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Evidence-based data needed to support ADA/EASD position statement
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Previous guidelines developed by the American Diabetes Association and the European Association for the Study of Diabetes have taken a prescriptive approach to assist clinicians with patients who display hyperglycemia and type 2 diabetes. However, recently increasing complexities evident in this patient population have prompted a joint task force to design a patient-centered approach. Endocrine Today spoke with authors of the position statement and other clinicians in the field to assess its effect and the critical role of individualized care.
“It’s a holistic approach, taking into account the patient’s age and comorbidities,” Andrew J.M. Boulton, MD, DSc, FRCP, EASDpresident and professor of medicine at the University of Manchester in the United Kingdom, told Endocrine Today. “In each patient, we consider their own wishes, their age, their chance of complications, longevity and more; not just glycemic control. That’s why this position statement is different from previous ones.”
Silvio E. Inzucchi, MD, lead author on the position statement and professor of medicine at Yale University School of Medicine, said physicians should consider multiple factors when choosing glycemic targets.
Source: Photo courtesy of The European Association for the Study of Diabetes.
In the past, recommendations emphasized HbA1c targets. However, the position statement published in the June issue of Diabetes Care and Diabetologia calls for a patient-centered approach in which glycemic targets are suggested to include a patient’s attitude and expected treatment efforts, risks and adverse effects, disease duration, life expectancy and other comorbidities. Additionally, the statement recommends that glycemic targets assess established vascular complications and what resources might be available to patients.
“In certain circumstances, you may not want to control blood glucose too tightly and put patients at risk for hypoglycemia. A key point is that side effects and adverse events of treatment will need to be considered in the overall scheme of things. One cannot have a simple monocular view on glucose control alone. The quality of life of the patient, the cost of their medications, the treatment ‘burden’ — all of those factors need to be judged by the clinician,” Silvio E. Inzucchi, MD, lead author on the position statement and professor of medicine at Yale University School of Medicine, told Endocrine Today.
Lessons from the literature
Inzucchi and the task force behind the new position statement reflected on reports from three short-term studies in 2008: Action to Control Cardiovascular Risk in Diabetes (ACCORD); Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation (ADVANCE); and the Veterans Affairs Diabetes Trial (VADT), besides the UK Prospective Diabetes Study (UKPDS).
ACCORD and VADT set an HbA1c goal of <6% with combinations of oral agents and insulin, whereas the ADVANCE trial attempted to bring HbA1c levels to ≤6.5% using a sulfonylurea, gliclazide. Ultimately, the ACCORD trial led to a 22% increase in total mortality, according to data.
“The studies taught us that not everyone with type 2 diabetes benefits from tight glycemic control — at least as far as CV risk factors are concerned. Even microvascular benefits in an older age group of patients may be limited to surrogate markers. It’s hard to know how you can extrapolate those two true reductions in clinical events such as renal failure, etc. We took that into consideration as well,” Inzucchi said.
Andrew J.M. Boulton
“Studies like the ACCORD trial, where there was an increase in mortality in the intensively treated group, and other data have come out about the dangers of severe hypoglycemia in people with cardiovascular disease,” Anne L. Peters, MD, co-author of the position statement and director of the USC Clinical Diabetes Program and professor at the Keck School of Medicine in Los Angeles, told Endocrine Today. “This prompted the organizations to create a position statement that sets the stage for more individualization tools to avoid having ACCORD-like outcomes in your practice.”
In 2008, the 10-year follow-up results from the UKPDS demonstrated that early intensive glucose control not only continued to reduce microvascular complications, but also modestly reduced risk for myocardial infarction and all-cause mortality. Additionally, benefits of earlier metformin therapy were sustained. However, the benefits of tight BP control reported before the trial was terminated did not continue over time, according to data.
HbA1c and reasonable goals
In the past, HbA1c has been used to judge the quality of health care delivery in this patient population. In an interview, David S. H. Bell, MD, endocrinologist at Southside Endocrinology in Birmingham, Ala., and an Endocrine Today Editorial Board member, said the earlier that HbA1c levels are lowered, the better the outcome. However, a patient-centered approach to this goal is necessary to address various age groups and comorbidities, he added. The elderly are an especially vulnerable patient population regarding managing HbA1c levels. Targets can vary depending on multiple comorbidities and/or life expectancies.
“Start early and treat intensively. Do not just let it go; make the patient realize they’ve got a serious disease. Don’t say they’ve got ‘a touch of diabetes’ or ‘borderline diabetes.’ This is a serious disease and we now have the tools to energetically treat this and get to goal, at least in the earlier stages,” Bell said.
Anne L. Peters
In an editorial published in Southern Medical Journal in 2010, Bell wrote that goals for HbA1c should be individualized based on clinical judgment.
“In those patients with a longer duration of diabetes (above 12 years) and/or who have known coronary artery disease, a reasonable goal for the HbA1c should be 7.5%, especially if obtaining this goal necessitates the use of sulfonylureas and/or insulins,” Bell wrote.
For those with multiple comorbidities and/or a decreased life expectancy and who require insulin or sulfonylureas for glycemic control, Bell wrote that he advises a goal of as high as 8% for HbA1c.
David S. H. Bell
Inzucchi and colleagues call for a general HbA1c target of <7%. When focusing on individualization, Inzucchi and colleagues wrote that tighter targets (6%-6.5%) should be applied to younger, healthier patients, whereas “looser targets” (7.5%-8%) are appropriate for older patients with more comorbidities, and who are more likely to develop hypoglycemia.
The position statement suggests that highly motivated patients with HbA1c levels already near the target of <7.5% are to be given an opportunity to take on a lifestyle change for 3 to 6 months before beginning medications such as metformin.
Antihyperglycemic therapy and comorbidities
Largely, the position statement states that clinical judgment is needed in areas regarding weight and sex/ethnicity, besides age. Intensive lifestyle interventions have been known to improve glycemic control and CV risk factors, the researchers wrote. According to the position statement, most patients with type 2 diabetes are overweight or obese (80%).
“In these patients, intensive lifestyle intervention can improve fitness, glycemic control and cardiovascular risk factors for relatively small changes in body weight,” Inzucchi and colleagues wrote.
Regarding sex, racial, ethnic or genetic differences, Inzucchi and colleagues wrote that there is little data comparing strategies based on the drug’s effect on a patient’s underlying cause of hyperglycemia. However, there are exceptions. Bone loss, for example, a potential side effect of pioglitazone, may be a greater cause for concern among female patients.
Additional attention should be paid to patients with comorbidities regardless of age or weight, including those who also have coronary artery disease, heart failure (HF), kidney and/or liver disease, or hypoglycemia.
Inzucchi and colleagues wrote that preliminary reports have suggested that glucagon-like peptide 1 receptor agonists and DPP-IV inhibitors are associated with improved CV risk or risk factors in patients with CAD or high risk for developing CAD. However, long-term studies are not yet available for this patient population.
Additionally, the researchers recommend that thiazolidinediones be avoided in HF patients.
“Metformin, previously contraindicated in heart failure, can now be used if the ventricular dysfunction is not severe, if patient’s cardiovascular status is stable, and if renal function is normal,” Inzucchi and colleagues wrote.
For patients with chronic kidney disease, Inzucchi and colleagues wrote that pioglitazone (Actos, Takeda) is not eliminated renally, but fluid retention still remains a concern. Most agents should be administered with caution in this patient population.
When it comes to treating patients with advanced liver disease, insulin may be the best option.
“Sulfonylureas can rarely cause abnormalities in liver tests but are not specifically contraindicated; meglitinides can also be used. If hepatic disease is severe, secretagogues should be avoided because of the increased risk of hypoglycemia,” they wrote.
Antihyperglycemic therapy and age
Adults aged 65 to 70 years often have a higher atherosclerotic disease burden, reduced renal function and more comorbidities, according to experts. For this reason, Inzucchi told Endocrine Today that the primary goal of treatment in this group is safe glucose lowering, avoiding hypoglycemia and avoiding as many side effects from medications as possible.
For younger adults, Inzucchi said there is a different protocol approach.
“For the younger individual, the person with fewer comorbidities, or the patient who doesn’t have any complications yet, those individuals should be brought down as close to normal as possible. You’re looking at several decades of future life, with plenty of time for the deleterious effects of hyperglycemia to take hold,” Inzucchi said. “If you don’t control the blood sugar, then you’re going to paying for it in later years and the effects of the glucose in an individual may be hard to quantify. But across populations, they’re quite significant.”
Currently, oral agents, insulin and non-insulin injectables are the therapeutic options available for antihyperglycemic therapy. Knowing the mechanisms, advantages and disadvantages of each of these can enhance patient-centered care, the researchers wrote.
“Those with moderate hyperglycemia or in whom lifestyle changes are anticipated to be unsuccessful should be promptly started on an antihyperglycemic agent (also usually metformin) at diagnosis, which can later be modified or possibly discontinued if lifestyle changes are successful,” Inzucchi and colleagues wrote.
If an adequate HbA1c target is not met after roughly 3 months, the researchers suggest a sulfonylurea, TZD (mainly, pioglitazone), DPP-IV inhibitor, GLP-1 receptor agonist or basal insulin.
Adverse effects and economic effects are often to blame for poor adherence. Gastrointestinal adverse effects can be tolerated by many, but for others, fluid retention may pose a clinical or aesthetic problem, the researchers wrote. Among postmenopausal women, there is concern for the potential risk for bone fractures.
“It must be acknowledged that costs are a critical issue driving the selection of glucose-lowering agents in many environments. For resource-limited settings, less expensive agents should be chosen,” Inzucchi and colleagues wrote.
Impact of position statement
Helena Rodbard, MD, FACP, MACE, an endocrinologist at Metabolic Consultants, LLC, in Rockville, Md., told Endocrine Today that the position statement was a vast improvement over the last algorithm, but that it failed in terms of guidance.
“They talked about individualization, but when they talk about the drugs; some of them had higher costs, some had more side effects. But, they did not give enough guidance for primary care physicians to look at the position statement as a cookbook approach. It was rather complex,” said Rodbard, who has written four letters regarding the ADA/EASD position statement. “It’s not specific by any means, and it needs to be adjusted to the individual.”
Helena Rodbard
Conversely, Peters said although many are slow to accept the position statement, she hopes it will be more widely understood.
“In my talking to clinicians, I’ve learned that at first they don’t like our position statement because we’re not prescriptive enough. But, they generally understand that if you individualize patient care and you use the concept of patient-centered care, then you cannot be prescriptive by definition because you’re allowing so much choice,” Peters said. “As I talk about the position statement and how I apply the recommendations, clinicians seem to like them. They are able to incorporate the concepts, particularly about the individualization of targets; and I just hope it becomes more widely done.”
Meanwhile, in the clinical residency program at the Wesley Family Medicine Center in Wichita, Kan., program director Paul Callaway, MD, Clinical Professor at the University of Kansas-Wichita said the position statement has made its way into his curriculum; using the chart found in the supplemental data of the document as a guide for residents.
“It’s something that the residents can come back and refer to even as they’re preparing their thoughts to discuss with the supervising physician. The thing that I try to emphasize in my teaching with medical students and residents is that diabetes never takes a day off — for the patient with diabetes it’s always there,” Callaway said. “The context of patient-centered care has been embraced by family medicine, internal medicine and pediatrics. Meeting the patient at their present level of understanding and engagement in self-care sets the stage for improved chronic disease management.”
Paul Callaway
Callaway said he frequently lectures on diabetes, with an interest in the long-term safety and durability of glucose lowering agents, as well as protection of the beta cell. The practicing primary care physician is thinking, “Can my patient afford it? Will they stay on it and are the side effects going to make compliance manageable?”
“For people that live in the diabetes literature, this position statement has an opportunity for immediate impact. For the primary care community, however, it will take a little longer for the position statement to filter into everyday practice,” Callaway said.
Although individualization is heavily suggested through the position statement, further research is warranted to determine clinical outcomes that will add evidence-based data to this approach. – by Samantha Costa
For more information:
- Bell DS. South Med J. 2010;103:854-855.
- Cefalu WT. Diabetes Care. 2012;35:1201-1203.
- Holman RR. N Engl J Med. 2008;359:1577-1589.
- Inzucchi SE. Diabetes Care. 2012;35:1364-1379.
- Nathan DM. Diabetes Care. 2009;32:193-203.
- Riddle MC. Diabetes Care. 2012;35:2100-2107.
- Rodbard HW. Diabetes Care. 2012;35:e70.
For more information:
- David S. H. Bell, MD, can be reached at Southside Endocrinology, 3928, Montclair Road, Mountain Brook, AL 35213; email: dshbell@yahoo.com.
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Andrew J.M. Boulton, MD, DSc(Hon), FRCP, can be reached at Manchester Royal Infirmary, Division of Medicine, Oxford Road, Manchester M13 9WL, United Kingdom; email: aboulton@med.miami.edu.
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Paul A. Callaway, MD, FAAFP, can be reached at the Wesley Family Medicine Center – E. 850 N. Hillside, Wichita, KS 67214; email: paul.callaway@wesleymc.com.
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Silvio E. Inzucchi, MD, can be reached at Endocrinology - Yale University School of Medicine, 333 Cedar St. (Fitkin 106), New Haven, CT 06510; email: silvio.inzucchi@yale.edu.
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Anne L. Peters, MD, CDE, can be reached at USC Westside Center for Diabetes, 150 N. Robertson Blvd., Suite #210, Beverly Hills, CA 90211; email: momofmax@mac.com.
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Helena Rodbard, MD, FACP, MACE, can be reached at Endocrine and Metabolic Consultants, 3200 Tower Oaks Blvd., Rockville, MD 20852; email: hrodbard@comcast.net.
Disclosures:
- Bell is a consultant for AstraZeneca, Bristol-Myers Squibb, Takeda and Santarus. He is also a speaker for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly & Co, Novo Nordisk, Takeda and Santarus. Callaway has served as a reviewer for Janssen Pharmaceuticals. Inzucchi reports advisory/consultancy fees from Boehringer Ingelheim, Merck and Takeda, and research funding or supplies to Yale University by Eli Lilly and Takeda. He also reports participation in medical educational projects for which unrestricted funding from Amylin, Boehringer Ingelheim, Eli Lilly, Merck, Novo Nordisk and Takeda was received by Yale University. Peters reports receiving lecture fees and/or fees for ad hoc consulting from Amylin, Boehringer Ingelheim, Lilly, Novo Nordisk, Sanofi and Takeda. Rodbard reports financial ties with Amylin, AstraZeneca, Biodel, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly & Co, Merck & Co, Novartis, Novo Nordisk, Roche Diagnostics, Sanofi and Valeritas.
Perspective
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Derek LeRoith, MD, PhD
The ADA and the EASD have produced a new position statement on management of hyperglycemia in patients with type 2 diabetes. This erudite position statement is meant to be more "patient-centered" than previous position or consensus algorithms produced by the ADA/EASD and AACE.
In general, treatment algorithms are meant to aid the health care professionals in their management decisions, but often become too cumbersome and complicated.
This publication is based on recent data from large trials including UKPDS, ACCORD, ADOPT and others, and posits that newly diagnosed patients with limited cardiovascular disease should be managed fairly intensively, whereas after years of diabetes, with some evidence of underlying CVD, management should be more judicious.
Furthermore, while previous algorithms from the ADA did not include the use of all available agents, this new position statement is more inclusive. And while it is universally accepted that all patients start therapy with lifestyle modifications and early use of metformin, the add-on therapy is left to the practicing health care professional who needs to understand the patients’ needs. These include socio-economics, degree of overweight/obesity, avoidance of hypoglycemia and other potential complications.
I believe this recent publication has us moving in the right direction.
Perspective
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Zachary T. Bloomgarden, MD, MACE
The ADA position statement is a thoughtful document which addresses a variety of aspects of the treatment of type 2 diabetes in a careful fashion.
I certainly agree with the idea of individualized care. The ADA statement has, however, put forward this idea in a fashion giving patients and physicians seven dimensions that can be used in deciding that an individual can be offered a lesser degree of glycemic control.
Those patients who are less motivated; those who have limited support systems; those experiencing adverse effects of treatment (in particular, hypoglycemia, but certainly many others); those with longer duration of diabetes; with shorter life expectancy; with additional illnesses; and with vascular disease … All would be considered reasons to reduce the intensiveness of glucose-lowering.
To my mind, enumerating all these seemingly reasonable caveats leads to a dilemma: put together in this fashion, this position statement could lead one to decide that there is no goal; that all is arbitrary and that one can treat a given person as intensively or loosely as one desires.
Going forward, we should endeavor to establish a more clearly defined goal (or set of goals) of treatment. While HbA1c levels of 6.5% or of less than 7% may be unrealistic for certain patients, being so flexible as to have no goal is equally undesirable.
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