Cover Story

Experts push to move ‘beyond HbA1c’ as main measure of diabetes outcomes

For nearly 3 decades, HbA1c has been the accepted gold-standard measurement of diabetes outcomes. Patients, clinicians, regulators and industry have relied on the 3-month average plasma glucose concentration to assess the efficacy of diabetes therapies and inform treatment decisions, and it has become the primary endpoint for most diabetes drug approval studies.

But HbA1c alone does not tell the full story of glycemic variability in patients with type 1 and type 2 diabetes. Advances in diabetes technology, including continuous glucose monitoring (CGM), now paint a fuller picture for patients of their daily glucose variability, including time spent in the normal glycemic range for a person with diabetes (70 mg/dL-180 mg/dL) and any episodes of hypoglycemia and hyperglycemia. Experts debate whether the time has come to consider a more comprehensive composite endpoint to determine the adequacy of diabetes therapies, one that may include HbA1c, but also incorporates metrics including time in range, hypoglycemia, change in body weight and patient-reported outcomes, such as health-related quality of life.

Stakeholders from across the diabetes community, including patient advocates, clinicians, regulatory officials and diabetes drug and device manufacturers, convened at a recent FDA public workshop on the matter, titled “Diabetes Outcome Measures Beyond Hemoglobin A1c,” to explore alternative, composite metrics to best measure diabetes outcomes.

According to David Marrero, PhD, immediate past president of health care and education for the ADA, more accurate assessment tools are needed before quality of life can be measured and compared across therapies.

Photo by Kristen Hanning, University of Arizona BioCommunications.

“We’re not dismissing HbA1c — it’s why we’ve had the success that we’ve had in terms of reducing complications of diabetes,” Robert Ratner, MD, FACP, FACE, chief scientific and medical officer for the American Diabetes Association, said during a round table discussion at the meeting. “We want to hold onto that. But, we want to move on to the next steps. Now that we’ve done better in terms of glycemic control, and we’re seeing a 60% reduction in heart attack, a 50% reduction in stroke, a 40% reduction in amputation, a 28% reduction in diabetic kidney disease ... how do we make life better, not just longer, for people with diabetes?”

‘A skeptical view’

Since the landmark Diabetes Control and Complications Trial in the early 1990s, which demonstrated that tight glucose control reduces the onset of microvascular complications associated with diabetes, change in HbA1c has been the traditional metric for determining the efficacy of any diabetes intervention. However, as CGM and other diabetes technologies provide more information on glucose variability in patients, recent studies have also called into question the value of tight glycemic control on diabetes outcomes. In a recent examination of meta-analyses, guidelines and randomized controlled trials, Rene Rodriguez-Gutierrez, MD, MSc, and Victor M. Montori, MD, MSc, both of the division of endocrinology, diabetes, metabolism and nutrition at the Mayo Clinic in Rochester, Minnesota, noted that tight glycemic control confers no substantial benefit on the risk for microvascular or macrovascular complications, despite a consistent RR reduction for nonfatal myocardial infarction.

“As of 2015, the evidence suggests that a skeptical view may be necessary to move diabetes mellitus care forward,” the researchers wrote. “The notion that tight glycemic control is clearly beneficial does not hold in the face of the evidence accrued during the past decade, evidence that has fallen short of confirming this notion. The contributions of [more than] 27,000 patients participating in [randomized controlled trials] of glycemic control, their clinicians, and the investigators that designed and conducted these trials question our confident reliance on tight glycemic control as the main, or, in some cases only, strategy to prevent complications in patients with type 2 diabetes mellitus. Perhaps as a result, guideline developers are now advocating for selecting less stringent HbA1c targets in patients with recurrent, severe hypoglycemia, high-comorbidity burden or limited life expectancy.”

Patient-reported outcomes

The push for a new composite measure has caught the attention of other regulatory agencies. In a June concept paper released by the European Medicines Agency (EMA) calling for a revision to the guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes, the authors noted that additional measures, including patient-reported outcomes, may be needed beyond HbA1c to evaluate the benefit of a diabetes treatment.

Bart J. Van der Schueren

“Patient groups have expressed concerns that HbA1c may be insufficient to establish benefit of glucose-lowering therapies and that additional measures need to be evaluated to characterize benefit,” the committee members wrote. “Depending on further assessment of this issue, it may be considered to include additional guidance with respect to potential endpoints other than those directly associated with glycemic control, eg, patient-reported outcome measures.”

A patient-reported outcome is defined as a report that comes directly from patients about the status of their health condition, without amendment or interpretation of the patient’s response by a clinician. The term can encompass anything from simple measures related to pain intensity to health-related quality of life, Elektra Papadopoulos, MD, MPH, acting director of the clinical outcome assessments staff in the Center for Drug Evaluation and Research, said.

“We have heard over and over ... that HbA1c doesn’t capture the full story with patient experience,” Papadopoulos said during the meeting. “Patients have glucose variability and, of course, hypoglycemic episodes, that aren’t really captured. We know that we need patient-reported outcomes to capture these.”

Missing in many studies, she said, are reports of milder episodes of hypoglycemia that cause symptoms for patients and affect their lives, influencing treatment adherence.

“There is a lot of variability in the patient’s experience, and this creates a lot of challenges,” she said.

Simon Heller

Perhaps the biggest challenge, according to some regulators, is to ensure all countries use the same validated patient-reported outcomes that can be translated and culturally adapted across multinational settings in any new composite measurement.

In March 2015, the glucagon-like peptide-1 receptor agonist dulaglutide (Trulicity, Eli Lilly), approved by the EMA in November 2014, became the first diabetes drug to have a patient-reported outcome (other than self-monitored blood glucose profiles) included in its European label. The label notes that the drug significantly improved total treatment satisfaction compared with exenatide (Byetta, AstraZeneca) twice daily, and that there was “significantly lower perceived frequency of hyperglycemia and hypoglycemia compared to exenatide twice daily.” (The drug was approved by the FDA in September 2014; no patient-reported outcomes are included in the U.S. label).

“Disease-specific patient-reported outcomes for diabetes might be extremely useful when using other endpoints, such as time in range,” Bart J. Van der Schueren, MD, PhD, Belgian member of the Committee for Medicinal Products for Human Use at the EMA and a clinical pharmacologist and endocrinologist at the University Hospital of Leuven, said during the meeting. “The time a patient is in range is available now from CGM. We have that information. We’ll need to check if that actually influences the quality of life in the patient. It’s the patient-reported outcome that’s going to validate an endpoint, such as time in range.”

Van der Schueren said he would like to see better use of new techniques, such as CGM, in future clinical trials.

“For a chronic, life-long disease, compliance with treatment is only feasible when a treatment improves or at least doesn’t negatively affect quality of life,” Van der Schueren told Endocrine Today. “In addition, patient-reported outcomes will help us to better understand how the quality of life of patients with diabetes is affected by glycemic variability.”

To date, no patient-reported outcomes have been included in U.S. labels for diabetes products. However, sponsors have been routinely collecting them in diabetes clinical trials in recent years to describe the patient impact of new products, Shana Traina, PhD, director of global market access for Janssen, said during the meeting. The lack of a universally accepted instrument, combined with the heterogeneity of disease presentation, are challenges to including such a description of benefit in a drug’s package insert, she said.

“Given that the experiences of people with diabetes are unique and personal, there are challenges with respect to measurement of the patient’s perspective of their disease and its treatments,” Traina told Endocrine Today. “It is difficult to capture the full patient experience while thinking traditionally about diabetes trial endpoints. The impact of treatments can be defined more broadly than simple reductions in HbA1c or how patients are feeling, functioning and surviving. A theme that comes from the literature, patient blogs and qualitative research is the concept of making disease management easier.”

Newer pharmaceutical agents for diabetes hold promise for improving glycemic control with less self-care burden and a lower risk for hypoglycemia or weight gain, Traina said.

“If these benefits could be summed up into a measure describing how easy or hard it is to manage one’s disease, this could be a meaningful and relevant endpoint to include in future clinical trial,” Traina said.

Quality-of-life measures, challenges

Individuals with diabetes report reduced health-related quality of life compared with age-matched people without diabetes and describe quality-of-life decreases with disease progression and the onset of complications associated with the disease, said David Marrero, PhD, immediate past president of health care and education for the ADA and professor of endocrinology and public health at the University of Arizona. However, measuring health-related quality of life as a patient-reported outcome, although important, can pose a challenge for several reasons, Marrero said.

“Changes in quality of life do not necessarily follow the same trajectory as changes in behavior or HbA1c,” he said. “Often, quality-of-life changes occur when changes in other variables are taking place or before.”

Marrero pointed to metformin, a drug known to sometimes cause gastrointestinal distress a few weeks after a patient initiates therapy.

George Grunberger

“[Metformin] has a weird impact on quality of life,” said Marrero, who has type 1 diabetes. “It depends when [symptoms] kick in. If you assess quality of life on either side of that issue, you would get different outcomes.”

In addition, he said, there is currently a lack of well-validated instruments across the life span that measure health-related quality of life.

“When you try to figure out, is there a recommendation you can make for a single instrument for health-related quality of life, the short answer is, no,” Marrero said. “There are very specific instruments for persons, both children and adults, [with] type 1 and type 2, that can be characterized differently in terms of the demands placed upon the individual. There are also generic instruments that measure components impacting health-related quality of life, but not specifically diabetes.

“With more accurate assessment tools that enable us to better understand the impact of treatments and compare between therapies, health-related quality of life can eventually become part of the clinical decision-making process and improve patient care,” he said. “I strongly recommend that the FDA start looking at quality-of-life impact as they consider the accuracy and quality-of-treatment decisions and treatment modalities being presented to them.”

Fear of hypoglycemia

Simon Heller, DM, FRCP, professor of clinical diabetes at Sheffield Teaching Hospitals, and honorary consultant physician with the NHS Foundation Trust in the United Kingdom and a member of the International Hypoglycaemia Study Group, recommended another measure to capture patient-reported outcomes: the hypoglycemia fear survey. The measure includes subscales measuring worry and behavior related to hypoglycemia; a second part of the scale looks at various measures patients may engage in to avoid hypoglycemia and its negative effects. The global group is also calling for a reclassification of hypoglycemia in clinical trials.

“Hypoglycemia matters to patients, and it should matter to clinicians, and it needs to be measured in more depth,” Heller told Endocrine Today.

“Inadequacy of current insulin delivery means that hypoglycemia is an inevitable consequence of tight glycemic targets. It’s arguably the major barrier preventing most patients from achieving glycemic targets. It predicts serious morbidity and mortality, and current study outcomes, in our view, fail to measure the full burden of hypoglycemia on people with diabetes,” Heller said during the FDA meeting.

Reports of severe hypoglycemia are rare in many clinical trials, leading to insufficient statistical power to compare interventions, he said.

Elektra Papadopoulos

“We’ve seen examples of that in pump trials and trials of the artificial pancreas,” Heller said. “We think there is an extremely strong case for a third, agreed-upon level ... denoting ‘major and serious’ hypoglycemia, which we think occurs at around 50 mg/dL to 55 mg/dL.”

This new designation would denote impaired cognitive function. Repeated incidents at this level cause reduced awareness and predict severe episodes and can predict cardiac arrhythmias and mortality, he said.

“At a level between ‘severe’ and the current FDA definition of 70 mg/dL, episodes have major consequences of morbidity, mortality and health economics, with additional effects on quality of life,” Heller told Endocrine Today. “These need to be captured, as they well allow new treatments which reduce hypoglycemia to be reimbursed.

“I would like to see a common classification to compare treatments in trials and beyond with far greater confidence,” Heller said. “This could make a real difference to patients and their families.”

The challenge with any patient-reported outcomes, Heller said, is that these will need to be compared in double blind studies if they are to be included in FDA- or EMA-approved labels, as they are influenced by subjective factors.

“This is important, as designing such studies is often very challenging,” Heller said.

A call for new measures, dialogue

HbA1c remains a useful surrogate to measure diabetes outcomes, but it is often far from the center of an individual patient–physician encounter, said George Grunberger, MD, FACP, FACE, president of the American Association of Clinical Endocrinologists.

“Unfortunately, [HbA1c] has become an almost god-like thing out there, and our members can be rewarded or punished for [patients] not achieving whatever HbA1c target is determined by their organization, which is not run by anyone who is present in the exam room,” Grunberger said. “So you can imagine a scenario with a physician who now fears patients are not achieving the target HbA1c ... and intensifies treatment in order to be in the HbA1c target, and now we have a conflict. Those are things that need to be discussed.”

Validated measures are also needed to determine how taking a medication affects professional and personal lives, he said.

“Remember, especially if you have a newly diagnosed patient in front of you in their 20s or 30s, you’re looking at maybe 30, 40, 50, even 60 years of treatment,” Grunberger said. “So how do you make sure that a therapy works as well in the long run and achieves what it is important to achieve as it does in a short-term trial? These are huge challenges.”

He said he would like to see two more meetings scheduled to continue the conversation on metrics for a new composite endpoint and alternative measures to HbA1c.

“There is clear recognition that we do need to go beyond simple biometrics and look at a different perspective for understanding how to approve and move forward new drugs, new devices, new therapies,” Marrero told Endocrine Today. “There is a patient voice that has to be recognized and has to be quantified. It has to be standardized in a way that can make sense. Moving forward, we need to have more extended dialogue, more specific recommendations, more focused applications on some of these ideas.” – by Regina Schaffer

Disclosure: Heller reports receiving research support and speaking fees or serving as an adviser or consultant for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Johnson & Johnson, Medtronic, Novo Nordisk, Sanofi Aventis and Takeda. Traina is the director of global market access for Janssen. Grunberger, Marrero, Papadopoulos, Ratner and Van der Schueren report no relevant financial disclosures.

Click here to read the POINTCOUNTER, "What metrics should be considered beyond HbA1c to best measure diabetes outcomes?"

For nearly 3 decades, HbA1c has been the accepted gold-standard measurement of diabetes outcomes. Patients, clinicians, regulators and industry have relied on the 3-month average plasma glucose concentration to assess the efficacy of diabetes therapies and inform treatment decisions, and it has become the primary endpoint for most diabetes drug approval studies.

But HbA1c alone does not tell the full story of glycemic variability in patients with type 1 and type 2 diabetes. Advances in diabetes technology, including continuous glucose monitoring (CGM), now paint a fuller picture for patients of their daily glucose variability, including time spent in the normal glycemic range for a person with diabetes (70 mg/dL-180 mg/dL) and any episodes of hypoglycemia and hyperglycemia. Experts debate whether the time has come to consider a more comprehensive composite endpoint to determine the adequacy of diabetes therapies, one that may include HbA1c, but also incorporates metrics including time in range, hypoglycemia, change in body weight and patient-reported outcomes, such as health-related quality of life.

Stakeholders from across the diabetes community, including patient advocates, clinicians, regulatory officials and diabetes drug and device manufacturers, convened at a recent FDA public workshop on the matter, titled “Diabetes Outcome Measures Beyond Hemoglobin A1c,” to explore alternative, composite metrics to best measure diabetes outcomes.

According to David Marrero, PhD, immediate past president of health care and education for the ADA, more accurate assessment tools are needed before quality of life can be measured and compared across therapies.

Photo by Kristen Hanning, University of Arizona BioCommunications.

“We’re not dismissing HbA1c — it’s why we’ve had the success that we’ve had in terms of reducing complications of diabetes,” Robert Ratner, MD, FACP, FACE, chief scientific and medical officer for the American Diabetes Association, said during a round table discussion at the meeting. “We want to hold onto that. But, we want to move on to the next steps. Now that we’ve done better in terms of glycemic control, and we’re seeing a 60% reduction in heart attack, a 50% reduction in stroke, a 40% reduction in amputation, a 28% reduction in diabetic kidney disease ... how do we make life better, not just longer, for people with diabetes?”

‘A skeptical view’

Since the landmark Diabetes Control and Complications Trial in the early 1990s, which demonstrated that tight glucose control reduces the onset of microvascular complications associated with diabetes, change in HbA1c has been the traditional metric for determining the efficacy of any diabetes intervention. However, as CGM and other diabetes technologies provide more information on glucose variability in patients, recent studies have also called into question the value of tight glycemic control on diabetes outcomes. In a recent examination of meta-analyses, guidelines and randomized controlled trials, Rene Rodriguez-Gutierrez, MD, MSc, and Victor M. Montori, MD, MSc, both of the division of endocrinology, diabetes, metabolism and nutrition at the Mayo Clinic in Rochester, Minnesota, noted that tight glycemic control confers no substantial benefit on the risk for microvascular or macrovascular complications, despite a consistent RR reduction for nonfatal myocardial infarction.

“As of 2015, the evidence suggests that a skeptical view may be necessary to move diabetes mellitus care forward,” the researchers wrote. “The notion that tight glycemic control is clearly beneficial does not hold in the face of the evidence accrued during the past decade, evidence that has fallen short of confirming this notion. The contributions of [more than] 27,000 patients participating in [randomized controlled trials] of glycemic control, their clinicians, and the investigators that designed and conducted these trials question our confident reliance on tight glycemic control as the main, or, in some cases only, strategy to prevent complications in patients with type 2 diabetes mellitus. Perhaps as a result, guideline developers are now advocating for selecting less stringent HbA1c targets in patients with recurrent, severe hypoglycemia, high-comorbidity burden or limited life expectancy.”

PAGE BREAK

Patient-reported outcomes

The push for a new composite measure has caught the attention of other regulatory agencies. In a June concept paper released by the European Medicines Agency (EMA) calling for a revision to the guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes, the authors noted that additional measures, including patient-reported outcomes, may be needed beyond HbA1c to evaluate the benefit of a diabetes treatment.

Bart J. Van der Schueren

“Patient groups have expressed concerns that HbA1c may be insufficient to establish benefit of glucose-lowering therapies and that additional measures need to be evaluated to characterize benefit,” the committee members wrote. “Depending on further assessment of this issue, it may be considered to include additional guidance with respect to potential endpoints other than those directly associated with glycemic control, eg, patient-reported outcome measures.”

A patient-reported outcome is defined as a report that comes directly from patients about the status of their health condition, without amendment or interpretation of the patient’s response by a clinician. The term can encompass anything from simple measures related to pain intensity to health-related quality of life, Elektra Papadopoulos, MD, MPH, acting director of the clinical outcome assessments staff in the Center for Drug Evaluation and Research, said.

“We have heard over and over ... that HbA1c doesn’t capture the full story with patient experience,” Papadopoulos said during the meeting. “Patients have glucose variability and, of course, hypoglycemic episodes, that aren’t really captured. We know that we need patient-reported outcomes to capture these.”

Missing in many studies, she said, are reports of milder episodes of hypoglycemia that cause symptoms for patients and affect their lives, influencing treatment adherence.

“There is a lot of variability in the patient’s experience, and this creates a lot of challenges,” she said.

Simon Heller

Perhaps the biggest challenge, according to some regulators, is to ensure all countries use the same validated patient-reported outcomes that can be translated and culturally adapted across multinational settings in any new composite measurement.

In March 2015, the glucagon-like peptide-1 receptor agonist dulaglutide (Trulicity, Eli Lilly), approved by the EMA in November 2014, became the first diabetes drug to have a patient-reported outcome (other than self-monitored blood glucose profiles) included in its European label. The label notes that the drug significantly improved total treatment satisfaction compared with exenatide (Byetta, AstraZeneca) twice daily, and that there was “significantly lower perceived frequency of hyperglycemia and hypoglycemia compared to exenatide twice daily.” (The drug was approved by the FDA in September 2014; no patient-reported outcomes are included in the U.S. label).

“Disease-specific patient-reported outcomes for diabetes might be extremely useful when using other endpoints, such as time in range,” Bart J. Van der Schueren, MD, PhD, Belgian member of the Committee for Medicinal Products for Human Use at the EMA and a clinical pharmacologist and endocrinologist at the University Hospital of Leuven, said during the meeting. “The time a patient is in range is available now from CGM. We have that information. We’ll need to check if that actually influences the quality of life in the patient. It’s the patient-reported outcome that’s going to validate an endpoint, such as time in range.”

Van der Schueren said he would like to see better use of new techniques, such as CGM, in future clinical trials.

“For a chronic, life-long disease, compliance with treatment is only feasible when a treatment improves or at least doesn’t negatively affect quality of life,” Van der Schueren told Endocrine Today. “In addition, patient-reported outcomes will help us to better understand how the quality of life of patients with diabetes is affected by glycemic variability.”

To date, no patient-reported outcomes have been included in U.S. labels for diabetes products. However, sponsors have been routinely collecting them in diabetes clinical trials in recent years to describe the patient impact of new products, Shana Traina, PhD, director of global market access for Janssen, said during the meeting. The lack of a universally accepted instrument, combined with the heterogeneity of disease presentation, are challenges to including such a description of benefit in a drug’s package insert, she said.

PAGE BREAK

“Given that the experiences of people with diabetes are unique and personal, there are challenges with respect to measurement of the patient’s perspective of their disease and its treatments,” Traina told Endocrine Today. “It is difficult to capture the full patient experience while thinking traditionally about diabetes trial endpoints. The impact of treatments can be defined more broadly than simple reductions in HbA1c or how patients are feeling, functioning and surviving. A theme that comes from the literature, patient blogs and qualitative research is the concept of making disease management easier.”

Newer pharmaceutical agents for diabetes hold promise for improving glycemic control with less self-care burden and a lower risk for hypoglycemia or weight gain, Traina said.

“If these benefits could be summed up into a measure describing how easy or hard it is to manage one’s disease, this could be a meaningful and relevant endpoint to include in future clinical trial,” Traina said.

Quality-of-life measures, challenges

Individuals with diabetes report reduced health-related quality of life compared with age-matched people without diabetes and describe quality-of-life decreases with disease progression and the onset of complications associated with the disease, said David Marrero, PhD, immediate past president of health care and education for the ADA and professor of endocrinology and public health at the University of Arizona. However, measuring health-related quality of life as a patient-reported outcome, although important, can pose a challenge for several reasons, Marrero said.

“Changes in quality of life do not necessarily follow the same trajectory as changes in behavior or HbA1c,” he said. “Often, quality-of-life changes occur when changes in other variables are taking place or before.”

Marrero pointed to metformin, a drug known to sometimes cause gastrointestinal distress a few weeks after a patient initiates therapy.

George Grunberger

“[Metformin] has a weird impact on quality of life,” said Marrero, who has type 1 diabetes. “It depends when [symptoms] kick in. If you assess quality of life on either side of that issue, you would get different outcomes.”

In addition, he said, there is currently a lack of well-validated instruments across the life span that measure health-related quality of life.

“When you try to figure out, is there a recommendation you can make for a single instrument for health-related quality of life, the short answer is, no,” Marrero said. “There are very specific instruments for persons, both children and adults, [with] type 1 and type 2, that can be characterized differently in terms of the demands placed upon the individual. There are also generic instruments that measure components impacting health-related quality of life, but not specifically diabetes.

“With more accurate assessment tools that enable us to better understand the impact of treatments and compare between therapies, health-related quality of life can eventually become part of the clinical decision-making process and improve patient care,” he said. “I strongly recommend that the FDA start looking at quality-of-life impact as they consider the accuracy and quality-of-treatment decisions and treatment modalities being presented to them.”

Fear of hypoglycemia

Simon Heller, DM, FRCP, professor of clinical diabetes at Sheffield Teaching Hospitals, and honorary consultant physician with the NHS Foundation Trust in the United Kingdom and a member of the International Hypoglycaemia Study Group, recommended another measure to capture patient-reported outcomes: the hypoglycemia fear survey. The measure includes subscales measuring worry and behavior related to hypoglycemia; a second part of the scale looks at various measures patients may engage in to avoid hypoglycemia and its negative effects. The global group is also calling for a reclassification of hypoglycemia in clinical trials.

“Hypoglycemia matters to patients, and it should matter to clinicians, and it needs to be measured in more depth,” Heller told Endocrine Today.

PAGE BREAK

“Inadequacy of current insulin delivery means that hypoglycemia is an inevitable consequence of tight glycemic targets. It’s arguably the major barrier preventing most patients from achieving glycemic targets. It predicts serious morbidity and mortality, and current study outcomes, in our view, fail to measure the full burden of hypoglycemia on people with diabetes,” Heller said during the FDA meeting.

Reports of severe hypoglycemia are rare in many clinical trials, leading to insufficient statistical power to compare interventions, he said.

Elektra Papadopoulos

“We’ve seen examples of that in pump trials and trials of the artificial pancreas,” Heller said. “We think there is an extremely strong case for a third, agreed-upon level ... denoting ‘major and serious’ hypoglycemia, which we think occurs at around 50 mg/dL to 55 mg/dL.”

This new designation would denote impaired cognitive function. Repeated incidents at this level cause reduced awareness and predict severe episodes and can predict cardiac arrhythmias and mortality, he said.

“At a level between ‘severe’ and the current FDA definition of 70 mg/dL, episodes have major consequences of morbidity, mortality and health economics, with additional effects on quality of life,” Heller told Endocrine Today. “These need to be captured, as they well allow new treatments which reduce hypoglycemia to be reimbursed.

“I would like to see a common classification to compare treatments in trials and beyond with far greater confidence,” Heller said. “This could make a real difference to patients and their families.”

The challenge with any patient-reported outcomes, Heller said, is that these will need to be compared in double blind studies if they are to be included in FDA- or EMA-approved labels, as they are influenced by subjective factors.

“This is important, as designing such studies is often very challenging,” Heller said.

A call for new measures, dialogue

HbA1c remains a useful surrogate to measure diabetes outcomes, but it is often far from the center of an individual patient–physician encounter, said George Grunberger, MD, FACP, FACE, president of the American Association of Clinical Endocrinologists.

“Unfortunately, [HbA1c] has become an almost god-like thing out there, and our members can be rewarded or punished for [patients] not achieving whatever HbA1c target is determined by their organization, which is not run by anyone who is present in the exam room,” Grunberger said. “So you can imagine a scenario with a physician who now fears patients are not achieving the target HbA1c ... and intensifies treatment in order to be in the HbA1c target, and now we have a conflict. Those are things that need to be discussed.”

Validated measures are also needed to determine how taking a medication affects professional and personal lives, he said.

“Remember, especially if you have a newly diagnosed patient in front of you in their 20s or 30s, you’re looking at maybe 30, 40, 50, even 60 years of treatment,” Grunberger said. “So how do you make sure that a therapy works as well in the long run and achieves what it is important to achieve as it does in a short-term trial? These are huge challenges.”

He said he would like to see two more meetings scheduled to continue the conversation on metrics for a new composite endpoint and alternative measures to HbA1c.

“There is clear recognition that we do need to go beyond simple biometrics and look at a different perspective for understanding how to approve and move forward new drugs, new devices, new therapies,” Marrero told Endocrine Today. “There is a patient voice that has to be recognized and has to be quantified. It has to be standardized in a way that can make sense. Moving forward, we need to have more extended dialogue, more specific recommendations, more focused applications on some of these ideas.” – by Regina Schaffer

PAGE BREAK

Disclosure: Heller reports receiving research support and speaking fees or serving as an adviser or consultant for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Johnson & Johnson, Medtronic, Novo Nordisk, Sanofi Aventis and Takeda. Traina is the director of global market access for Janssen. Grunberger, Marrero, Papadopoulos, Ratner and Van der Schueren report no relevant financial disclosures.

Click here to read the POINTCOUNTER, "What metrics should be considered beyond HbA1c to best measure diabetes outcomes?"