As obesity rate rises, ‘double diabetes’ looms large
An October report from the CDC’s National Center for Health Statistics revealed a startling increase in the prevalence of obesity in the U.S., with rates now approaching 20% in children and 40% in adults for 2015-2016.
The growing epidemic has not spared those with type 1 diabetes. Today, obesity prevalence is as high or higher among patients with type 1 diabetes as in the general population. According to 2015 data from the T1D Exchange Clinic Registry, nearly 40% of children and adolescents with the disease also have overweight or obesity, putting them at increased risk for insulin resistance, hypertension and dyslipidemia — all the hallmarks of not type 1, but type 2 diabetes.
“You see these patients with type 1 diabetes, who clearly had a strong family history of type 2 diabetes, and you kind of felt they had both,” Francine Kaufman, MD, a former president of the American Diabetes Association and chief medical officer and vice president of global medical, clinical and health affairs for Medtronic Diabetes, told Endocrine Today. “There are different genes and environmental triggers for each. It would be the same as saying someone has type 1 diabetes and asthma, or diabetes and another disorder. ... ‘Double diabetes,’ perhaps, characterizes it best.”
Historically, patients with type 1 diabetes were lean, unlike their counterparts with type 2 diabetes, which often presents in the setting of overweight or obesity, according to Osama Hamdy, MD, PhD, FACE, medical director of the Obesity Clinical Program at Joslin Diabetes Center and associate professor of medicine at Harvard Medical School.
“What had been the view in type 1 for years is that these patients are lean, they are not insulin resistant and so on,” Hamdy told Endocrine Today. “The reality over the last 10 to 15 years is that the whole dynamic has changed.”
Today, a clinician is likely to have a patient with type 1 diabetes with a host of type 2-related comorbidities, bringing unique risks and requiring more careful management.
“In clinic, what we see are patients who have classic type 1 diabetes — onset in the teens or earlier — who struggle with their weight,” Richard E. Pratley, MD, senior investigator at the Translational Research Institute for Metabolism and Diabetes at Florida Hospital, Orlando, told Endocrine Today. “Their insulin requirements are much higher than somebody who doesn’t have obesity. Control is, oftentimes, worse. They can have issues related to food, in ways that many people who have obesity do. You have subclinical eating disorders. ... Our challenge is trying to balance good glycemic control with healthy weight management.”
Pratley, who called the nomenclature of double diabetes “a little misleading,” said the problem is growing, whereas any evidence on how to tackle it is lacking.
“What we call it is probably important, but it’s not the driving thing,” Pratley said. “The driving thing is to realize that there are these issues that result in medical consequences, and we need to treat the causative factors.”
‘Creating the perfect storm’
The causes behind the steady uptick in overweight and obesity in type 1 diabetes are multifactorial, including an increasingly sedentary lifestyle and the easy availability of highly palatable, unhealthy foods and sugar-sweetened beverages. But one contributor, Hamdy said, is partly a byproduct of innovations in managing type 1 diabetes.
“With new technology and more sophistication in the younger generation, people are optimizing their insulin therapy more than ever,” Hamdy said. “People with type 1 diabetes have many tools: They have continuous glucose monitoring, they have insulin pumps, so they are not injecting insulin two to four times a day like in the old days. They can inject five, 10, even 15 times per day, correcting for every high glucose level.”
Exogenous insulin comes with drawbacks, Hamdy said. It does not perfectly mimic endogenous insulin and has a more enhanced effect on inhibiting protein catabolism, stimulating lipogenesis and slowing basal metabolism, while also acting on insulin-like growth factor I receptors to stimulate growth. Because patients with type 1 diabetes are insulin deficient, these effects of exogenous insulin are magnified, Hamdy said, particularly as clinicians and patients focus on intensive insulin therapy.
“If you put that individual in an environment where they say, ‘I can eat whatever I want and I will just cover for it with additional insulin,’ you are basically creating the perfect storm,” Hamdy said. “More carbohydrates, more fat, bigger portions, more insulin, and that’s where we are.”
Arriving at a diagnosis
Pediatric patients showing traits of type 2 diabetes were once a rare curiosity, according to Kaufman, a former head of the division of endocrinology and metabolism at Children’s Hospital Los Angeles. But by the mid-1990s, she said, about 20% of newly diagnosed patients “looked like type 2.”
As a principal investigator for the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, Kaufman examined such patients more closely, including screening them for GAD-65 and insulinoma-associated protein 2 autoantibodies strongly associated with type 1 diabetes, and discovered something surprising.
Of the 1,206 patients screened and considered clinically to have type 2 diabetes, 118 (9.8%) were antibody positive; of these, 71 (5.9%) were positive for a single antibody, and 47 (3.9%) were positive for both antibodies.
“The antibody-positive group is significantly different from the antibody-negative group, with fewer clinical and laboratory findings characteristic of type 2 diabetes and more findings similar to those found in type 1 diabetes (even though participation was limited to overweight or obese individuals),” Kaufman and colleagues wrote in Diabetes Care. “However, one cannot reliably distinguish, phenotypically, between individual participants with positive GAD-65 or IA-2 antibodies and those without antibodies.”
The findings, Kaufman said, left researchers wondering how to treat these patients.
“They clinically looked like type 2, but some of them had multiple antibodies and a different profile than the average type 2, with less C-peptide, a need for more insulin, and lots of overall elements of insulin resistance, like hypertension or dyslipidemia,” Kaufman said. “We all questioned: Should they be on metformin?”
The findings underline an important point, according to Yehuda Handelsman, MD, FACP, FNLA, MACE, medical director and principal investigator of the Metabolic Institute of America in Tarzana, California. Although many patients with type 1 diabetes may develop obesity and type 2 traits, some patients present with type 2 traits and may, in fact, be misdiagnosed.
“In many centers in the U.S., when [physicians] see a child with overweight and diabetes, they often diagnose as type 2 diabetes and treat with medications accordingly,” Handelsman told Endocrine Today. “However, those kids could also have type 1, and often it is missed. Sometimes they even test for an antibody and if the antibody doesn’t show, they confirm type 2, which may or may not be true, exposing such a kid to a future calamity.”
Handelsman said clinicians must not make a “reverse misdiagnosis,” assuming an adolescent with obesity, high triglycerides and low HDL cholesterol, for example, must have type 2 diabetes because of the presentation.
“It is my recommendation that every kid diagnosed with diabetes should have a comprehensive profile of antibodies to see whether they have type 1 diabetes before they diagnose such kids with type 2,” Handelsman said. “We ought to prevent diagnosis errors in kids who may be overweight or obese, but actually have type 1 diabetes.”
For young patients with type 1 diabetes, having overweight or obesity potentially has serious metabolic consequences, particularly during adolescence.
In a study from Children’s Hospital of Pittsburgh of UPMC, Ingrid M. Libman, MD, PhD, associate professor in the division of pediatric endocrinology and diabetes, and colleagues reported that children with overweight or obesity already had higher systolic blood pressure and lower HDL cholesterol, both risk factors for cardiovascular disease, 3 months after diabetes onset. Moreover, in an analysis of 11,348 youths with type 1 diabetes enrolled in the T1D Exchange between September 2010 and August 2012, Libman and colleagues found that youths with type 1 diabetes and obesity were at least three times more likely to have hypertension and twice as likely to have dyslipidemia as youths with type 1 diabetes who maintained a healthy weight.
“We know that if you have type 1 diabetes by itself, the risk for cardiovascular disease is higher than the general population, but, for the most part, you don’t see that in the child,” Libman told Endocrine Today. “If you add obesity at this young age, you are seeing some more risk factors than you would see in a child with type 1 diabetes alone. Even at the onset of diabetes, when diagnosed with type 1, if you’re overweight, you have higher systolic blood pressure and lower HDL cholesterol, which are risk factors for CVD.”
Many nutrition-based approaches for weight loss have been studied in individuals both with and without diabetes, but few studies are specific to patients with type 1 diabetes, Hamdy and colleagues wrote in an analysis published in Current Diabetes Reports. Although several studies suggest sustained weight loss with Mediterranean, vegetarian or low-carbohydrate diets, for example, the ADA has determined there is no ideal macronutrient component for meal plans, and current recommendations state that patients with diabetes should work with nutritionists to develop individualized eating plans.
Hamdy has been implementing two ideas in his “Why WAIT” program at Joslin to help patients with type 1 diabetes and obesity control their body weight, he said. One is to inject short-acting insulin immediately after a meal, rather than before. This way, he said, patients are feeding themselves, and not “feeding the insulin they injected.”
“I said, why not inject based on what you ate, not on what you are assuming you would eat, since you may not eat it all?” Hamdy said. “With the ultra-short-acting insulin, it works very well. They are not under pressure to eat that whole big meal; they inject exactly what they need.
“The newly approved ultra-fast insulin aspart plus niacinamide (vitamin B3) [Fiasp, Novo Nordisk] may make this technique much easier since it is approved to be injected after meals,” Hamdy said. “Currently, I’m using insulin glulisine [Apidra, Sanofi-Aventis], which is slightly faster than aspart [NovoLog/NovoRapid, Novo Nordisk] and lispro [Humalog, Lilly] insulins.”
In another method — what Hamdy calls “reverse calculation” —patients plan how much insulin they will inject and count carbohydrates for that amount of insulin.
“You say, ‘Today, I will only inject 10 units, instead of the usual 15 units, to limit insulin-induced weight gain, but I will eat what is matching the 10 units,’” Hamdy said. “I am planning my carbs based on the amount of insulin I would like to inject rather than planning the insulin dose based on the carbs. If they eat more, they still can inject more, but I found this is a trick to use with short-acting insulin to prevent weight gain or induce weight loss, and it has been working well.”
Pratley said more research must also be done with pharmacologic agents.
“There are lot of opportunities to continue to work with pharmacologic treatments, which is something we don’t normally employ in patients with type 1 diabetes, in part because those people are excluded from all of our trials,” Pratley said. “But, we really should be learning how to use the drugs better.
“We’ve got zero evidence,” Pratley said. “And I think that’s one of the barriers.”
Currently, insulin is the only pharmacologic treatment approved for type 1 diabetes in children. For adults with type 1 diabetes, insulin and the injectable amylin analogue pramlintide (Symlin, AstraZeneca) are the only FDA-approved agents, although more clinicians are turning to metformin, commonly prescribed for type 2 diabetes, and anti-obesity medications for weight loss. The use of SGLT-2 inhibitors, DPP-IV inhibitors or GLP-1 receptor agonists, approved for adults with type 2 diabetes, are not indicated for type 1 diabetes.
“For people who have type 1 diabetes, we have limited options,” Handelsman said. “But, when I see a patient with type 1 diabetes developing traits of insulin resistance of type 2 and the insulin requirements are going up, I will consider treating that patient with metformin. I might consider a thiazolidinedione, recognizing that we need to balance the side effects with insulin, like fluid overload.”
In a large clinical study published in JAMA, Libman and colleagues found that 6 months of adjunctive metformin therapy did not improve glycemic outcomes in adolescents with overweight and type 1 diabetes. However, it showed some beneficial effect on measures of obesity, including weight and BMI.
Increasingly, more interest has been shown in using off-label agents for type 1 diabetes. In an analysis of the use of adjuvant pharmacotherapy in type 1 diabetes published in Diabetes Care, using data from the T1D Exchange in the U.S. and the Prospective Diabetes Follow-up (DPV) registry in Germany and Austria, researchers found that metformin was the most commonly reported noninsulin medication used in both registries (3.5% and 1.3%, respectively). For T1D Exchange, metformin was followed by the use of GLP-1 receptor agonists (0.91%), SGLT2 inhibitors (0.63%) and DPP-IV inhibitors (0.04%). The use of any adjuvant medication was associated with older age, higher BMI and longer diabetes duration in both registries.
“I’m still bothered why metformin isn’t recommended for those with overweight or obesity with type 1 diabetes,” Hamdy said. “Metformin, in clinical practice, is valuable for overweight and obesity with type 1. It makes them more sensitive to their insulin, and their requirement for insulin goes down.”
Researchers have begun studying the safety and efficacy of SGLT2 inhibitors in type 1 diabetes. In the DEPICT-1 study presented at the European Association for the Study of Diabetes (EASD) annual meeting in September, researchers analyzed data from 833 adults with poorly controlled type 1 diabetes randomly assigned to dapagliflozin (Farxiga, AstraZeneca) 5 mg, 10 mg or placebo for 24 weeks. At week 24, both doses of dapagliflozin significantly reduced HbA1c compared with placebo.
In the Tandem3 study, also presented this fall at EASD, researchers evaluated data from 1,402 adults with type 1 diabetes receiving treatment with any insulin therapy who were randomly assigned to sotagliflozin, a dual SGLT1 and SGLT2 inhibitor, or placebo for 24 weeks. Researchers found that more patients in the sotagliflozin group achieved an HbA1c of 7% or less vs. placebo (29.6% vs. 15.8%) and experienced a greater reduction in body weight (difference, –2.98 kg); however, more patients in the sotagliflozin group also experienced diabetic ketoacidosis compared with placebo (3% vs. 0.6%).
“There is no guideline on how to do it, and I’m not telling people go off-label,” Handelsman said. “But, if I have a 53-year-old man with type 1 for 28 years, and he now has a BMI of 34 kg/m² and has changes in lipids and high blood pressure and the insulin dose is very high, I think I can say you have both conditions, and I can manage with drugs for both conditions.”
Addressing all barriers
With limited options approved for patients with type 1 diabetes and obesity, providers must go back to basics in new ways, Libman said, using strategies like increased patient engagement and expanding the care team.
“I know this sounds simplistic, but we have to look at shared decision making, involving the family and the patient and the health care team in making decisions together,” Libman said.
“Sometimes we tend to be glucocentric and are not thinking about the patient overall,” Libman said. “We should be using a team approach. We should have certified diabetes educators, dietitians, psychologists and social workers as part of our team.”
Providers should also strive to be advocates in their communities for making healthier choices easier, Kaufman said.
“It’s critically important as a pediatrician to advocate for good nutrition in schools and neighborhoods, to make the healthier choices the more accessible choices,” Kaufman said. “In the world we live in right now, it’s exactly the opposite.” – by Regina Schaffer
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- Hales CM, et al. NCHS Data Brief. 2017;288:1-8.
- Libman IM, et al. JAMA. 2015;doi:10.1001/jama.2015.16174.
- Libman IM, et al. JCEM. 2015;doi:10.1210/jc.2014-2340.
- Lyons SK, et al. Diabetes Care. 2017;doi:10.2337/dc17-0403.
- Mottalib A, et al. Curr Diab Rep. 2017;doi:10.1007/s11892-017-0918-8.
- Redondo MJ, et al. Acta Diabetol. 2016;doi:10.1007/s00592-015-0785-1.
- T1D Exchange. U.S. Youth with Type 1 Diabetes Overweight, but Obesity Epidemic Also Affecting European Youth. Available at: https://t1dexchange.org/pages/u-s-youth-with-type-1-diabetes- overweight-but-obesity-epidemic-also-affecting-european-youth/. Accessed Oct. 20, 2017.
- For more information:
- Osama Hamdy, MD, PhD, FACE, can be reached at Joslin Diabetes Center, One Joslin Place, Boston, MA 02215; email: email@example.com.
- Yehuda Handelsman, MD, FACP, FNLA, FACE, can be reached at Metabolic Institute of America, 18372 Clark St. #212, Tarzana, CA 91356; email: firstname.lastname@example.org.
- Francine Kaufman, MD, can be reached at Medtronic Diabetes, 18000 Devonshire St., Northridge, CA 91325; email: email@example.com.
- Ingrid Libman, MD, PhD, can be reached at Children’s Hospital of Pittsburgh of UPMC, Division of Pediatric Endocrinology and Diabetes, 4401 Penn Ave., Pittsburgh, PA 15224; email: firstname.lastname@example.org.
- Richard Pratley, MD, can be reached at the Translational Institute for Metabolism and Diabetes at Florida Hospital, 301 Princeton Ave., Orlando, FL 32804; email: email@example.com.
Disclosures: Hamdy reports he has received research grant support from Abbott Nutrition, Intarcia, the National Dairy Council, Novo Nordisk and Metagenics; personal fees from AstraZeneca and Merck; and is a shareholder for Healthimation LLC. Handelsman reports he has received research grants, consulting and speakers’ fees or honoraria from Aegerion, Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, BI-Lilly, Bristol-Myers Squibb, Eisai, Gan & Lee, Grifols, Hanmi, Intarcia, Janssen, Lexicon, Lilly, Merck, Novo Nordisk, Regeneron and Sanofi. Kaufman is chief medical officer and vice president of global medical, clinical and health affairs for Medtronic Diabetes. Libman reports she has received a grant from JDRF and a grant to her institution from Novo Nordisk. Pratley reports he has received research support, consulting and speakers’ fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Hanmi Pharmaceuticals, Janssen, Lexicon, Ligand, Merck, Novo Nordisk, Sanofi and Takeda.