Post-pancreatitis diabetes mellitus ( PPDM) is a common consequence of chronic pancreatitis (CP). However, patients with PPDM are often misclassified as type 2 diabetics. However, clinically significant complications may be more frequent in PPDM, and insulin and metformin are prescribed more often, suggesting a more aggressive phenotype than in T2DM. Greater awareness of PPDM is needed to optimize disease management.
Chronic pancreatitis can severely impair quality of life and also result in life-threatening long-term consequences. CP is characterized by inflammation, progressive fibrotic destruction of glandular tissue, or obstruction of the excretory ducts, leading to irreversible impairment of both exocrine and endocrine functions. Long-term complications include abdominal pain, exocrine pancreatic insufficiency, malnutrition, low bone mineral density, pseudocysts, splanchnic vascular complications, diabetes mellitus, and pancreatic cancer. While diabetes is a common complication of CP, 5% to over 80% varies widely and is largely dependent on etiology, geographic location, and duration of follow-up.
To date, there are no standardized diagnostic criteria for diabetes secondary to pancreatitis. Recently, a PPDM definition has been proposed in an attempt to simplify the distinction from other types of diabetes (mainly type 1 and type 2 diabetes), which may help PPDM to be better recognized by physicians from different specialties who frequently deal with these patients. According to this concept, PPDM should be suspected in all adults with a history of pancreatitis who meet the American Diabetes Association (ADA) diagnostic criteria for diabetes. Confirmed type 1 or type 2 diabetes before the first episode of pancreatitis or exercise-induced hyperglycemia during (or within 3 months of) pancreatitis precludes a diagnosis of PPDM.
Patients with PPDM can develop potentially life-threatening acute complications due to “brittle diabetes,” in which glucose levels fluctuate rapidly from hyperglycemia to severe hypoglycemia after administration of exogenous insulin in the absence of a contra-regulatory hormone response. In addition, diabetic complications are thought to be more pronounced in PPDM than in type 2 diabetes, but because of the paucity of evidence, it is unclear whether these assumptions translate into clinically relevant adverse outcomes. This question was investigated by scientists led by Dr. Ana Dugic from the Karolinska Institutet in Stockholm in a retrospective analysis [1].
Cumulative incidence increases with years
The authors conducted a cohort study with retrospectively collected data from patients with definite CP treated at Karolinska University Hospital between January 1999 and December 2020. A cause-specific Cox regression analysis was performed to evaluate predictors of PPDM. The Fine-Gray subdistribution hazard model was used to estimate the risk of complications and the need for therapy, with death as a competing risk.
481 patients with CP were identified. At the time of CP diagnosis, 23% of patients had type 2 diabetes (n=109). 246 subjects did not have diabetes and 126 developed PPDM during the course of their disease, with the cumulative incidence of PPDM increasing over time: after 5 years, it was 5.1%; after 10 years, 13.2%; after 15 years, 27.5%; and after 20 years, 38.9% (Fig. 1). Compared with CP patients without diabetes, patients with PPDM were predominantly male (55% vs. 75%), more often had an alcoholic etiology (44% vs. 62%), and prior acute pancreatitis. The only independent predictor of PPDM was the presence of pancreatic calcifications (aHR=2.45; 95% CI 1.30-4.63). Patients with PPDM had higher rates of microangiopathy (aSHR=1.59; 95% CI 1.02-2.52) and infection (aSHR=4.53; 95% CI 2.60-9.09) compared with CP patients with type 2 diabetes (T2DM). The rate of insulin use was three times higher, while metformin was taken twice as often in the same comparison.
however, biguanides have been shown to have a survival benefit in PPDM patients. Because patients with chronic pancreatitis are at increased risk of developing pancreatic disease, the antineoplastic properties of metformin for PPDM patients may be of Interestingly, no association was found between prior episodes of acute pancreatitis and PPDM risk in CP patients, the authors write. This suggests that the mechanism underlying the twofold increased risk of diabetes in patients with acute pancreatitis (but without CP) described in population-based studies does not seem to apply to most CP patients. Therefore, it could be suggested that diabetes associated with acute pancreatitis is mediated by different mechanisms than those involved in the development of diabetes in patients with chronic disease.
Metformin with survival benefit
She said her study was the first to examine microvascular complications in PPDM and demonstrated an increased rate of clinically significant complications such as neuropathy, nephropathy, and retinopathy in patients with PPDM compared with CP patients with type 2 diabetes. In addition, when comparing the two groups, the infection rate was 4.5 times higher in PPDM and the insulin requirement was three times higher in PPDM patients compared to CP patients with type 2 diabetes. Overall, these data underscore a more aggressive disease phenotype in PPDM and the need for earlier initiation of therapy, according to Dr. Dugic et al. Biguanides are advised as the first choice of treatment, and continuous biguanide therapy has been recommended regardless of patients’ insulin requirements.
Patients with PPDM, often misclassified as T2DM, are frequently treated with insulin as monotherapy or switched directly to insulin after a brief trial of oral glucose lowering. Unlike insulin can be additional benefit.
Other antidiabetic agents, on the other hand, carry risks: Sulfonylureas pose a risk of hypoglycemia, and SGLT2 inhibitors pose a risk of diabetic ketoacidosis in patients with absolute insulin deficiency. A significant association with pancreatitis was found for DPP4 inhibitors-but this was not true for GLP1 receptor agonists. A correct and timely diagnosis of PPDM is therefore of great importance for the choice of antidiabetic therapy, the authors conclude.
Source:
- Dugic A, Hagström H, Dahlman I, et al: Post-pancreatitis diabetes mellitus is common in chronic pancreatitis and is associated with adverse outcomes. United European Gastroenterol Journal 2023; 11: 79-91; doi: 10.1002/ueg2.12344.
GASTROENTEROLOGY PRACTICE 2023; 1(1): 24-25
