Literature
From Pages to Practice
Published August 14, 2019
The surgeon Fredrick Banting and his assistant Charles Best purified insulin after conducting a series of pancreatic duct ligations and pancreatectomies on dogs in the 1920s at the University of Toronto. Their findings changed dramatically the prognosis of patients with type 1 diabetes who at the time had grim prognoses. Today, almost a century later, patients with type 1 diabetes are dependent on insulin for survival.
Type 1 diabetes is a chronic autoimmune condition thought to be caused by environmental factors that trigger autoimmune destruction of pancreatic beta cells in individuals who are at genetic risk. This destruction is a slow process, characterized by three stages of progressive insulin deficiency. Can we prevent progression to insulin deficiency in patients at high risk for the development of diabetes?
In a phase 2, randomized, double-blind, placebo-controlled trial, Herold and colleagues evaluated the efficacy of a 14-day course of teplizumab, an anti-CD3 monoclonal antibody that reduces the ability of CD8 T lymphocytes to kill beta cells, in preventing progression to diabetes in relatives of patients with type 1 diabetes. After a mean follow-up of 3 years, the median time to the diagnosis of type 1 diabetes was 48 months in the teplizumab group, compared with 24 months in the placebo group (hazard ratio, 0.41; 95% confidence interval, 0.22 to 0.78; P=0.006). Overall, 43% of teplizumab recipients progressed to diabetes, compared with 72% of placebo recipients.
Editorialists Clifford Rosen and Julie Ingelfinger note that although the onset of diabetes was delayed, “the results should not be taken to imply that immune modulation constitutes a potential curative approach.” Rather, further studies are required to identify the patients best suited for treatment.
The following NEJM Journal Watch summary explains the study and results in further detail:
Preventing Type 1 Diabetes with Teplizumab
Bruder Stapleton, MD reviewing Herold KC et al. N Engl J Med 2019 Jun 9 Rosen CJ and Ingelfinger JR. N Engl J Med 2019 Jun 9
Because type 1 diabetes mellitus (DM) is the result of immune destruction of pancreatic islet cells, immunologic interventions have shown promise in delaying its onset. In a phase II, international, randomized, placebo-controlled trial, researchers tested the efficacy of a 14-day regimen of intravenous teplizumab, an anti-CD3 antibody, for delaying the development of clinical DM in 76 at-risk participants. Most were children (ages 8–18; median age, 13–14 years) and white. All had a relative with DM, at least two DM-related autoantibodies, and recent abnormal glucose tolerance tests.
The median time to diagnosis of clinical DM was 48 months in the teplizumab group compared with 24 months in the placebo group (P=0.006). DM developed at an annual rate of 15% in the teplizumab cohort compared with 36% in the placebo group; the most profound between-group difference occurred in the first year — 7% vs. 44%, respectively. Having HLA-DR4 was associated with better response to teplizumab, as were absences of HLA-DR3 and antibodies to zinc transporter 8. Five times more adverse events were reported in the teplizumab group than in the placebo group (112 vs. 32); the most frequent adverse events among teplizumab recipients were transient lymphopenia (75%) and rash (36%).
Comment: Immune therapy can delay onset of clinical DM in those already in early stages of its natural history. While this is a significant advance, as editorialists state, it is not yet a cure. Yet these impressive results hold promise for the future.
Browse more From Pages to Practice »
