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Addition of Neutral Protamine Lispro Insulin or Insulin Glargine to Oral Type 2 Diabetes Regimens for Patients with Suboptimal Glycemic Control: A Randomized Trial

Katherine Esposito, MD, PhD; Miryam Ciotola, MD; Maria Ida Maiorino, MD; Roberto Gualdiero, MD; Bruno Schisano, PhD; Antonio Ceriello, MD; Flora Beneduce, MD; Giovanni Feola, MD; and Dario Giugliano, MD, PhD
[+] Article and Author Information

ClinicalTrials.gov registration number: NCT00641407.


From the Second University of Naples and Azienda Sanitaria Locale Napoli 5, Naples, Italy, and Warwick Medical School, Coventry, United Kingdom.


Grant Support: In part by the Second University of Naples.

Potential Financial Conflicts of Interest: None disclosed.

Reproducible Research Statement:Study protocol and data set: Not available. Statistical code: Available from Dr. Giugliano (e-mail, dario.giugliano@unina2.it).

Requests for Single Reprints: Dario Giugliano, MD, PhD, Division of Metabolic Diseases, Policlinico Seconda Università di Napoli, Piazza L. Miraglia, 80031 Naples, Italy; e-mail, dario.giugliano@unina2.it.

Current Author Addresses: Drs. Esposito, Ciotola, Maiorini, Gualdiero, Schisano, Feola, and Giugliano: Department of Geriatrics and Metabolic Diseases, Second University of Naples, Piazza L. Miraglia, 2, 80031 Naples, Italy.

Dr. Ceriello: Warwick Medical School, Clinical Science Research Institute, Clinical Science Building, University Hospital, Walsgrave Campus, Clifford Bridge Road, Coventry CV2 2DX, United Kingdom.

Dr. Beneduce: Division of Internal Medicine, ASLNA5, Vico Equense/Sorrento, Naples, Italy.

Author Contributions: Conception and design: K. Esposito, M. Ciotola, A. Ceriello, D. Giugliano.

Analysis and interpretation of the data: K. Esposito, R. Gualdiero, F. Beneduce, G. Feola, D. Giugliano.

Drafting of the article: K. Esposito, D. Giugliano.

Critical revision of the article for important intellectual content: K. Esposito, M. Ciotola, M.I. Maiorino, B. Schisano, A. Ceriello, D. Giugliano.

Final approval of the article: K. Esposito, M. Ciotola, M.I. Maiorino, R. Gualdiero, B. Schisano, A. Ceriello, F. Beneduce, G. Feola, D. Giugliano.

Provision of study materials or patients: K. Esposito, D. Giugliano.

Statistical expertise: K. Esposito, D. Giugliano.

Obtaining of funding: K. Esposito, D. Giugliano.

Administrative, technical, or logistic support: K. Esposito, G. Feola, D. Giugliano.

Collection and assembly of data: K. Esposito, M. Ciotola, M.I. Maiorino, R. Gualdiero, B. Schisano, F. Beneduce, D. Giugliano.


Ann Intern Med. 2008;149(8):531-539. doi:10.7326/0003-4819-149-8-200810210-00005
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Background: Injection of long-acting insulin at bedtime is a common therapeutic approach for patients with type 2 diabetes that is poorly controlled with oral regimens. Neutral protamine lispro (NPL) insulin has demonstrated better glycemic control and similar incidence of hypoglycemic events than that of neutral protamine Hagedorn insulin.

Objective: To compare the clinical efficacy and safety of bedtime NPL insulin or insulin glargine in patients with type 2 diabetes who had suboptimal glycemic control while receiving stable doses of metformin and sulfonylurea.

Design: Open-label, randomized trial.

Setting: Teaching hospital (Azienda Ospedaliera Universitaria, Second University of Naples), Naples, Italy.

Patients: 116 adults receiving stable doses of metformin plus sulfonylurea for longer than 90 days with hemoglobin A1c (HbA1c) levels of 7.5% to 10% and fasting plasma glucose levels of 6.7 mmol/L or greater (≥120 mg/dL).

Intervention: 10 IU of NPL insulin or insulin glargine injected subcutaneously at bedtime with weekly dose titrations to target fasting glucose levels less than 5.6 mmol/L (<100 mg/dL) in addition to stable oral regimens. Patients receiving nighttime sulfonylurea before the study were switched to metformin.

Measurements: The primary outcome was change in HbA1c levels from baseline to week 36. Secondary outcomes were HbA1c levels less than 7%, self-reported hypoglycemic episodes, insulin dose, self-monitored glucose level, and body weight. Twenty patients in each group had continuous glucose monitoring for 3 consecutive days before adding insulin and at week 36.

Results: Improvement in HbA1c levels was similar in both groups (1.83% and 1.89% for NPL and glargine, respectively). The difference between the groups was 0.06 percentage point (95% CI, −0.1 to 0.15 percentage points). Secondary outcomes did not differ between groups. Hemoglobin A1c levels less than 7% occurred in 62% of patients receiving NPL and 64% of patients receiving glargine (difference, 2.0 percentage points [CI, −1.1 to 5.0 percentage points]). Fasting plasma glucose levels less than 5.6 mmol/L (<100 mg/dL) occurred in 40% of patients receiving NPL and 41% of patients receiving glargine (difference, 1.0 percentage point [CI, −0.9 to 3.0 percentage points]). Any hypoglycemic event occurred in 74% of patients receiving NPL and 67% of patients receiving glargine (difference, 7 percentage points [CI, −5 to 13 percentage points]). Continuous glucose level monitoring in the patients who had this measurement did not differ statistically.

Limitation: The study was not blinded, had limited power to detect differences in hypoglycemic events, and did not obtain continuous glucose level monitoring for all patients.

Conclusion: Similar glycemic control occurred with the addition of NPL or glargine insulin to oral regimens in patients with poorly controlled type 2 diabetes. Hypoglycemia was similar in the 2 groups, but sample size limited the ability to make a definite safety assessment.

Figures

Grahic Jump Location
Figure 1.
Study flow diagram.

NPL = neutral protamine lispro.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Fasting plasma glucose and hemoglobin A1c levels at baseline and during the 36-week treatment period.

Vertical bars indicate SEs. NPL = neutral protamine lispro.

Grahic Jump Location
Grahic Jump Location
Figure 3.
Diurnal blood glucose profiles.

Diurnal blood glucose profiles were measured at baseline and before the last visit (36 weeks). Vertical bars indicate SEs. NPL = neutral protamine lispro.

Grahic Jump Location
Grahic Jump Location
Figure 4.
Continuous glucose monitoring in a subset of patients (20 in each group).

NPL = neutral protamine lispro.

Grahic Jump Location

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Summary for Patients

Comparison of Two Types of Insulin Added to Diabetes Pills in Poorly Controlled Type 2 Diabetes

The summary below is from the full report titled “Addition of Neutral Protamine Lispro Insulin or Insulin Glargine to Oral Type 2 Diabetes Regimens for Patients with Suboptimal Glycemic Control. A Randomized Trial.” It is in the 21 October 2008 issue of Annals of Internal Medicine (volume 149, pages 531-539). The authors are K. Esposito, M. Ciotola, M.I. Maiorino, R. Gualdiero, B. Schisano, A. Ceriello, F. Beneduce, G. Feola, and D. Giugliano.

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