to study whether a behavioral intervention for comorbid insomnia could improve sleep and headache in adults with chronic migraine. The researchers enrolled 31 individuals in the study who met the diagnostic criteria for chronic migraine and insomnia. People with medication overuse were excluded from the study. Participants were randomized to cognitive behavioral therapy for insomnia (CBTi) administered in three 30-minute sessions, or to sham treatment.

Both groups received training in five skills. Participants who received CBTi were advised to adhere to a consistent bedtime that allowed eight hours in bed, to avoid other activities while in bed (eg, reading or watching TV), and to discontinue naps. These participants also were instructed to get out of bed and engage temporarily in quiet activity if they were unable to fall asleep after 30 minutes (ie, stimulus control). Finally, this group also underwent sleep restriction.

The control group received instructions to maintain a consistent liquid intake, to eat a serving of protein in the morning, to perform acupressure near the elbow, to practice range-of-motion exercises in the morning, and to eat dinner at a consistent time every evening. The same therapist administered both treatments to reduce allegiance effects.

All participants maintained daily headache diaries, completed self-report measures, and underwent actigraphy. The study’s primary outcome was reduction in headache frequency at two weeks post-treatment and at six-week follow-up.

CBTi Improved Sleep and Headache

The control group had a slightly lower headache frequency at baseline (20.5 days/month) than did the active group (22.7 days/month). The population’s mean age was 30.8, 90.3% of the sample was female, and 80.6% were Caucasian.

At two weeks post treatment, headache frequency was reduced by 26.9% for participants who received CBTi and by 36.2% for controls. At six weeks, headache frequency was reduced by 48.9% for the CBTi group and by 25.0% for controls. At six weeks, people who received CBTi also were 60% less likely to have headache, compared with controls. Individuals who received CBTi continued to improve after the intervention ended, said Dr. Smitherman. In contrast, individuals in the control group regressed toward their baseline conditions.

Participants’ insomnia symptoms were significantly correlated with the probability of headache, as well as with changes in disability. The actigraphy data indicated that CBTi produced significantly larger increases in total sleep time and sleep efficiency than sham treatment. CBTi also was associated with greater reductions in self-reported insomnia severity, compared with sham treatment.

Insomnia and Bipolar Disorder

Sleep restriction is not recommended for patients with bipolar disorder because it can promote manic episodes, said Dr. Smitherman. Alternatives for these patients include training in progressive muscle relaxation or referral to a provider for behavioral therapy.

Neurologists need larger and longer studies of behavioral therapy, Dr. Smitherman added. “We need to isolate the mechanisms of action.” One of the mechanisms appears to be that changes in sleep improve migraine, given the associations that data analyses reveal.

Suggested Reading

Calhoun AH, Ford S. Behavioral sleep modification may revert transformed migraine to episodic migraine. Headache. 2007;47(8):1178-1183.

Rains JC, Poceta JS. Headache and sleep disorders: review and clinical implications for headache management. Headache. 2006;46(9):1344-1363.

Smitherman TA, Walters AB, Davis RE, et al. Randomized controlled pilot trial of behavioral insomnia treatment for chronic migraine with comorbid insomnia. Headache. 2016;56(2):276-291.

SAN DIEGO—A behavioral intervention for comorbid insomnia in people with chronic migraine may reduce headache frequency by approximately 50%, according to research presented at the 58th Annual Scientific Meeting of the American Headache Society. Improvements in headache frequency and sleep efficiency continue after the intervention ends, as is the case with many behavioral therapies.

More than 38% of migraineurs sleep less than six hours per night, compared with about 10% of the general population. In addition, the prevalence of insomnia is much higher among individuals with headache than among the general population. “Most people who present for treatment of migraine have insomnia, and that’s true even of episodic migraineurs,” said Todd Smitherman, PhD, Associate Professor of Clinical Psychology at the University of Mississippi in Oxford.

Treatment Included Stimulus Control

Dr. Smitherman and colleagues conducted a randomized controlled pilot trial to study whether a behavioral intervention for comorbid insomnia could improve sleep and headache in adults with chronic migraine. The researchers enrolled 31 individuals in the study who met the diagnostic criteria for chronic migraine and insomnia. People with medication overuse were excluded from the study. Participants were randomized to cognitive behavioral therapy for insomnia (CBTi) administered in three 30-minute sessions, or to sham treatment.

Both groups received training in five skills. Participants who received CBTi were advised to adhere to a consistent bedtime that allowed eight hours in bed, to avoid other activities while in bed (eg, reading or watching TV), and to discontinue naps. These participants also were instructed to get out of bed and engage temporarily in quiet activity if they were unable to fall asleep after 30 minutes (ie, stimulus control). Finally, this group also underwent sleep restriction.

The control group received instructions to maintain a consistent liquid intake, to eat a serving of protein in the morning, to perform acupressure near the elbow, to practice range-of-motion exercises in the morning, and to eat dinner at a consistent time every evening. The same therapist administered both treatments to reduce allegiance effects.

All participants maintained daily headache diaries, completed self-report measures, and underwent actigraphy. The study’s primary outcome was reduction in headache frequency at two weeks post-treatment and at six-week follow-up.

CBTi Improved Sleep and Headache

The control group had a slightly lower headache frequency at baseline (20.5 days/month) than did the active group (22.7 days/month). The population’s mean age was 30.8, 90.3% of the sample was female, and 80.6% were Caucasian.

At two weeks post treatment, headache frequency was reduced by 26.9% for participants who received CBTi and by 36.2% for controls. At six weeks, headache frequency was reduced by 48.9% for the CBTi group and by 25.0% for controls. At six weeks, people who received CBTi also were 60% less likely to have headache, compared with controls. Individuals who received CBTi continued to improve after the intervention ended, said Dr. Smitherman. In contrast, individuals in the control group regressed toward their baseline conditions.

Participants’ insomnia symptoms were significantly correlated with the probability of headache, as well as with changes in disability. The actigraphy data indicated that CBTi produced significantly larger increases in total sleep time and sleep efficiency than sham treatment. CBTi also was associated with greater reductions in self-reported insomnia severity, compared with sham treatment.

Insomnia and Bipolar Disorder

Sleep restriction is not recommended for patients with bipolar disorder because it can promote manic episodes, said Dr. Smitherman. Alternatives for these patients include training in progressive muscle relaxation or referral to a provider for behavioral therapy.

Neurologists need larger and longer studies of behavioral therapy, Dr. Smitherman added. “We need to isolate the mechanisms of action.” One of the mechanisms appears to be that changes in sleep improve migraine, given the associations that data analyses reveal.

Suggested Reading

Calhoun AH, Ford S. Behavioral sleep modification may revert transformed migraine to episodic migraine. Headache. 2007;47(8):1178-1183.

Rains JC, Poceta JS. Headache and sleep disorders: review and clinical implications for headache management. Headache. 2006;46(9):1344-1363.

Smitherman TA, Walters AB, Davis RE, et al. Randomized controlled pilot trial of behavioral insomnia treatment for chronic migraine with comorbid insomnia. Headache. 2016;56(2):276-291.

SAN DIEGO—A behavioral intervention for comorbid insomnia in people with chronic migraine may reduce headache frequency by approximately 50%, according to research presented at the 58th Annual Scientific Meeting of the American Headache Society. Improvements in headache frequency and sleep efficiency continue after the intervention ends, as is the case with many behavioral therapies.

More than 38% of migraineurs sleep less than six hours per night, compared with about 10% of the general population. In addition, the prevalence of insomnia is much higher among individuals with headache than among the general population. “Most people who present for treatment of migraine have insomnia, and that’s true even of episodic migraineurs,” said Todd Smitherman, PhD, Associate Professor of Clinical Psychology at the University of Mississippi in Oxford.

Treatment Included Stimulus Control

Dr. Smitherman and colleagues conducted a randomized controlled pilot trial to study whether a behavioral intervention for comorbid insomnia could improve sleep and headache in adults with chronic migraine. The researchers enrolled 31 individuals in the study who met the diagnostic criteria for chronic migraine and insomnia. People with medication overuse were excluded from the study. Participants were randomized to cognitive behavioral therapy for insomnia (CBTi) administered in three 30-minute sessions, or to sham treatment.

Both groups received training in five skills. Participants who received CBTi were advised to adhere to a consistent bedtime that allowed eight hours in bed, to avoid other activities while in bed (eg, reading or watching TV), and to discontinue naps. These participants also were instructed to get out of bed and engage temporarily in quiet activity if they were unable to fall asleep after 30 minutes (ie, stimulus control). Finally, this group also underwent sleep restriction.

The control group received instructions to maintain a consistent liquid intake, to eat a serving of protein in the morning, to perform acupressure near the elbow, to practice range-of-motion exercises in the morning, and to eat dinner at a consistent time every evening. The same therapist administered both treatments to reduce allegiance effects.

All participants maintained daily headache diaries, completed self-report measures, and underwent actigraphy. The study’s primary outcome was reduction in headache frequency at two weeks post-treatment and at six-week follow-up.

CBTi Improved Sleep and Headache

The control group had a slightly lower headache frequency at baseline (20.5 days/month) than did the active group (22.7 days/month). The population’s mean age was 30.8, 90.3% of the sample was female, and 80.6% were Caucasian.

At two weeks post treatment, headache frequency was reduced by 26.9% for participants who received CBTi and by 36.2% for controls. At six weeks, headache frequency was reduced by 48.9% for the CBTi group and by 25.0% for controls. At six weeks, people who received CBTi also were 60% less likely to have headache, compared with controls. Individuals who received CBTi continued to improve after the intervention ended, said Dr. Smitherman. In contrast, individuals in the control group regressed toward their baseline conditions.

Participants’ insomnia symptoms were significantly correlated with the probability of headache, as well as with changes in disability. The actigraphy data indicated that CBTi produced significantly larger increases in total sleep time and sleep efficiency than sham treatment. CBTi also was associated with greater reductions in self-reported insomnia severity, compared with sham treatment.

Insomnia and Bipolar Disorder

Sleep restriction is not recommended for patients with bipolar disorder because it can promote manic episodes, said Dr. Smitherman. Alternatives for these patients include training in progressive muscle relaxation or referral to a provider for behavioral therapy.

Neurologists need larger and longer studies of behavioral therapy, Dr. Smitherman added. “We need to isolate the mechanisms of action.” One of the mechanisms appears to be that changes in sleep improve migraine, given the associations that data analyses reveal.

Suggested Reading

Calhoun AH, Ford S. Behavioral sleep modification may revert transformed migraine to episodic migraine. Headache. 2007;47(8):1178-1183.

Rains JC, Poceta JS. Headache and sleep disorders: review and clinical implications for headache management. Headache. 2006;46(9):1344-1363.

Smitherman TA, Walters AB, Davis RE, et al. Randomized controlled pilot trial of behavioral insomnia treatment for chronic migraine with comorbid insomnia. Headache. 2016;56(2):276-291.

Health care has not been at the top of the agenda in this presidential campaign, but it remains a highly contentious political issue. Because the Affordable Care Act (aka Obamacare) was all about expanding health care coverage and not much about cost containment, it is not surprising that health care insurance costs continue to escalate.

The Accountable Care Organization demonstrations around the country have shown that some, but not all, health care organizations are able to bend the steep cost incline downward using incentives, bundled payments, excellent primary care access, and care coordination. But we are once again seeing large increases in insurance premiums, and no one is happy about that.

Take your pick of candidates, but don't expect a difference in your practice "hassle factor"—or paycheck.

Practical solutions are scarce. Good solutions for controlling rising health care costs are difficult to come by in the United States. There are a variety of suggestions and approaches favored by one party or the other that will be decided through political and administrative channels. The Medicare Access and CHIP Reauthorization Act of 2015 (MACRA), the Merit-based Incentive Payment System (MIPS), and alternative payment models (APMs) are the federal government’s new programs that have been set out to encourage quality, while controlling costs in outpatient settings.¹ These programs have bipartisan support and are not going away.

In addition, each state is reorganizing Medicaid in an attempt to improve quality and reduce costs. Usually these cost control/quality improvement programs are foisted on us by federal or state governments (which pay for about 64% of health care costs in the United States), by insurers, or both. Fortunately, the American Academy of Family Physicians has been putting the interests of family physicians in front of legislators and policy makers to try to ease the pain as much as possible.

What can YOU do? If you have the time and the stomach for it, join forces with AAFP to become involved in the politics of health care reform and speak up for family medicine and primary care. In your own office or clinic, put the “Choosing Wisely” campaign² (from the American Board of Internal Medicine) into practice: Focus on reducing unnecessary tests and treatments.

In the end, no matter which party occupies the White House for the next 4 years, health care payment reform is inevitable. Both parties agree that the steep rise in health care costs is unsustainable. So take your pick of presidential candidates, but don’t expect that choice to make a lot of difference in your practice “hassle factor”—or paycheck.

Health care has not been at the top of the agenda in this presidential campaign, but it remains a highly contentious political issue. Because the Affordable Care Act (aka Obamacare) was all about expanding health care coverage and not much about cost containment, it is not surprising that health care insurance costs continue to escalate.

The Accountable Care Organization demonstrations around the country have shown that some, but not all, health care organizations are able to bend the steep cost incline downward using incentives, bundled payments, excellent primary care access, and care coordination. But we are once again seeing large increases in insurance premiums, and no one is happy about that.

Take your pick of candidates, but don't expect a difference in your practice "hassle factor"—or paycheck.

Practical solutions are scarce. Good solutions for controlling rising health care costs are difficult to come by in the United States. There are a variety of suggestions and approaches favored by one party or the other that will be decided through political and administrative channels. The Medicare Access and CHIP Reauthorization Act of 2015 (MACRA), the Merit-based Incentive Payment System (MIPS), and alternative payment models (APMs) are the federal government’s new programs that have been set out to encourage quality, while controlling costs in outpatient settings.¹ These programs have bipartisan support and are not going away.

In addition, each state is reorganizing Medicaid in an attempt to improve quality and reduce costs. Usually these cost control/quality improvement programs are foisted on us by federal or state governments (which pay for about 64% of health care costs in the United States), by insurers, or both. Fortunately, the American Academy of Family Physicians has been putting the interests of family physicians in front of legislators and policy makers to try to ease the pain as much as possible.

What can YOU do? If you have the time and the stomach for it, join forces with AAFP to become involved in the politics of health care reform and speak up for family medicine and primary care. In your own office or clinic, put the “Choosing Wisely” campaign² (from the American Board of Internal Medicine) into practice: Focus on reducing unnecessary tests and treatments.

In the end, no matter which party occupies the White House for the next 4 years, health care payment reform is inevitable. Both parties agree that the steep rise in health care costs is unsustainable. So take your pick of presidential candidates, but don’t expect that choice to make a lot of difference in your practice “hassle factor”—or paycheck.

Health care has not been at the top of the agenda in this presidential campaign, but it remains a highly contentious political issue. Because the Affordable Care Act (aka Obamacare) was all about expanding health care coverage and not much about cost containment, it is not surprising that health care insurance costs continue to escalate.

The Accountable Care Organization demonstrations around the country have shown that some, but not all, health care organizations are able to bend the steep cost incline downward using incentives, bundled payments, excellent primary care access, and care coordination. But we are once again seeing large increases in insurance premiums, and no one is happy about that.

Take your pick of candidates, but don't expect a difference in your practice "hassle factor"—or paycheck.

Practical solutions are scarce. Good solutions for controlling rising health care costs are difficult to come by in the United States. There are a variety of suggestions and approaches favored by one party or the other that will be decided through political and administrative channels. The Medicare Access and CHIP Reauthorization Act of 2015 (MACRA), the Merit-based Incentive Payment System (MIPS), and alternative payment models (APMs) are the federal government’s new programs that have been set out to encourage quality, while controlling costs in outpatient settings.¹ These programs have bipartisan support and are not going away.

In addition, each state is reorganizing Medicaid in an attempt to improve quality and reduce costs. Usually these cost control/quality improvement programs are foisted on us by federal or state governments (which pay for about 64% of health care costs in the United States), by insurers, or both. Fortunately, the American Academy of Family Physicians has been putting the interests of family physicians in front of legislators and policy makers to try to ease the pain as much as possible.

What can YOU do? If you have the time and the stomach for it, join forces with AAFP to become involved in the politics of health care reform and speak up for family medicine and primary care. In your own office or clinic, put the “Choosing Wisely” campaign² (from the American Board of Internal Medicine) into practice: Focus on reducing unnecessary tests and treatments.

In the end, no matter which party occupies the White House for the next 4 years, health care payment reform is inevitable. Both parties agree that the steep rise in health care costs is unsustainable. So take your pick of presidential candidates, but don’t expect that choice to make a lot of difference in your practice “hassle factor”—or paycheck.

MUNICH – A group of 12 genes that influence blood sugar appears to help drive the risk of heart disease, independent of type 2 diabetes.

The genome-wide association study determined that every 1 mmol/L increase in fasting glucose associated with these genes increased the risk of coronary heart disease by 43%, Jordi Merino, PhD, said at the annual meeting of the European Association for the Study of Diabetes.

“Our results quantify the causal relationship between isolated, genetically increased fasting glucose and heart disease risk beyond the genetic effect of type 2 diabetes,” said Dr. Merino of Massachusetts General Hospital, Boston. “They suggest that modulating glycemia may provide cardiovascular benefit.”

©Gio_tto/Thinkstock

It’s known that patients with type 2 diabetes have a higher incidence of coronary heart disease, even after accounting for traditional cardiovascular risk factors, he said. But five large prospective randomized studies – including the much-vaunted ACCORD – failed to find convincing evidence that managing blood glucose in patients with diabetes exerts any benefit on cardiovascular outcomes. In fact, patients assigned to intensive management (blood glucose targeted to below 6%) had a relative increase in all-cause mortality of 22% and an absolute increase of 1%, without any differences in cardiovascular mortality (5% vs. 4%; hazard ratio, 1.22) (N Engl J Med. 2008;358:2545-59).

However, a 2014 subanalysis of ACCORD found that outcomes for ischemic heart disease were significantly better in the intensively managed group. There was a 20% reduction in the risk of heart attack; a 19% reduction in a combined endpoint of heart attack; and similar reductions in the risk of coronary revascularization and unstable angina (Lancet. 2014;384:1936-41).

“We believed genetics might help to answer the question about this discrepancies in findings,” Dr. Merino said.

To investigate this, he and his colleagues plumbed the largest meta-analyses of genome-wide association studies of glucose and insulin regulation. MAGIC (the Meta-Analyses of Glucose and Insulin-related traits Consortium) is a collaborative effort that has combined genetic data from 55 studies.

MAGIC investigators have identified dozens of loci that influence levels of fasting glucose, fasting insulin, and hemoglobin A_1c. The project includes data on 133,000 subjects without type 2 diabetes.

They used these data to conduct a Mendelian randomization analysis – a way of establishing causality between a specific gene and a specific clinical trait. Such an analysis is valid only when there are no other functional pathways between the genetic variant and the outcome and when confounding factors that could also affect the outcome can be controlled for.

MAGIC found 234 genetic variants that influence fasting glucose. Some of these also increase the risk of type 2 diabetes; after excluding those, Dr. Merino was left with 107 candidate genes. A disequilibrium analysis further pruned the group, leaving 12 genes that are independently associated with fasting glucose regulation.

He and his colleagues then applied data from the CARDIoGRAMplusC4D Consortium, which is searching for multiple risk loci for coronary artery disease and myocardial infarction in several large genetic studies. They created a five-level risk score for the glycemia-modulating genes and used to it determine how much genetically driven glucose variability affected the risk of heart disease in 5,000 subjects included in the Framingham Heart Study. The analysis controlled for lipids, blood pressure, and body mass index, he noted.

In a model that included all 12 of the variants, the investigators found that every 1 mmol/L increase in fasting glucose was associated with a significant 43% increase in the risk of heart disease.

A second analysis excluded one of the genes, but the significant association with increased risk of heart disease was preserved, at 34% per 1 mmol/L increase in fasting glucose. Individually, 10 of the genes raised the risk of coronary heart disease from a low of 6% (OR 1.06) to a high of almost 400% (OR 3.8).

The final pleiotropic analysis excluded all genes that could have more than one effect on heart disease; five genes survived to this level. Overall, they raised the risk of heart disease by 33%. Individually, the relative increased risks ranged from a low of 12% (odds ratio, 1.12) to a high of 87% (OR, 1.87). One gene was associated with a 25% risk reduction.

Dr. Merino had no financial disclosures.

[email protected]

MUNICH – A group of 12 genes that influence blood sugar appears to help drive the risk of heart disease, independent of type 2 diabetes.

The genome-wide association study determined that every 1 mmol/L increase in fasting glucose associated with these genes increased the risk of coronary heart disease by 43%, Jordi Merino, PhD, said at the annual meeting of the European Association for the Study of Diabetes.

“Our results quantify the causal relationship between isolated, genetically increased fasting glucose and heart disease risk beyond the genetic effect of type 2 diabetes,” said Dr. Merino of Massachusetts General Hospital, Boston. “They suggest that modulating glycemia may provide cardiovascular benefit.”

©Gio_tto/Thinkstock

It’s known that patients with type 2 diabetes have a higher incidence of coronary heart disease, even after accounting for traditional cardiovascular risk factors, he said. But five large prospective randomized studies – including the much-vaunted ACCORD – failed to find convincing evidence that managing blood glucose in patients with diabetes exerts any benefit on cardiovascular outcomes. In fact, patients assigned to intensive management (blood glucose targeted to below 6%) had a relative increase in all-cause mortality of 22% and an absolute increase of 1%, without any differences in cardiovascular mortality (5% vs. 4%; hazard ratio, 1.22) (N Engl J Med. 2008;358:2545-59).

However, a 2014 subanalysis of ACCORD found that outcomes for ischemic heart disease were significantly better in the intensively managed group. There was a 20% reduction in the risk of heart attack; a 19% reduction in a combined endpoint of heart attack; and similar reductions in the risk of coronary revascularization and unstable angina (Lancet. 2014;384:1936-41).

“We believed genetics might help to answer the question about this discrepancies in findings,” Dr. Merino said.

To investigate this, he and his colleagues plumbed the largest meta-analyses of genome-wide association studies of glucose and insulin regulation. MAGIC (the Meta-Analyses of Glucose and Insulin-related traits Consortium) is a collaborative effort that has combined genetic data from 55 studies.

MAGIC investigators have identified dozens of loci that influence levels of fasting glucose, fasting insulin, and hemoglobin A_1c. The project includes data on 133,000 subjects without type 2 diabetes.

They used these data to conduct a Mendelian randomization analysis – a way of establishing causality between a specific gene and a specific clinical trait. Such an analysis is valid only when there are no other functional pathways between the genetic variant and the outcome and when confounding factors that could also affect the outcome can be controlled for.

MAGIC found 234 genetic variants that influence fasting glucose. Some of these also increase the risk of type 2 diabetes; after excluding those, Dr. Merino was left with 107 candidate genes. A disequilibrium analysis further pruned the group, leaving 12 genes that are independently associated with fasting glucose regulation.

He and his colleagues then applied data from the CARDIoGRAMplusC4D Consortium, which is searching for multiple risk loci for coronary artery disease and myocardial infarction in several large genetic studies. They created a five-level risk score for the glycemia-modulating genes and used to it determine how much genetically driven glucose variability affected the risk of heart disease in 5,000 subjects included in the Framingham Heart Study. The analysis controlled for lipids, blood pressure, and body mass index, he noted.

In a model that included all 12 of the variants, the investigators found that every 1 mmol/L increase in fasting glucose was associated with a significant 43% increase in the risk of heart disease.

A second analysis excluded one of the genes, but the significant association with increased risk of heart disease was preserved, at 34% per 1 mmol/L increase in fasting glucose. Individually, 10 of the genes raised the risk of coronary heart disease from a low of 6% (OR 1.06) to a high of almost 400% (OR 3.8).

The final pleiotropic analysis excluded all genes that could have more than one effect on heart disease; five genes survived to this level. Overall, they raised the risk of heart disease by 33%. Individually, the relative increased risks ranged from a low of 12% (odds ratio, 1.12) to a high of 87% (OR, 1.87). One gene was associated with a 25% risk reduction.

Dr. Merino had no financial disclosures.

[email protected]

MUNICH – A group of 12 genes that influence blood sugar appears to help drive the risk of heart disease, independent of type 2 diabetes.

The genome-wide association study determined that every 1 mmol/L increase in fasting glucose associated with these genes increased the risk of coronary heart disease by 43%, Jordi Merino, PhD, said at the annual meeting of the European Association for the Study of Diabetes.

“Our results quantify the causal relationship between isolated, genetically increased fasting glucose and heart disease risk beyond the genetic effect of type 2 diabetes,” said Dr. Merino of Massachusetts General Hospital, Boston. “They suggest that modulating glycemia may provide cardiovascular benefit.”

©Gio_tto/Thinkstock

It’s known that patients with type 2 diabetes have a higher incidence of coronary heart disease, even after accounting for traditional cardiovascular risk factors, he said. But five large prospective randomized studies – including the much-vaunted ACCORD – failed to find convincing evidence that managing blood glucose in patients with diabetes exerts any benefit on cardiovascular outcomes. In fact, patients assigned to intensive management (blood glucose targeted to below 6%) had a relative increase in all-cause mortality of 22% and an absolute increase of 1%, without any differences in cardiovascular mortality (5% vs. 4%; hazard ratio, 1.22) (N Engl J Med. 2008;358:2545-59).

However, a 2014 subanalysis of ACCORD found that outcomes for ischemic heart disease were significantly better in the intensively managed group. There was a 20% reduction in the risk of heart attack; a 19% reduction in a combined endpoint of heart attack; and similar reductions in the risk of coronary revascularization and unstable angina (Lancet. 2014;384:1936-41).

“We believed genetics might help to answer the question about this discrepancies in findings,” Dr. Merino said.

To investigate this, he and his colleagues plumbed the largest meta-analyses of genome-wide association studies of glucose and insulin regulation. MAGIC (the Meta-Analyses of Glucose and Insulin-related traits Consortium) is a collaborative effort that has combined genetic data from 55 studies.

MAGIC investigators have identified dozens of loci that influence levels of fasting glucose, fasting insulin, and hemoglobin A_1c. The project includes data on 133,000 subjects without type 2 diabetes.

They used these data to conduct a Mendelian randomization analysis – a way of establishing causality between a specific gene and a specific clinical trait. Such an analysis is valid only when there are no other functional pathways between the genetic variant and the outcome and when confounding factors that could also affect the outcome can be controlled for.

MAGIC found 234 genetic variants that influence fasting glucose. Some of these also increase the risk of type 2 diabetes; after excluding those, Dr. Merino was left with 107 candidate genes. A disequilibrium analysis further pruned the group, leaving 12 genes that are independently associated with fasting glucose regulation.

He and his colleagues then applied data from the CARDIoGRAMplusC4D Consortium, which is searching for multiple risk loci for coronary artery disease and myocardial infarction in several large genetic studies. They created a five-level risk score for the glycemia-modulating genes and used to it determine how much genetically driven glucose variability affected the risk of heart disease in 5,000 subjects included in the Framingham Heart Study. The analysis controlled for lipids, blood pressure, and body mass index, he noted.

In a model that included all 12 of the variants, the investigators found that every 1 mmol/L increase in fasting glucose was associated with a significant 43% increase in the risk of heart disease.

A second analysis excluded one of the genes, but the significant association with increased risk of heart disease was preserved, at 34% per 1 mmol/L increase in fasting glucose. Individually, 10 of the genes raised the risk of coronary heart disease from a low of 6% (OR 1.06) to a high of almost 400% (OR 3.8).

The final pleiotropic analysis excluded all genes that could have more than one effect on heart disease; five genes survived to this level. Overall, they raised the risk of heart disease by 33%. Individually, the relative increased risks ranged from a low of 12% (odds ratio, 1.12) to a high of 87% (OR, 1.87). One gene was associated with a 25% risk reduction.

Dr. Merino had no financial disclosures.

[email protected]