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New-onset diabetes was associated with a significantly higher risk of progression to pancreatic cancer in patients with low-risk pancreatic cysts, a researcher reported.

In a large database study and at 5 years, the adjusted cumulative progression rate to pancreatic cancer in patients with new-onset diabetes was 2.2% (95% CI 1.8-2.6), with linear progression over 7 years, according to Adam Schweber, MD, of NewYork-Presbyterian/Columbia University Medical Center in New York City.

The finding provides strong support for the inclusion of hemoglobin A1c (HbA1c), fasting glucose, and other markers of diabetes mellitus in cyst surveillance algorithms, he said in a presentation at the American College of Gastroenterology virtual meeting.

Schweber noted that the transformation of pancreatic cystic neoplasm to pancreatic cancer has been investigated in previous studies, but those were significantly limited by small sample sizes and selection bias, yielding highly variable progression results. Reliable identification of novel risk factors and biomarkers for malignant transformation such as metabolic status has therefore been difficult.

For the current study, the researchers sourced information on patients making claims for pancreatic cysts from 2008 to 2017 in the IBM MarketScan insurance claims database, which covers more than 180 million patients.

Patients were divided into three groups: no diabetes, previous diabetes, and new-onset diabetes. To ensure a focus on low-risk patients, those with a history of worrisome features or prior pancreatic pathology, such as jaundice or pancreatitis, were excluded, as were those who developed pancreatic cancer or had surgery within 6 months of diagnosis. Eligible patients were evaluated for at least 2 years following cyst diagnosis.

Kaplan-Meier analysis and Cox proportional hazard modeling assessed the risk of progression to pancreatic cancer, and the association of progression with metabolic status. Results were standardized by age and insurance coverage.

From the 137,970 patients with a diagnosis of pancreatic cyst, 14,279 low-risk patients fulfilled study criteria. New-onset diabetes patients were those who had a claim for diabetes in the evaluation period but not in a previous look-back period.

The cumulative risk of progression increased at a nearly linear rate over 7 years (R=0.979, P<0.001). Both a prior history of diabetes (HR 2.01, 95% CI 1.89-2.14) and new-onset diabetes following cyst diagnosis (HR 3.24, 95% CI 3.03-3.46) were associated with a greater risk of progression.

The 5-year adjusted progression rate for the three diabetes groups were :

• No diabetes: 1.5% (95% CI 1.1-1.9)
• Prior history of diabetes: 3.1% (95% CI 2.1-4.1)
• New-onset diabetes: 4.6% (95% CI 3.1-6.1)

While noting that this is the first large-scale, real-world study of the malignant progression of low-risk pancreatic cysts, Schweber cautioned that patients' diabetes status is not accurately reflected in claims data.

He added that although the findings require further validation, "given the ease and low cost of diabetes screening, we strongly support the inclusion of HbA1c and fasting glucose in algorithms for pancreatic cyst surveillance."

James Farrell, MBChB, of the Yale Center for Pancreatic Disease in New Haven, Connecticut, commented that the study was important for its use of large insurance claims data to identify the association.

"Although it has both all the strengths, such as large numbers, as well as the weaknesses of large database studies, it does appear to support the link and importance between sugar control and new-onset diabetes with pancreatic cancer risk including in patients with pancreatic cysts," said Farrell, who was not involved in the research. "It will require prospective validation [and] study of the value of incorporation of both glucose and HbA1c into routine pancreatic cyst surveillance programs."

Farrell added that while longstanding diabetes mellitus is a known risk factor for pancreatic cancer, new-onset diabetes -- particularly in middle age -- is an increasingly recognized significant risk factor for pancreatic malignancy. Current practice is to survey the vast majority of pancreatic cysts in an attempt to identify those that may undergo malignant transformation.

Diane Simeone, MD, of NYU Langone Health in New York City, said the concept that elevated HbA1c signals pancreatic malignancy "has been out there," and this study adds further support. Elevated HbA1c can be a consequence of malignancy, since malignancy elaborates neoplastic cells that can promote a diabetic state, especially in the context of weight loss, added Simeone, who was not involved in the study.

"The next key step is larger-scale longitudinal studies to see if elevated HbA1c, especially with reduced BMI, can be a preclinical marker of pancreatic cancer," she said.

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