Escalating obesity prevalence and severity has led to type 2 diabetes being diagnosed in ever-younger people, including children. medwireNews rounds up the accumulating evidence suggesting a particularly severe diabetes course in these young people.
The recent worldwide increases in obesity prevalence have resulted in people developing type 2 diabetes at continually younger ages; there are now even sufficient numbers of children with the condition to allow large pediatric intervention studies, such as TODAY and RISE.
But these children have more than just hyperglycemia. For example, analysis of the SEARCH for Diabetes in Youth registry shows that children with type 2 diabetes have multiple cardiovascular disease (CVD) risk factors or manifestations, such as arterial stiffness (in nearly half of the cohort), hypertension, and diabetic kidney disease [1]. Large waist circumference was present in nearly three-quarters of these children and this increased by more than 17 percentage points over a 10-year period [2]; this rising trend was also observed for cardiometabolic risk factors among participants of the TODAY study [3,4], despite them being part of a clinical trial.
Likewise, young adults with diabetes have multiple CVD risk factors and complications [5]. One large study showed these younger people were more often obese than those who were older at diagnosis and had a more unhealthy lipid profile (higher triglycerides and lower levels of high-density lipoprotein cholesterol) [6].
This study also showed a worse trajectory of glycemic control among people diagnosed before the age of 45 years; by 8 years after diagnosis glycated hemoglobin (HbA1c) levels were around 5 mmol/mol (0.45%) higher in this group than in people who were older at diagnosis. This is in line with other research findings that are beginning to shape the notion that the high burden of cardiometabolic risk in people diagnosed at a young age makes for a more aggressive phenotype of type 2 diabetes.
In a study from 2003, conducted in nearly 8000 adults with type 2 diabetes, around 20% had been diagnosed between the ages of 18 and 44 years and 18% of these required insulin therapy, compared with 11% of those who were older at diagnosis [7]. They also had significantly higher HbA1c at diagnosis, which improved less during follow-up, despite the higher rate of insulin use.
Although there have been no direct comparisons between adults and children with diabetes, the TODAY investigators found a 52% rate of metformin failure (ie, loss of glycemic control) over less than 4 years in their cohort of children and adolescents [8], which they noted is markedly higher than the metformin failure rate reported for adults – 21% over 5 years in the ADOPT study, for example [9].
The RISE study showed that even intensive treatment with insulin does not seem to slow the progression of diabetes in children [10], again contrary to findings in adults [11]. And it confirmed a pathophysiological basis for this disease progression, showing an inexorable decline in beta-cell function.
Knock-on effects
This severe trajectory leads, inevitably, to an increased rate of CVD. In the aforementioned 2003 study of almost 8000 adults, although absolute rates of macrovascular disease were higher in the older group, people who were younger than 45 years at diabetes diagnosis were eight times more likely to be affected than age- and sex-matched people without diabetes, whereas the risk increase was a markedly smaller fourfold for those who were older at diagnosis [7].
A more recent analysis, of the Health and Retirement Study, suggests that this rule of earlier onset equating to more serious disease also applies within the upper end of the lifespan. Indeed, the researchers reported that developing diabetes after the age of 70 years had no effect on people’s risk for CVD or any other measured outcome. Those aged 60–69 years, by contrast, had an increased risk for CVD if they were diagnosed with diabetes, and those in the 50–59 year age group had increased risk for CVD plus stroke, disability, and mortality.
Several studies have now looked specifically at the issue of mortality, finding, unsurprisingly given the associated poor cardiometabolic risk profile, that a young age at diabetes onset has life-shortening effects. An analysis of the Swedish National Diabetes Register showed a general excess mortality risk attributed to type 2 diabetes, but also found this to be modified by age (as well as uncontrolled HbA1c and nephropathy). Among people without these other two risk factors, those younger than 55 years had a markedly increased mortality risk, whereas for those aged 75 years or older, diabetes per se posed no additional risk [12].
Another study showed that the longer diabetes duration associated with early onset explained much of the increased mortality risk [13]. The researchers compared people who were the same chronological age but had 10-year differences in diabetes duration and found that the person with the longer duration (ie, younger age at diagnosis) had a significantly increased risk for both all-cause and CVD mortality.
Interestingly, the effect of diabetes duration was stronger with younger age at diagnosis, so that, for example, a longer diabetes duration had a larger impact on a person aged 50 years than on one aged 60 years.
The researchers said: “This may be because in younger people there are fewer additional risk factors, and so the impact of hyperglycaemia is greater than among older people, in whom a range of other risk factors is typically also present.”
Most recent at the time of writing was another analysis of the Swedish National Diabetes Register, looking at CVD and non-CVD mortality plus a range of other CVD outcomes, including heart failure and stroke [14]. This confirmed the significant and exaggerated risk associated with diagnosis at a young age (by 40 years old) and accounted for diabetes duration; the researchers attributed the poor outcomes to the particularly high cardiometabolic risk in people who develop diabetes at a young age.
“The profile of an individual developing diabetes, say, in his 30s or 40s, is quite different – vastly different almost – from someone developing diabetes in their 80s, who tends to be leaner or less evidently obese,” lead study author Naveed Sattar (University of Glasgow, UK) tells medwireNews.
He believes that the relative plasticity and good health of organs in young people means that “to develop diabetes at a younger age you have to have much more insulin resistance, much more fat gain, to overwhelm the pancreas’s ability to make insulin.”
This is quite different from, for example, a relatively lean 80-year-old in whom “the pancreas has now got so old that it just happens to trickle into diabetes,” he says, adding: “So it’s a different process and I don’t think people really understand that.”
None of these studies adjusted for cardiovascular risk factors such as BMI, glycemic control, and comorbidities. In a study based on UK National Diabetes Audit data, the investigators were able to adjust for such variables, which significantly attenuated the association between onset age (20–39 vs ≥60 years) and mortality risk, but did not entirely eliminate it. This study, however, did not include controls without diabetes.
Sattar notes that these studies “all look at face value that they’re answering the same question, but they’re not. They’re always trying to do it in slightly different ways, and they have different strengths and limitations.”
More than just cardiovascular risk?
Despite the good evidence that diabetes duration and cardiovascular risk underpin the aggressive type 2 diabetes phenotype seen in younger people, there is also evidence of other factors at play. Most straightforward is the notion that younger people with diabetes are less diligent about managing their condition than older people. As seen in data from the Australian National Diabetes Audit, younger people found it harder to follow dietary advice, to remember to take medications, and to regularly check their blood glucose, all factors that could contribute to poor glycemic control and rapid progression of diabetes and vascular risk [15].
Another potential contributor is genetic vulnerability. Genetic risk for type 2 diabetes is driven by small effects of multiple common variants, which could conceivably influence disease progression as well as its initial development [16,17]. Indeed, Sattar notes that the strongest genetic associations with type 2 diabetes are those linked to beta-cell function.
“There are clearly lots of people who have BMI of 35 who don’t have diabetes,” says Sattar. “The ability of your pancreas to respond is partly dictated by genetics – that dictates how well your beta cells will respond.”
Related to this is ethnicity, he says, with South Asian, Black, and Chinese people prone to developing diabetes at lower average BMIs and younger ages than White people. “That can’t be due just to total obesity, total excess fat,” says Sattar, “but maybe where the fat is.”
“But there’s probably other genetic factors that we simply just don’t have a grasp on at the moment. And we need a lot more research to understand why certain ethnicities get diabetes a lot faster.”
Regardless of the contributing factors, a young age at diabetes diagnosis clearly identifies a group of people in urgent need of intervention. In their publication, Sattar’s team pointed out that current CVD guidelines have a higher threshold for CVD medication use in younger people, and that consequently this age group receives less intensive preventive treatment [14].
Sattar accepts the need to avoid over-medicating people, but stresses that this less intensive approach “ignores the point that if someone develops diabetes at the age of 35 years for example they’ve got a higher lifetime risk and they’ve got more life–years to lose, so actually we might want to think about giving more people who develop diabetes in their 30s statins than we are currently.”
In addition to the well-established benefits of antihypertensive and antihyperlipidemic medications, two diabetes medication classes – glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors – have proven cardioprotective effects.
Sattar says: “I think we need to think about using drugs that promote weight loss and have cardiovascular benefit probably sooner rather than later, rather than going with the old metformin, insulin, sulfonylureas, that doesn’t make any sense anymore – not for these younger people.”
Another option, shown to be successful in people with a relatively recent diagnosis, is weight loss via a total meal replacement very-low-calorie diet, which the DiRECT trial showed could reverse diabetes in nearly half of the study participants, sustained at 2 years in more than a third [18].
DiRECT investigator Roy Taylor (University of Newcastle, UK) attributed this to the “very high percentage of people with type 2 diabetes who really hate their condition,” giving them the motivation stick to the diet and lose sufficient weight to achieve remission.
Sattar notes that the DiRECT participants were mostly in their 50s, and says: “When you go younger, under 40 certainly in White populations, my guess is you might have to lose 20 to 25 kilograms,” rather than the 15 kilogram target weight loss in DiRECT.
“Which is more difficult [but] I’m not saying it’s impossible, and even if you can get them to lose say 10 kilograms that might have a huge impact on the improvement in glycemic control for that individual, particularly if they can sustain that benefit, and it might have a huge impact on their lifetime risk.”
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