Randomized Controlled Study of Metformin and Sitagliptin on Long-term Normoglycemia Remission in African American Patients With Hyperglycemic Crises

Abstract

OBJECTIVEAfter intensive insulin treatment, many obese African American patients with new-onset diabetic ketoacidosis (DKA) and severe hyperglycemia are able to achieve near-normoglycemia remission. The optimal treatment to prevent hyperglycemic relapses after remission is not known.RESEARCH DESIGN AND METHODSThis prospective, 4-year, placebo-controlled study randomly assigned 48 African American subjects with DKA and severe hyperglycemia to metformin 1,000 mg daily (n = 17), sitagliptin 100 mg daily (n = 16), or placebo (n = 15) after normoglycemia remission. Hyperglycemic relapse was defined as fasting glucose >130 mg/dL (7.2 mmol/L) and HbA1c >7.0% (53 mmol/mol). Oral glucose tolerance tests were conducted at randomization and at 3 months and then every 6 months for a median of 331 days. Oral minimal model and incremental area under the curve for insulin (AUCi) were used to calculate insulin sensitivity (Si) and β-cell function, respectively. Disposition index (DI) was calculated as a product of Si and incremental AUCi.RESULTSRelapse-free survival was higher in sitagliptin and metformin (P = 0.015) compared with placebo, and mean time to relapse was significantly prolonged in the metformin and sitagliptin groups compared with the placebo group (480 vs. 305 days, P = 0.004). The probability of relapse was significantly lower for metformin (hazard ratio 0.28 [95% CI 0.10–0.81]) and sitagliptin (0.31 [0.10–0.98]) than for placebo. Subjects who remained in remission had a higher DI (P = 0.02) and incremental AUCi (P < 0.001) than those with hyperglycemia relapse without significant changes in Si.CONCLUSIONSThis study shows that near-normoglycemia remission was similarly prolonged by treatment with sitagliptin and metformin. The prolongation of remission was due to improvement in β-cell function.

Diabetic Ketoacidosis: A Common Debut of Diabetes Among African Americans With Type 2 Diabetes

“…With intensive insulin treatment, ketosis-resistant patients also achieve near-normoglycemia remission from insulin (11,12,27). Our group along with McFarlane et al showed that similar remission from insulin occurs in obese AA patients who present with severe hyperglycemia (glucose levels >400 mg/dL) without the presence of ketoacidosis (11,12,21,26). …”

“…We and others have shown that treatment with sulfonylureas can prolong the period of near-normoglycemia remission (25,41). More recently, we also showed that treatment with metformin or sitagliptin is equally efficacious in prolonging near-normoglycemia remission (21). We studied 48 AA patients who presented with severe hyperglycemia and DKA and randomized the patients who achieved remission from insulin to metformin, sitagliptin, or placebo.…”

“…Unlike patients with type 1 diabetes, most patients with KPDM have physical signs consistent with type 2 diabetes such as acanthosis nigricans, obesity, and abdominal adiposity (12). Further, almost 80% of patients with KPDM have a strong family history of type 2, and there is a higher prevalence in males compared to females (17,21). KPDM has been well described in Blacks (11,12,15,22) but has also been shown to affect other populations at high risk for type 2 diabetes such as Chinese, Japanese, Hispanic, and South Asian populations (7,22–24).…”

“…After acute treatment, patients with KPDM are insulin resistant, frequently requiring an initial subcutaneous starting insulin dose of 0.8 to 1.2 units/kg/day (12). Unlike the insulin dependence seen in type 1 diabetes after a few weeks (usually 2 to 12 weeks), insulin requirements decrease, and approximately 70% of patients who present with obese DKA achieve near-normoglycemia remission (21) and are able to remain off insulin therapy (Table 2). The definition of near-normoglycemia remission varies, but near-normoglycemia remission is defined by our group as glycated hemoglobin A1c (HbA1c) < 7% and the ability to maintain fasting blood glucose <130 mg/dL off subcutaneous insulin therapy for at least 1 week (12).…”

“…These patients who are ketosis resistant have a similar clinical course as patients who present with DKA. At presentation, these patients who present with severe hyperglycemia also require similar amounts of insulin as patients who present with DKA (21). With intensive insulin treatment, ketosis-resistant patients also achieve near-normoglycemia remission from insulin (11,12,27).…”