Optimal Therapy to Prolong Normoglycemia Remission Proposed

Researchers found that Sitagliptin and Metformin therapy may prevent hyperglycemic relapses in obese African Americans

Diabetic ketoacidosis (DKA), a serious but preventable complications of diabetes, continues to affect ethnic populations disproportionately,1 calling for improved treatment options.

While intensive insulin treatment can achieve near normoglycemia in a majority of African American patients with obesity and new onset, unprovoked DKA, an optimal regimen for maintaining remission has now been identified. Findings published in Diabetes Care show that monotherapy with either metformin or the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin prolonged the time to hyperglycemic relapse to an average 480 days from 305 days by improving β-cell function.2

“We know that obese African American patients who present with new onset DKA and severe hyperglycemia achieve remission after short-term insulin treatment and can often have normal blood glucose levels without any therapy,” said lead author Priyathama Vellanki, MD, assistant professor in the Division of Endocrinology, Metabolism and Lipids at Emory University School of Medicine in Atlanta, Georgia. “However, many of them will eventually lose their β-cell function.”

Unprovoked DKA in the absence of type 1 diabetes mellitus (DM1) is primarily caused by defects in insulin secretion and sensitivity, and intensive insulin treatment results in a recovery of β-cell function and near-normoglycemia remission in the majority of patients. Since hyperglycemia eventually recurs in many patients who are treated with diet alone, and sulfonylureas increased the risk of hypoglycemia, the researchers sought to determine the optimal treatment for African Americans with both obesity and DKA to prolong the period of normoglycemic remission.

“This study makes it clear that it is not necessarily a given that those patients who present with severe hyperglycemia and DKA need to stay on insulin,” noted Caroline Apovian, MD, a professor of medicine and pediatrics at Boston University School of Medicine in Boston, Massachusetts, who was not involved in the study but commented as a member of the EndocrineWeb editorial board.

Clinical Applicability

This study is the first randomized placebo-controlled longitudinal study to examine the efficacy of metformin and sitagliptin aimed to prolong normoglycemia in obese African American patients suffering from DKA and severe hyperglycemia.2 However, further work remains, and Dr. Vellanki noted, “We do not know if continued therapy with either agent will keep patients in near-normoglycemia remission in the longer term, and we also need to know if this prevents complications in the future.”

Other concerns for future study were highlighted by Dr. Apovian including determining if the effects of these drugs are similar in other patient populations, and whether weight loss might enhance the effect of metformin and sitagliptin in this population for remission of hyperglycemia.

“The results were achieved without a decrease in weight,” Dr. Apovian told EndocrineWeb. “That you can prolong remission of hyperglycemia with metformin and sitagliptin without changes in diet and weight is surprising.”2

Study Details

This study examined the efficacy of two drugs used to manage type 2 diabetes, metformin and sitagliptin, to extend near-normoglycemia remission in patients with DKA.2 Metformin decreases glucose release by the liver and increases insulin sensitivity, and sitagliptin, like other DPP-4 inhibitors, increases circulating insulin levels and inhibits the release of glucagon from the pancreas.

This prospective, randomized study included African American patients between the ages of 18 and 65 years who were overweight or obese (BMI ≥28 kg/m2) and presented with new-onset, unprovoked DKA. A total of 48 participants achieved near-normoglycemia remission after discontinuing insulin for 1 week and were randomized to receive metformin 1,000 mg daily, sitagliptin 100 mg daily, or placebo.

Patients were then evaluated every 4 weeks for 3 months, and then every 3 months for 27 months or until they experienced hyperglycemia relapse, defined as a fasting blood glucose level >130 mg/dL, a random blood glucose level >180 mg/dL for 2 consecutive days, or an HbA1C ≥7%. Study participants also received diet counseling and were encouraged to exercise during each follow-up visit.

The mean time to hyperglycemia relapse was 480 days in the combined metformin and sitagliptin groups vs. 305 days in the placebo group (P = .004). Hyperglycemia relapse-free survival was higher in both treatment groups than placebo (P = .015), and patients randomized to receive either drug were about 70% less likely to have a hyperglycemia relapse than those receiving placebo. The authors report no significant difference in hyperglycemia relapse-free survival between the groups receiving metformin or sitagliptin.

The study authors reported that measures of disposition index (DI) and incremental area under the curve for insulin (AUCi) were significantly higher in study participants who remained in remission than those who experienced hyperglycemia relapse (DI, P = .02; AUCi, P <.001). These differences were not present in the study population at randomization, indicating that the extension of near-normoglycemia remission was due to improved β-cell function in patients who remained in remission compared to those who relapsed. 

Continue Reading:
Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial
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