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

Esposito, Katherine; Ciotola, Miryam; Maiorino, Maria Ida; Gualdiero, Roberto; Schisano, Bruno; Ceriello, Antonio; Beneduce, F.; Feola, Giovanni; Giugliano, Dario

doi:10.7326/0003-4819-149-8-200810210-00005

Cited by 46 publications

(52 citation statements)

References 33 publications

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“…For both insulin treatment groups, postprandial excursions were similar at baseline and endpoint, indicating continued efficacy of exenatide BID. In studies where basal insulin was added to OAMs (without exenatide BID), T2D patients showed distinctly different SMPG profiles with greater post-breakfast and post-dinner glycaemic excursions 3,15,30–32. Endpoint FPG values were substantially above target levels for both treatment group; however, FPG values were within the range observed in previous treat-to-target studies (5.6–7.4 mmol/l) 3,15,30–32.…”

Section: Discussionmentioning

confidence: 99%

Comparison of insulin lispro protamine suspension versus insulin glargine once daily added to oral antihyperglycaemic medications and exenatide in type 2 diabetes: a prospective randomized open‐label trial

Arakaki

Blevins

Wise

et al. 2013

Diabetes Obesity Metabolism

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AimsTo compare efficacy and safety of two, once-daily basal insulin formulations [insulin lispro protamine suspension (ILPS) vs. insulin glargine (glargine)] added to oral antihyperglycaemic medications (OAMs) and exenatide BID in suboptimally controlled type 2 diabetes (T2D) patients.MethodsThis 24-week, open-label, multicentre trial randomized patients to bedtime ILPS (n = 171) or glargine (n = 168). Non-inferiority of ILPS versus glargine was assessed by comparing the upper limit of 95% confidence intervals (CIs) for change in haemoglobin A1c (HbA1c) from baseline to week 24 (adjusted for baseline HbA1c) with non-inferiority margin 0.4%.ResultsNon-inferiority of ILPS versus glargine was demonstrated: least-squares mean between-treatment difference (ILPS minus glargine) (95% CI) was 0.22% (0.06, 0.38). Mean HbA1c reduction was less for ILPS- versus glargine-treated patients (−1.16 ± 0.84 vs. −1.40 ± 0.97%, p = 0.008). Endpoint HbA1c < 7.0% was achieved by 53.7% (ILPS) and 61.7% (glargine) (p = NS). Overall hypoglycaemia rates (p = NS) and severe hypoglycaemia incidence (p = NS) were similar. Nocturnal hypoglycaemia rate was higher in patients treated with ILPS versus glargine (p = 0.004). Weight gain was similar between groups (ILPS: 0.27 ± 3.38 kg; glargine: 0.66 ± 3.93 kg, p = NS). Endpoint total insulin doses were lower in patients treated with ILPS versus glargine (0.30 ± 0.17 vs. 0.37 ± 0.17 IU/kg/day, p < 0.001).ConclusionsILPS was non-inferior to glargine for HbA1c change over 24 weeks, but was associated with less HbA1c reduction and more nocturnal hypoglycaemia. Treat-to-target basal insulin therapy improves glycaemic control and is associated with minimal weight gain when added to OAMs and exenatide BID for suboptimally controlled T2D.

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Section: Discussionmentioning

confidence: 99%

Comparison of insulin lispro protamine suspension versus insulin glargine once daily added to oral antihyperglycaemic medications and exenatide in type 2 diabetes: a prospective randomized open‐label trial

Arakaki

Blevins

Wise

et al. 2013

Diabetes Obesity Metabolism

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“…Diamant et al10 defined it as an episode between bedtime and breakfast. Esposito et al11 defined it as an episode between bedtime and being awake in the morning. Raskin et al12 defined nocturnal hypoglycemia as an episode between 11 pm and 8 am.…”

Section: Resultsmentioning

confidence: 99%

Hypoglycemia: a review of definitions used in clinical trials evaluating antihyperglycemic drugs for diabetes

Balijepalli¹,

Druyts²,

Siliman³

et al. 2017

CLEP

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ObjectiveTo understand the severity and potential impact of heterogeneity in definitions of hypoglycemia used in diabetes research, we aimed to review the hypoglycemia definitions adopted in randomized controlled trials (RCTs).MethodsWe reviewed 109 RCTs included in the Canadian Agency for Drugs and Technologies in Health reports for the second- and third-line therapy for the patients with type 2 diabetes (T2D).ResultsNearly 60% (n=66) of the studies reviewed presented the definitions for overall hypoglycemia, and another 20% (n=22) of the studies reported the results for hypoglycemia but did not report a definition. Among these 66 studies, only 9 (14%) followed the American Diabetes Association/European Medicines Agency specified guidelines to define hypoglycemia, with an exact threshold of plasma glucose ≤3.9 mmol/L. Fifty-two of the 66 studies (79%) used a threshold considerably lower than the recommended ≤3.9 mmol/L, and 16 studies used a threshold between 3.8 and 4.0 mmol/L. The proportion of the trials that used a cutoff value of <3.1 mmol/L appeared to be slightly similar among the more commonly used non-insulin treatments, GLP-1s (7 of 18 [39%]), thiazolidinediones (TZDs; 6 of 11 [55%]), DPP-4s (12 of 19 [64%]), and sulfonylureas (11 of 20 [55%]). Among trials with intermediate-long-acting insulins (neutral protamine Hagedorn insulin, detemir, glargine), 7 of 26 trials (27%) used a cutoff of <3.1 mmol/L. The definition of severe hypoglycemia was also subject to substantial heterogeneity, in both the utilized threshold and accompanying soft definitions.ConclusionThis review demonstrates that substantial heterogeneity exists in the definition of overall, severe/major, and nocturnal hypoglycemia across RCTs investigating T2D interventions.

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“…A previous study in patients starting on once-daily insulin showed a mean insulin glargine dose of 57 +/− 15 units [24]. A meaningful decrease would be a difference of at least 14 units.…”

Section: Methodsmentioning

confidence: 99%

Patients with Type 2 Diabetes Mellitus failing on oral agents and starting once daily insulin regimen; a small randomized study investigating effects of adding vildagliptin

et al. 2014

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BackgroundThe addition of a DDP4-inhibitor to existing insulin therapy reduces HbA1c. However, no data exist about the addition of these agents at the beginning of insulin treatment in type 2 diabetes while this could especially be interesting because it is during this period that considerable residual beta cell function is still present. The benefit of such a strategy could be a lower insulin dose required for glycemic control. The hypothesis of our study was that adding a DPP4-inhibitor at the beginning of insulin treatment could lead to less exogenous insulin requirement, a reduction of hyperinsulinemia and side effects (hypoglycemia and weight gain), less glucose variability and improvement of insulin and glucagon dynamics during a mixed meal test.ResultsIn this small clinical trial (trial registration NTR2022) 9 patients were randomized to receive vildagliptin and 6 to receive placebo in addition to start of once daily insulin treatment. Unfortunately, due to a difficult inclusion, the preset sample size of 40 patients could not be met. Median units of insulin at the end of the study was 47 U in the placebo group and 34 U in the vildagliptin group. Median glycemic variability (SD) at the end of study was 2.1 in the placebo group and 1.5 in the vildagliptin group. Median weight gain at the end of study was 3 kg in the placebo and 0.5 kg in the vildagliptin group. Occurrence of hypoglycemia was low in both groups. Insulin, C-peptide, glucose and glucagon levels were comparable during mixed meal tests.ConclusionsThis small randomized study did not have sufficient power to detect effects of the addition of vildagliptin to the start of once daily long-acting insulin. However in our opinion adding a DPP4-inhibitor, especially in this group remains a very interesting approach. This study could be used as a guidance for larger studies that are required to investigate the effects of this intervention on insulin requirements, glycemic variability, hypoglycemia and weight gain.Electronic supplementary materialThe online version of this article (doi:10.1186/1756-0500-7-579) contains supplementary material, which is available to authorized users.

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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

Abstract: 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.

Cited by 46 publications

References 33 publications

Comparison of insulin lispro protamine suspension versus insulin glargine once daily added to oral antihyperglycaemic medications and exenatide in type 2 diabetes: a prospective randomized open‐label trial

Comparison of insulin lispro protamine suspension versus insulin glargine once daily added to oral antihyperglycaemic medications and exenatide in type 2 diabetes: a prospective randomized open‐label trial

Hypoglycemia: a review of definitions used in clinical trials evaluating antihyperglycemic drugs for diabetes

Patients with Type 2 Diabetes Mellitus failing on oral agents and starting once daily insulin regimen; a small randomized study investigating effects of adding vildagliptin

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