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ORIGINAL ARTICLE
Year : 2014  |  Volume : 1  |  Issue : 4  |  Page : 209-213

A comparative, randomized pilot study of insulin glargine versus insulin detemir as add-on therapy in uncontrolled type 2 diabetic patients


1 Department of Pharmacology, MGM Medical College, Aurangabad, Maharashtra, India
2 Consultant-Medical Communication Plasma Medical Services, Nerul, Navi Mumbai, India

Date of Submission30-Jun-2014
Date of Decision14-Oct-2014
Date of Acceptance04-Nov-2014
Date of Web Publication11-Dec-2014

Correspondence Address:
Deepak S Bhosle
Department of Pharmacology, MGM Medical College, Aurangabad, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2347-9906.146797

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  Abstract 

Objective: The aim was to compare the efficacy and safety of insulin glargine versus insulin detemir as add-on therapy in type 2 diabetes patients inadequately controlled on oral hypoglycemic agents. Materials and Methods: A total of 40 patients were randomized in two groups to receive either insulin glargine or insulin detemir in addition to their current medications. The dose of insulin was titrated to achieve glycosylated hemoglobin (HbA1c) targets of <7%. After randomization of patients, oral hypoglycemic medications were unchanged. Patients were followed for 24 weeks. The number of patients achieving target HbA1c (<7%), mean reduction in fasting and predinner blood glucose and number of hypoglycaemic events were observed in both the groups. Results: Significantly more number of patients in the glargine group (60%) achieved target HbA1c of <7% (p < 0.05) compared with detemir (25%) group. Mean reductions in the fasting and predinner blood glucose were similar in both the group (p > 0.05). Significantly less number of hypoglycemic episodes were observed in glargine group (14 versus 2). Conclusion: In uncontrolled type 2 diabetes patients, insulin glargine is better suited for achieving glycemic control compared with insulin detemir with less incidence of hypoglycemia.

Keywords: Detemir, glargine, type 2 diabetes mellitus


How to cite this article:
Bhosle DS, Bobde JA, Patil AD, Bhagat A, Shaikh A. A comparative, randomized pilot study of insulin glargine versus insulin detemir as add-on therapy in uncontrolled type 2 diabetic patients. J Obes Metab Res 2014;1:209-13

How to cite this URL:
Bhosle DS, Bobde JA, Patil AD, Bhagat A, Shaikh A. A comparative, randomized pilot study of insulin glargine versus insulin detemir as add-on therapy in uncontrolled type 2 diabetic patients. J Obes Metab Res [serial online] 2014 [cited 2020 Sep 21];1:209-13. Available from: http://www.jomrjournal.org/text.asp?2014/1/4/209/146797


  Introduction Top


Diabetes mellitus is a growing problem across the world including in India. The current prevalence of diabetes in India is 9.09%. India with 65.1 million people with diabetes ranks second in the world after China. [1] Glycemic control in type 2 diabetes mellitus (T2DM) becomes increasingly challenging with longer duration of disease. Progressive reduction in the functioning of β-cells and insulin resistance, with increase in hepatic glucose output due to glucagon dysregulation leads to increased fasting and postprandial glucose levels. Medical management of diabetes usually include step wise approach of adding oral antihyperglycemic drugs based on the targeted blood glucose level, followed by adding basal insulin and then prandial insulin. [2] This progression, despite use of therapeutic agents, is generally associated with persistently elevated glycosylated hemoglobin (HbA1c) levels and decreased chances of achieving glycemic targets with longer duration of diabetes. [2],[3],[4],[5],[6] Tight glycemic control is hence mandatory in diabetes care given proven beneficial effects on the risk of vascular complications. [7],[8] Insulin is an important component of care for achieving this target in patients with type 1 diabetes, and is also indicated in T2DM patients with suboptimal glycemic control despite aggressive treatment with oral antihyperglycemic drugs in addition to lifestyle changes. Chronically elevated blood glucose level in T2DM is associated with significant morbidity and mortality. Many T2DM patients will eventually require insulin treatment to maintain good glycemic control. There are still uncertainties about the optimal insulin treatment regimens for T2DM, but the long-acting insulin analogues are beneficial. Though the comparisons of insulin detemir or insulin glargine with neutral protamin hagedorn (NPH) insulin are available, direct comparison these two insulin analogs is limited. The long-acting insulin analogs like glargine (G) and detemir (D) show more physiological pharmacokinetics and pharmacodynamics compared with NPH insulin that is, they show a flatter action profile with a longer duration of action, [9],[10],[11],[12] as well as lower within-subject variability, [12] and lower fluctuations in serum levels. [13] However, these two analogues are structurally and chemically different entities. [10] Therefore they might have different pharmacokinetics. Porcellati et al. [14] have demonstrated that G differs from D in terms of the duration of action in type 1 diabetes. The objective of our study was to compare the effects of insulin detemir and insulin glargine as add-on treatment in the management of T2DM.


  Materials and methods Top


In this open label, single center, prospective, randomized comparative clinical study, adult patients >18 years of age and of either sex, with uncontrolled T2DM (HbA1c > 8%) on oral hypoglycemic agents and requiring initiation of a basal insulin were included. Patients with prior use of insulin except for gestational diabetes were excluded from the study. Pregnant women, lactating mothers, patients with current use of drugs affecting glycemic control like systemic corticosteroids, nonselective sympathetic blockers and weight loss drugs, patients with history of ketoacidosis and self-reported inability to recognize hypoglycemia were excluded from the study. Safety laboratory investigations (serum creatinine, blood urea, serum alanine aminotransferase or aspartate aminotransferase) and electrocardiogram (ECG) were done at baseline. Patients having serum alanine aminotransferase or aspartate aminotransferase more than two fold above the upper limit of normal were also not included in the study. The patients were screened after taking an informed consent. Out of total screened, fifteen patients were ineligible for inclusion in the study because they were either on insulin before enrolment in the study (except for acute rescue insulin therapy) or were prescribed premixed insulin at the start of study. The study protocol was approved by local ethics committee. The patients were randomized to receive either detemir (group A) or glargine (group B). The study drugs were administered subcutaneously at bedtime using disposable pen devices for 24 weeks. Starting dose of insulin was 10 IU and was titrated up to 20 IU according to daily self-monitored capillary fasting and predinner blood glucose measurements using Glucometer (Optium Xceed™, Abbott Laboratories). Oral hypoglycemic agents were continued as per prestudy dosages. The patients were evaluated at baseline, 12 and 24 week. The patients were asked to test blood glucose in case of hypoglycemia (blood glucose level ≤70 mg/ml) related symptoms. Fasting blood sugar (mg/dl), predinner sugar level (mg/dl) and HbA1c were tested at follow-up visits, that is, 12 and 24 weeks. All these tests were carried out using NGSP certified methods.

The primary outcome measure was percentage of patients achieving HbA1c <7% without symptomatic hypoglycemia (blood glucose levels ≤70 mg/dl). This level was chosen because lower levels can induce hypoglycemic unawareness. [15] Other measures included difference in the fasting blood glucose and predinner blood glucose between two groups. The signs and symptoms of hypoglycemia were explained to the patients. The patients were requested to report in case they develop symptoms such as hunger pain, tremor, weakness, palpitation or profuse sweating. The safety was assessed by recording the number of patients presenting with hypoglycemic symptoms/episodes. Safety laboratory investigations and ECG were repeated at the end of study. Patient compliance and accountability of use of oral hypoglycemic agents was checked during follow up and during telephonic discussion in case of hypoglycemic symptom reporting. Mann-Whitney U-test was used to compare the means between two groups. Statistical analysis was two tailed and p < 0.05 was considered to be significant. SPSS package version 11 was used for the analysis.


  Results Top


Out of 40 patients, 20 were randomized to receive detemir (group A) and 20 to glargine (group B). A total of 28 males and 12 females were included in the study. Mean duration of diabetes was 7.8 (±5.7) years. [Table 1] shows the mean age and baseline laboratory parameters in both the groups.

There was no significant difference in the age and baseline laboratory parameters, that is, HbA1c, baseline fasting blood glucose level and baseline predinner blood glucose between two groups (p > 0.05) [Table 1]. Significantly more number of patients in the glargine group achieved target HbA1c of <7% (p < 0.05) compared to detemir group [Figure 1].
Figure.1. Percentage of patients with glycosylated hemoglobin <7%

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Table 1: Baseline parameters


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At 12 weeks, difference between HbA1c, fasting blood glucose and predinner blood glucose was not significantly different in both the groups (all p > 0.05) [Table 2].
Table 2: Comparison of variables at 12 weeks


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Similarly, at 24 weeks, difference between HbA1c, fasting blood glucose and predinner blood glucose was not significantly different in both the groups (all p > 0.05) [Table 3].
Table 3: Comparison of variables at 24 weeks


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Five patients in detemir group and one patient in glargine group reported hypoglycemia [Table 4].
Table 4: Hypoglycemic episodes


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All the patients showing hypoglycemia reported adrenergic symptoms such as hunger pain, tremor, weakness, palpitation or sweating. No patient developed symptoms of neuroglycopenia.

All the patients who developed hypoglycemic symptoms had blood glucose ranging between 40-70 mg/dl. Only one patient who received detemir showed blood glucose of 27 mg/dl. Down titration of insulin dose was required in this patient. The symptoms of hypoglycemia improved in all cases after food or sugar. None of the patient required hospitalization or concomitant medications for the treatment of hypoglycemia. No significant difference was seen in the safety laboratory investigations and ECG at the end of study after therapy in both the groups.


  Discussion Top


Basal insulin is an effective treatment for lowering glycemic levels in patients with T2DM not adequately controlled on oral treatment alone; [2] however, the risk of hypoglycemia and weight gain are some of the limitations for starting insulin therapy. [16],[17]

Our study results are in concurrence with Tsai et al. [18] in terms of delay in the initiation of insulin therapy where the authors showed that mean duration of diabetes was approximately nine years before starting basal insulin in Asian patients while our study population comprised of poorly controlled T2DM with mean duration of diabetes for close to eight years.

The results of our prospective, randomized study showed that initiation of insulin analogues in patients with long-standing T2DM failing oral hypoglycemic agent therapy provided clinically important improvements in glycemic control. This "treat-to target" comparison between glargine and detemir in insulin-naive patients with T2DM demonstrated that glargine and detemir result in similar improvements in HbA1c and but risk of hypoglycemia with insulin detemir is higher.

In literature the studies comparing detemir and glargine showed many similarities and few differences in terms of clinical benefits. [19],[20] These insulin analogues are effective in reducing blood glucose levels and improving the quality of life patients. [21] Insulin detemir and insulin glargine have advantages over NPH in terms of prolonged duration of activity and lack of pronounced insulin peak unlike NPH [22] These properties may help in reducing the incidence of nocturnal and overall hypoglycemia. Once daily glargine has shown similar efficacy to NPH and detemir in improving glycemic control, although patients treated with glargine were able to reach their target without experiencing nocturnal hypoglycemia. [19]

The duration of action of insulin glargine is around 24 hours, that is, glargine shows sustained action without pronounced peaks of action, [23] while insulin detemir has dose dependent duration of action. [24] To study the duration of action of both preparations, we evaluated the effect on predinner blood glucose level by giving both the insulins once daily after titrating the doses. There was no significant difference in the predinner or fasting blood glucose between two groups. Use of insulin detemir can reduce the risk of hypoglycemia. [25] A Cochrane review has showed no significant differences in hypoglycaemia between two treatment groups. [26] In our study five patients and one patient receiving detemir and glargine respectively reported hypoglycemic episodes. Insulin detemir binds to albumin. At steady state, the concentration of unbound insulin is significantly reduced, resulting in stable plasma insulin levels. [25] Based on the mechanism of action, we hypothesize two possibilities explaining hypoglycemia seen in some patients. Chances of hypoglycemia may be more initially when concentration of free insulin is higher. Less serum albumin in some people resulting in more free insulin concentration could be another explanation for patients showing hypoglycemia in our study. However, this needs to be confirmed. Because of no previously published studies have shown similar results and small sample size in both the groups in the study, we suggest that these results should be carefully interpreted. It would be interesting to compare the levels of free insulin in patients with hypoglycemia receiving insulin detemir and glargine.

The percentage of patients achieving <7% HbA1c was higher with insulin glargine compared to insulin detemir. A reduction of 1% in HbA1c is associated with a 14% reduction in myocardial infarction, a 14% reduction in all-cause mortality, a 37% reduction in micro vascular complications, and a 21% reduction in overall diabetic complications. [27] Thus, the additional reduction in HbA1c achieved by switching to a glargine based regimen can be considered clinically meaningful. The mean reduction in fasting and predinner blood sugar was similar in both groups. Though no difference was seen in HbA1c level at 12 and 24 weeks between two groups, greater percentage of patients achieved their targets in glargine group.

The study limitations include open label design, small sample size and short duration. Inclusion of some important parameter like weight gain, body mass index of patients could also be studied. Another shortcoming of the study include self-reporting methods used for reporting hypoglycemic events; patients were not requested to provide specific details of each episode like nocturnal or daytime hypoglycemia. We feel, large randomized studies are required to confirm these findings.


  Conclusion Top


Insulin glargine is significantly effective in achieving target level HbA1c in large number of patients compared to insulin detemir with less incidence of hypoglycemia. However, there is no difference in the glycemic control parameters (HbA1c, fasting and predinner blood glucose) between basal insulin analogues, glargine and detemir.

 
  References Top

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Lepore M, Pampanelli S, Fanelli C, Porcellati F, Bartocci L, Di Vincenzo A, et al. Pharmacokinetics and pharmacodynamics of subcutaneous injection of long-acting human insulin analog glargine, NPH insulin, and ultralente human insulin and continuous subcutaneous infusion of insulin lispro. Diabetes 2000;49:2142-8.  Back to cited text no. 10
    
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Le Floch JP, Lévy M, Mosnier-Pudar H, Nobels F, Laroche S, Gonbert S, et al. Comparison of once-versus twice-daily administration of insulin detemir, used with mealtime insulin aspart, in basal-bolus therapy for type 1 diabetes: Assessment of detemir administration in a progressive treat-to-target trial (ADAPT). Diabetes Care 2009;32:32-7.  Back to cited text no. 13
    
14.
Porcellati F, Rossetti P, Busciantella NR, Marzotti S, Lucidi P, Luzio S, et al. Comparison of pharmacokinetics and dynamics of the long-acting insulin analogs glargine and detemir at steady state in type 1 diabetes: A double-blind, randomized, crossover study. Diabetes Care 2007;30:2447-52.  Back to cited text no. 14
    
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20.
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26.
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27.
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