Call for Better Management of Diabetes in Youth

Written by Kathleen Doheny

Presentations by Phil Zeitler, MD, PhD, and Carla Greenbaum, MD

Management of youth with diabetes, both type 1 and 2, needs to improve greatly, was the consensus of an expert panel at the American Diabetes Association 77th Annual Scientific Sessions, in a session, New Therapies for Diabetes in Youth—What the Future May Bring.1

Beyond Metformin: For Youth with Type 2

''I think the key issue here is we are not adequately managing this problem now in a large number of patients," Phil Zeitler, MD, PhD, section head of endocrinology and professor of pediatrics-endocrinology at Children's Hospital Colorado told EndocrineWeb, "We need to be thinking very creatively and aggressively about how we approach these patients, addressing each aspect of glucose metabolism as well as their cardiovascular risk."

Youth onset T2D is rare, Dr. Zeitler reminded attendees. The U.S. incidence is about 5,000 cases a year, and the prevalence is about 35,000 cases with more girls than boys receiving a diagnosis.2 Type 2 diabetes is closely linked with obesity, a rapid B-cell loss, and high rates of monotherapy failure.3 The onset of comorbidities is rapid, he said.

In type 2, Dr. Zeitler said, ''what matters is if you are adequately compensating for the degree of resistance." Over the years, treatment options have expanded greatly—from animal insulin in the 1920s to multiple choices today.

What Works in the Array of Choices for Type 2 Diabetes?

Dr. Zeitler reviewed the benefits and disadvantages of various T2D therapy choices and their effects not only on glycemic control but for reducing the risk of comorbidities. These patients have a long life ahead provided blood glucose and comorbidity risks are managed well, he said.

Thiazolidinediones—These lower Hemoglobin (Hb) A1c by 1 or 2%, but there is no evidence for cardiovascular risk reduction; and they are linked with weight gain, which is a serious detraction.

GLP-1 agonists—Can lower HbA1c by 1% and are linked with weight loss, but have limited evidence for reducing cardiovascular risk.

DPP-4 inhibitors—These can lower HbA1c by 0.4 to 0.8%, and are ''weight neutral.'' Hypoglycemia is not an issue but some questions remain about hepatic dysfunction with vildagliptin and alogliptin. No evidence exists for cardiovascular risk reduction.

SGLT-2 inhibitors—These lower HbA1c by 0.5 to 0.7%, and reduce systolic blood pressure by 1.3 to 7.3 mmHg. Weight loss averages 2-3 kg, with no hypoglycemia. Empagliflozin had documented efficacy in reducing cardiovascular risk.

On the Unclear List—Five agents have no known role for youth-onset T2D:

Why So Few Options to Treat Youth with T2D?

While insulin and metformin are FDA-approved for use in children, the other treatments are not. There are a number of factors including few research centers experienced in managing youth-onset T2D and the rarity of it, said Dr. Zeitler.

Yet, there is a glimmer of hope, he said. “As of September 2015, 11 clinical safety and efficacy trials and 3 pharmacokinetic studies have been ongoing,” examining agents including DPP-4 inhibitors, GLP-1 analogs, SGLT2 inhibitors, insulins, and colesevelam.

“Teens with T2D have a rapid, progressive b-cell loss,” Dr. Zeitler said, “and that loss is a primary predictor of failure to maintain glycemic control.” HbA1c over 6.3% after metformin is initiated is a predictor of monotherapy failure,3,4 he said.

When Metformin Isn’t Enough—Initiate the Right Combination Therapy Early

“The next step is add-on therapy to get patients to target,” said Dr. Zeitler. “If a patient is metformin intolerant and has severe resistance, choose TZD therapy; If there is obesity, select a GLP-1 agonist, and when the youth is obese and has hypertension, prescribe an SGLT2 inhibitor.”

What is crucial, he said, is early initiation of combination therapy for glycemic control, as well as careful thought about managing secondary factors and comorbidities, such as hypertension, microalbuminuria, and dyslipidemia.

“More attention is needed to formalize an approach to aggressive treatment that will account for lowering the risk of cardiovascular disease in youth,1,3 he said.

Treating Type 1 as the AutoImmune Disease It Is

''As endocrinologists, we are pretty complacent about this disease," says Carla Greenbaum, MD, director of the Diabetes Research Program at the Benaroya Research Institute, Virginia Mason, Seattle. She spoke on T1D in youth and the challenges clinicians face in managing this population.1

"For 95 years we have been treated diabetes with insulin," she says. "We have not moved on from insulin." It's time, said Dr. Greenbaum,"When you look at the data [about diabetes control in this population], it's terrible.''

It simply should not be this way, she told EndocrineWeb. "It's very important for clinicians to recognize that we now can identify youth who will develop T1D," she said since we know that they have two or more antibodies that will inevitably develop into diabetes.''

"The question becomes—How would we treat it? We want to use disease-modifying therapy'' and since T1D is an autoimmune disease, immunotherapy is needed, Dr. Greenbaum said.

Greater Need for Attention to Risks for Early Diagnosis

When two or more islet cell autoantibodies are detected, yet the person has no symptoms or sign of hyperglycemia, then that is the time to intervene, she said. She is chair of TrialNet, which has screening sites throughout North America.

Her TrialNet Abatacept Prevention Studys enrolling individuals 6 years of age and older who have two autoantibodies and normal glucose tolerance in an investigational drug trial for abatacept [CTLA4], which is currently FDA-approved for rheumatoid arthritis and polyarticular juvenile idiopathic arthritis.4

Endocrinologists should also discuss risk with the family members of children and teens with T1D, she said. "You should tell people that if they have a family member [with T1D], their risk is 15 times greater for developing the disease themselves.''

Another good practice is to refer children at risk for diabetes to a clinical trial, if possible, she said.

ADA Scientific Statement on Staging Presymptomatic T1D

Managing T2D in teenagers can come with many different challenges than for adults, according to the American Diabetes Association (ADA). On its website, it offers a 32-page booklet, Information for Youth and Their Families Living with Type 2 Diabetes, available for free downloading by practitioners or their patients.5

In 2015, the ADA, in collaboration with the JDRF and the Endocrine Society, published a scientific statement on staging presymptomatic T1D,6 of which Dr. Greenbaum was a co-author.  It acknowledges that type 1 diabetes is a continuum ''that progresses sequentially, at variable, but predictable rates through distinct identifiable stages prior to the onset of symptoms." Stage 1 is defined as the presence of b-cell autoimmunity, the presence of two or more islet autoantibodies although the patient is normoglycemic and without symptoms.

Dr. Zeitler reported serving as a research design consultant for Daiichi Sankyo, Merck, Takeda Pharmaceuticals, Janssen, Boehringer-Ingelheim and Eli Lilly. Dr. Greenbaum disclosed no conflict of interest.

Sources

  1. Zeitler P,  Greenbaum C.  New Therapies for Diabetes in Youth—What the Future May Bring. Presented at: the American Diabetes Association 77th Scientific Sessions, June 9-13, 2017, in San Diego, California.
  2. Nadeau, K.J. et al. "Youth-Onset Type 2 Diabetes Consensus Report: Current Status, Challenges, and Priorities." Diabetes Care. 2016;39(9):1635-1642.
  3. Zeitler P, Hirst K, Copeland KC, et al. HbA1c After a Short Period of Monotherapy With Metformin Identifies Durable Glycemic Control Among Adolescents With Type 2 Diabetes. Diabetes Care. 2015;38(12):2285-2292.
  4. Benaroya Research Institute. Trialnet Abatacept Prevention Study. https://www.benaroyaresearch.org/our-research/diabetes-clinical-research/find-study/trialnet-pathway/trialnet-abatacept  Accessed June 15, 2017.
  5. American Diabetes Association: Information for Youth and Their Families Living With Type 2 Diabetes. http://www.diabetes.org/living-with-diabetes/parents-and-kids/childen-and-type-2/. Accessed June 15, 2017.
  6. Insel RA, Dunne JL, Atkinson MA, et al. Staging presymptomatic type 1 diabetes: a scientific statement from the JDRF, the Endocrine Society, and the American Diabetes Association. Diabetes Care. 2015;38(10):1964-74.