ENDOCRINOLOGY
Making Associations
What will it take to give kids with type 2 diabetes a better outlook ?
In May of 2004 , a group of researchers kicked off the largest and most comprehensive study of the treatment of youth-onset type 2 diabetes ever undertaken : Treatment Options for Type 2 Diabetes in Adolescents and Youth ( TODAY ). Nearly 700 participants , ages 10 to 17 , underwent aggressive treatment with either metformin , a combination of metformin and rosiglitazone , or a combination of metformin and lifestyle medicine . The results , published in the New England Journal of Medicine in 2012 ( 1 ), were dismal .
Rates of failure , defined as a loss of glycemic control , topped 50 % with treatment by metformin alone . Participants who received lifestyle medicine in addition to metformin did slightly better , with a 46.6 % failure rate . The best combination was metformin and rosiglitazone , which still produced a failure rate of 38.6 % ( rosiglitazone was restricted by the FDA in 2010 after studies linked it to heart attacks ).
“ The most obvious takeaway was that these kids experienced a much higher rate of complications than their adult counterparts ,” says pediatric endocrinologist Phil Zeitler , MD , PhD , principal investigator of TODAY . “ We wanted a clearer picture of where these kids were headed .”
To get it , the multicenter TODAY team conducted TODAY2 , which extended treatment to 2014 and continued with observation-only follow-up through January 2020 . Those results , also published this summer in the New England Journal of Medicine ( 2 ), are equally alarming .
CLUSTER OF COMPLICATIONS
By TODAY2 ’ s end , 67.5 % of participants had developed hypertension . More than half had dyslipidemia , a stunning 54.8 % had diabetic kidney disease , 32.4 % had nerve disease and 51 % developed retinal disease , some in the advanced stages . More than 60 % had at least one complication , and 28.4 % had two or more .
“ We ’ d been following these kids for 15 years at that point , so we saw a lot of this coming ,” says Dr . Zeitler . “ But to see it all together in context , to look at the rate of appearance of complications , to see the clustering of the complications , that was disturbing . It ’ s not just that most of them have some complications . It ’ s that quite a few of them have a lot . And they ’ re young .”
Indeed , the mean age at completion of the study was 26 years old , and the health condition of some participants was incredibly grave – six had congestive heart failure . That ’ s anomalous for a pediatric population to say the least , but it ’ s also difficult to attribute definitively to diabetes , in large part because there ’ s no baseline established . TODAY2 establishes the baseline .
In many ways , the real work of parsing out the data is just beginning .
TEASING OUT THE ASSOCIATIONS
Diabetes wreaks havoc on the microvasculature in ways that are not entirely understood , but the effects produce a set of classic diabetes complications : retinopathy , neuropathy , nephropathy . TODAY2 collected data on all of them . The New England Journal paper defined diabetic nephropathy , for example , as elevated urine albumin-to-creatine ratio , or UACR . But that ’ s not the only way TODAY2 assessed it .
“ The kidneys lose some ability to filter blood as we age ,” says pediatric endocrinologist Petter Bjornstad , MD . “ About 1 ml / min / 1.73m 2 per year is the normal loss of glomerular filtration rate , or GFR . Three times that loss would be considered rapid GFR decline . So that ’ s another phenotype of diabetic kidney disease .”
With fourteen years of data on estimated GFR , Dr . Bjornstad and team could get a detailed picture of participants ’ kidney function , documenting hyperfiltration early in the course of illness , followed by a rapid decline in eGFR . The TODAY Study Group found that
6 | CHILDREN ’ S HOSPITAL COLORADO