98 People with type 1 diabetes (previously called juvenile diabetes) are 4.29 times more likely to develop bladder cancer, according to a systematic review and meta-analysis by researchers at the Keck School of Medicine of USC. The new analysis is the first to control for the effects of tobacco smoking, a factor that likely obscured the heightened risk in earlier studies. The findings were published in the journal Diabetes Research and Clinical Practice. Bladder cancer is a relatively common disease, affecting about 2% of the US population. Cigarette smoking accounts for about half of all bladder cancer in the US and Europe, but the causes of the remaining cases are poorly understood. Recent data suggest that type 2 diabetes may play a role, but years of epidemiological studies found no link between type 1 diabetes and bladder cancer. A new analysis explains why a possible link may have been overlooked. Because smoking is a strong contributor to bladder cancer, studies that aim to identify other risk factors must control for — or separate — the influence of smoking from the influence of any other proposed causes. No previous studies on type 1 diabetes and cancer had done so. “Of nine original studies and one meta-analysis published before ours, none had adequately controlled for smoking. When we evaluated the vulnerabilities of these studies and addressed them, we found a very clear pattern indicating substantially elevated risk for bladder cancer in people with type 1 diabetes,” said Victoria K. Cortessis, PhD, a clinical professor of population and public health sciences at the Keck School of Medicine and the study’s senior author. The new findings offer important clues about the causes of bladder cancer and may guide decision making by patients with type 1 diabetes and their healthcare providers. For example, avoiding or quitting smoking may be especially important for this group, Cortessis said. For years, studies that tracked people with type 1 diabetes found no increased risk of bladder cancer — and a closer look reveals why. Most datasets on type 1 diabetes originated from studies that followed patients diagnosed with the condition over time. The initial purpose was to understand how type 1 diabetes affected patients by tracking events such as hospitalisations and early complications. Data on smoking, however, were either not collected or asked about only once and never updated. Years later, researchers used these same datasets to explore a different question: Does type 1 diabetes raise the risk of other diseases, such as bladder cancer, in adulthood? To investigate this, they compared disease rates among people with type 1 diabetes to rates in the general population. These analyses found no increased risk of bladder cancer. The problem was that smoking — a major contributor to bladder cancer — had not been accurately measured in either group. Without reliable data, it was impossible to determine how much of the observed bladder cancer risk was linked to smoking versus type 1 diabetes itself. The Keck School of Medicine team suspected that people with type 1 diabetes may smoke less than the general population. After managing a serious health condition early in life, these individuals may have been more health-conscious as adolescents and adults. If true, lower smoking rates could distort comparisons and mask any increased bladder cancer risk associated with type 1 diabetes. To investigate this, first author Helena Oskoui Bennett, MPH, a student at the Keck School when the research was conducted, gathered data from authoritative sources such as the World Health Organization to estimate smoking prevalence in populations where the original studies were carried out. Patterns identified using a technique called meta-regression supported the team’s hypothesis and helped explain why earlier analyses failed to detect a connection. After accounting for smoking patterns, the researchers estimated that people with type 1 diabetes were 4.29 times more likely to develop bladder cancer. The reason for the link between type 1 diabetes and bladder cancer is not yet clear, but researchers suspect that the disease may trigger biological changes that contribute to cancer development. For this reason, careful management of diabetes — including maintaining healthy blood sugar levels — could be important for reducing bladder cancer risk. These biological changes may also interact with the effects of smoking to increase risk further. “More work is needed to understand the mechanisms at play, but it’s possible that there is a biological synergy between diabetes and smoking that increases risk more than either factor alone,” Cortessis said. The study emerged from the team’s broader analysis of type 2 diabetes, another condition linked to bladder cancer. They are now reviewing nearly 100 studies on type 2 diabetes and its treatments to identify the factors driving the increased risk.