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Comparison of insulin glargine with human premix insulin in patients with type 2 diabetes inadequately controlled on oral hypoglycemic drugs in a 24-week randomized study among Indian population.

INTRODUCTION: Type 2 diabetes is a progressive disorder of [beta]-cell dysfunction. Patients using oral therapy for it seldom achieve and maintain the recommended 7% HbA1c goal for glycemic control (1,2) and are exposed to increasing risks of diabetic complications as control worsens over time (3,4).

However, the majority of patients with a longer duration of diabetes remain poorly controlled with oral agents, and use of insulin, which could improve glycemic control, is often long delayed and not aggressive enough. The reluctance to initiate insulin therapy seems partly due to its perceived complexity, and fear of hypoglycemia, which may be the greatest barrier (5).

A regimen that may make initiation of insulin simpler and more effective has been tested in several small studies (6-8). A single bedtime injection of long-acting (basal) insulin is added while prior oral agents are continued, and insulin is systematically titrated, seeking a defined fasting glucose target. Glargine, a long-acting insulin analog with a more favourable 24h time-action profile (no pronounced peak) than long- or intermediate-acting human insulin preparations (9-10), may be especially suited to this regimen. We compared the abilities of glargine and human premix insulin to reduce HbA1c to 7% when added to ongoing oral therapy and the hypoglycemia accompanying this effort using a simple algorithm for insulin dosage titration seeking fasting blood glucose (FBG) target of 100 mg/dl.

SUBJECTS AND METHODS: Enrolled subjects were men or women aged 30-70 years, with type 2 diabetes, and treated with stable doses of one or more oral hypoglycemic drugs (sulfonylurea, metformin or pioglitazone) for [greater than or equal to] 6 months. There were no significant differences in the mean age, racial distribution, BMI, admission blood glucose, or HbA1c between treatment groups (Table 1). Inclusion criteria included BMI between 26 and 40 kg/[m.sup.2], HbA1c more than 7.5, and FBG [greater than or equal to] 140 mg/dl at screening. Exclusion criteria included prior use of insulin, current use of an [alpha]-glucosidase inhibitor or a rapid-acting insulin secretagogue, use of other agents affecting glycaemic control (including systemic glucocorticoids, nonselective [beta]-sympathetic blockers, and anti obesity drugs), history of ketoacidosis or self-reported inability to recognize hypoglycemia, or serum creatinine ([greater than or equal to] 1.5 mg/dl for men and [greater than or equal to] 1.4 mg/dl for women), and a history of drug or alcohol abuse.

This single centre, randomized, parallel, 24-week comparative study was performed at Sri Aurobindo Medical College, Indore between January 2009 and September 2012. Written informed consent has been taken from subjects prior to study.

Patients were randomized to either glargine (Lantus; Aventis) or human premix insulin (mixture of 30% neutral soluble insulin and 70% isophane insulin) to be administered subcutaneously at bedtime (glargine) or twice a day (human premix insulin), using a pen injector or insulin syringe as preferred by patient for 24 weeks. Oral hypoglycemic drugs were continued at similar dosages. The starting dose of glargine insulin was 10 IU/day, and dosage was titrated weekly according to laboratory blood glucose levels or self-monitored capillary fasting blood glucose measurements using meters (Accu-Chek Advantage; Roche Diagnostics) that provide values corresponding closely to laboratory measurements of plasma glucose. Dosages titrated till target FBG of [less than or equal to] 100 mg/dl achieved. (Table 2)

Subjects visited centre at baseline and 1, 3, 5, 7, 10, 12, 18 and 24 weeks and contacted telephonically on 2, 4, 6, 8, 9, 11, 13, 14, 20 and 22 weeks. Glucose values and insulin changes were recorded each time. Subjects were asked to test glucose whenever they experienced symptoms that might be related to hypoglycemia and to record the results. Subjects documenting hypoglycemia by glucose levels [less than or equal to] 70 mg/dl were asked to reduce insulin dose by 2 units. Insulin titration started after one week if symptoms of hypoglycemia did not recur. Weight was measured, and venous blood for FPG was collected between 0800 and 0900 h at each visit. Blood for HbA1c was collected at baseline and 12 and 24 weeks. Qualitative variables were tested using Chi square test and p values were calculated between two groups. p value of < 0.05 was considered statistically significant. Averages were expressed between groups as mean [+ or -] standard deviation or percentage.

RESULTS: Out of 750 patients screened, 370 were treated with glargine and 380 with human premix insulin. A total of 5 insulin glargine recipients and 15 human premix insulin recipients withdrew from the study after beginning treatment. In 3 insulin glargine subjects and 9 human premix insulin subjects, the reason was the subject's desire to discontinue or loss to follow-up. Two insulin glargine subjects (0.54%) and six human premix insulin subjects (1.57%) discontinued treatment because of adverse events.

Figure-A illustrates that the mean improvements in HbA1c were similar: -3.00 [+ or -] 1.68% for glargine and -2.89 [+ or -] 1.79% for human premix insulin (P = 0.3861). The proportions of patients achieving HbA1c <7% were also similar (76.3 and 75.5%, respectively), but fewer human premix insulin than glargine-treated patients reached HbA1c <6.5% (14.6 and 26.7%, respectively).

Change in FBG from baseline was significant at end point in both groups (P < 0.0001). Similar proportions of subjects receiving insulin glargine (29.6%) and NPH (27.1%) achieved FBG <90 mg/dl by study end point. (Figure B).

Risk of hypoglycemia was significantly higher with human premix insulin. We found that subjects in the insulin glargine group had 12 episodes of hypoglycemia documented by a blood glucose value <70 mg/dl, compared with subjects in the human premix insulin group who reported 42 episodes (significance level 0.00002).

Weight gain was significantly higher with human premix insulin versus glargine: 1.4 [+ or -] 0.02 and 0.4 [+ or -] 0.012 kg (P < 0.0001). Average glargine insulin dose was 0.26 IU/kg and average human premix insulin dose was 0.64 IU/kg (Figure C).

DISCUSSION: Insulin glargine was developed as improved long-acting, basal insulin. It is an analogue of human insulin that is produced in a non-pathogenic strain of Escherichia coli. Insulin glargine differs from human insulin by the addition of two arginine amino acids to the C-terminus of the B-chain and the replacement of asparagine at position A21 by glycine. These changes shift the isoelectric point so that the molecule is soluble at an acid pH, but less soluble at neutral physiological pH levels. This results in a clear solution (pH 4.0) that when injected forms a precipitate in the subcutaneous tissue, which delays absorption and prolongs duration of action. (11) The absorption characteristics of insulin glargine are not affected by the site of injection (arm, leg, or abdominal regions). Furthermore, compared with NPH insulin, the absorption rate is significantly slower with approximately 50% of the injected dose of insulin glargine still detectable after 24 hours compared with approximately 20% of the NPH insulin dose (12).

A potential major advantage of insulin glargine over NPH insulin and ultralente preparations is a lack of pronounced peaks in plasma insulin concentrations and a more constant delivery of insulin over a 24 hour period. This smooth profile was clearly shown in studies of insulin glargine versus NPH insulin in healthy volunteers and of insulin glargine versus NPH and ultralente insulin in patients with type 1 diabetes (13,14). In fact, in this later study, the delayed absorption of insulin glargine provided a consistent delivery of insulin that closely mimicked insulin delivery by continuous subcutaneous insulin infusion (CSII). Furthermore, in this study, interindividual variability in plasma insulin concentrations was lower with insulin glargine than with NPH or ultralente. These pharmacokinetic studies highlight the potential of insulin glargine to be improved basal insulin for patients with diabetes.

Riddle et al (2003) compared the addition of either insulin glargine or NPH insulin with existing regimens of one or two oral antidiabetic agents. This 24-week, randomized trial enrolled 756 patients. Although both basal insulins reduced FPG and HbA1c levels by similar amounts (FPG: 6.4 mmol/L versus 6.6 mmol/L; HbA1c: 6.96% versus 6.97% for insulin glargine and NPH insulin, respectively), 25% more patients attained a target HbA1c level of = 7% without experiencing nocturnal hypoglycemia with insulin glargine than with NPH insulin (p < 0.05). The overall rate of hypoglycemia, rate of symptomatic events, and rate of confirmed events in the insulin glargine group were reduced by 21%, 29%, and 41%, respectively (15). Yki-Jarvinen's group designed a similar trial, but the treatment period was one year. Again, insulin glargine and NPH insulin reduced HbA1c levels by a similar amount, but there was less nocturnal hypoglycemia (9.9% versus 24.0% of patients, p < 0.001) and insulin glargine was associated with better post-meal glucose control than NPH insulin (9.9 mmol/L versus 10.7 mmol/L, p < 0.002) (16).

While some studies have shown similar rates of hypoglycemia when compared with NPH insulin, there is also evidence insulin glargine can maintain effective glucose control and reduce risk of hypoglycemia. Rosenstock et al (2001) randomized 518 patients with type 2 diabetes, who were already being treated with basal NPH insulin and regular insulin, to receive either insulin glargine or NPH insulin once- or twice daily. While improvements in HbA1c were comparable, the group who switched to insulin glargine showed a 25% decrease in the rate of nocturnal hypoglycemia (26.5% versus 35.5%, p = 0.0136). A recent meta analysis of four open-label, randomized trials of insulin glargine versus NPH insulin adds further weight to this assertion. In total, 2304 patients were randomized and while glycemic control was similar between groups, there was a significant and consistent reduction in the risk of hypoglycemia. (17) While in our study insulin glargine and human premix insulin both associated with significant reductions in fasting blood sugar and HbA1c but hypoglycaemia risk was lesser with insulin glargine.

Weight gain has long been an issue with insulin therapy. Insulin glargine has been associated with a mean weight gain of up to 2.02 kg in a 39-month study of 239 patients being treated in combination with oral antidiabetic agents, but many studies have reported no significant weight gain despite significant improvements in HbA1c (18). Some evidence suggests that insulin glargine may be associated with less weight gain than NPH insulin. In two studies, NPH insulin was associated with significantly more weight gain than insulin glargine [19, 20]. In a 16-week trial in patients with type 2 diabetes, weight gain was 0.4 kg with insulin glargine versus 1.4 kg with NPH insulin (p < 0.0007) [17]. In contrast, one study reported similar gains in mean body weight following 1 year of treatment of patients with type 2 diabetes with insulin glargine (+2.6 kg, n = 214) and NPH insulin (+2.3 kg, n = 208) [16]. While in our study weight gain was significantly higher with human premix insulin versus glargine: 1.4 [+ or -] 0.02 and 0.4 [+ or -] 0.012 kg (P < 0.0001).

Case reports of nausea and vomiting in patients receiving insulin glargine have been published (21), although these adverse events are not seen in our study.

CONCLUSION: Managing diabetes with insulin is primarily based on the balance between the necessity of tight glycemic control and the risks associated with hypoglycemia. Insulin glargine appears to improve this balance such that at least equivalent glycemic control can be achieved with a lower risk of hypoglycemia than traditional basal insulins. In patients with type 2 diabetes, the reduced risk of hypoglycemia with insulin glargine, combined with the flexibility of once-daily dosing at any time of the day, is likely to make insulin a more acceptable option, which may mean that patients are more open to start insulin earlier and to intensify their insulin sooner. In the long-term this may lead to improvements in HbA1c and thereby a reduction in the long-term complications of diabetes. Insulin glargine treatment was associated with significantly less weight gain than NPH insulin treatment (0.40 vs. 1.40 kg). Presumably, the difference in weight gain despite comparable improvement in glycemic control reflects the less frequent hypoglycemia seen with insulin glargine, the correction of which requires supplemental caloric intake.

[FIGURE A OMITTED]

[FIGURE B OMITTED]

[FIGURE C OMITTED]

REFERENCES:

(1.) Harris MI, Eastman RC, Cowie CC, Flegal KM, Eberhardt MS: Racial and ethnic differences in glycemic control in adults with type 2 diabetes. Diabetes Care 22: 403-408, 1999

(2.) Turner RC, Cull CA, Frighi V, Holman RR, UK Prospective Diabetes Study Group: Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). JAMA 281: 2005-2012, 1999

(3.) Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, et al: Association of glycemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 321: 405-411, 2000

(4.) Klein R, Klein BEK, Moss SE: Relation of glycemic control to diabetic microvascular complications of diabetes mellitus. Ann Intern Med 124:90-96, 1996

(5.) Hayward RA, Manning WG, Kaplan SH, Wagner EH, Greenfield S: Starting insulin therapy in patients with type 2 diabetes: effectiveness, complications, and resource utilization. JAMA 278: 1663-1669, 1997

(6.) Taskinen M-R, Sane T, Helve E, Karonen S-L, Nikkila EA, Yki-Jarvinen H: Bedtime insulin for suppression of overnight free fatty acid, blood glucose, and glucose production in NIDDM. Diabetes 38: 580-588, 1989

(7.) Riddle MC: Evening insulin strategy. Diabetes Care 13: 676-686, 1990

(8.) Shank ML, DelPrato S, DeFronzo RA: Bedtime insulin/daytime glipizide: effective therapy for sulfonylurea failures in NIDDM. Diabetes 44: 165-172, 1995

(9.) Bolli GB, Owens DR: Insulin glargine (Commentary). Lancet 356: 443-444, 2000

(10.) Rosenstock J, Schwartz SL, Clark CM Jr, Park GD, Donley DW, Edwards MB: Basal insulin therapy in type 2 diabetes: 28-week comparison of insulin glargine (HOE901) and NPH insulin. Diabetes Care 24: 631-636, 2001

(11.) Bahr M, Kolter T, Seipke G, Eskel J. Growth promoting and metabolic activity of the human insulin analogue [GlyA21, ArgB31, ArgB32] insulin (HOE 901) in muscle cells. Eur J Pharmacol.1997; 320:259-65.

(12.) Owens DR, Coates PA, Luzio SD, Tinbergan JP, Kurzals R. Pharmacokinetics of 125Ilabeled insulin glargine (HOE 901) in healthy men: comparison with NPH insulin and the influence of different subcutaneous injection sites. Diabetes Care. 2000; 23:813-19.

(13.) Heinemann L, Linkeschova R, Rave K, Hompesch R, Sedlak M, Heise T. Time-action profile of the long-acting insulin analog insulin glargine (HOE901) in comparison with those of NPH insulin and placebo. Diabetes Care.2000; 23: 644-9.

(14.) Lepore M, Pampanelli S, Fanelli C, Porcellati F, Bortocci L, DiVincenjo 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.

(15.) Riddle MC, Rosenstock J, Gerich J. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care. 2003; 26: 3080-6.

(16.) Yki-Jarvinen H, Dressler A, Ziemen M. Less nocturnal hypoglycemia and better post-dinner glucose control with bedtime insulin glargine compared with bedtime NPH insulin during insulin combination therapy in type 2 diabetes. HOE 901/3002 Study Group. Diabetes Care.2000; 23: 1130-6.

(17.) Rosenstock J, Schwartz SL, Clark CM Jr, Park GD, Donley DW, Edwards MB. Basal insulin therapy in type 2 diabetes: 28-week comparison of insulin glargine (HOE 901) and NPH insulin. Diabetes Care. 2001; 24: 631-6.

(18.) Dunn CJ, Plosker GL, Keating GM, Mckeage K, Scott LJ. Insulin glargine: an updated review of its use in the management of diabetes mellitus. Drugs. 2003; 63: 1743-78.

(19.) Raskin P, Klaff L, Bergenstal R, Halle JP, Donley D, Mecca T. A 16-week comparison of the novel insulin analog insulin glargine (HOE 901) and NPH human insulin used with insulin lispro in patients with type 1 diabetes. Diabetes Care. 2000; 23: 1666-71.

(20.) Garg SK, Paul JM, Karsten JI, Menditto L, Gottlieb PA. Reduced severe hypoglycemia with insulin glargine in intensively treated adults with type 1 diabetes. Diabetes Technol Ther. 2004; 6: 589-95.

(21.) Dixon AN, Bain SC. Nausea and vomiting due to insulin glargine in patient with type 1 diabetes mellitus. BMJ. 2005; 330: 455.

Abhishek Singhai, Subodh Banzal, Dolly Joseph, Rajesh Kumar Jha, Pragya Jain

1. Assistant Professor, Department of Medicine, Sri Aurobindo Medical College & PG Institute, Indore, India.

2. Associate Professor, Department of Endocrinology, Sri Aurobindo Medical College & PG Institute, Indore, India.

3. Associate Professor, Department of Medicine, Sri Aurobindo Medical College & PG Institute, Indore, India.

4. Professor & Head, Department of Medicine, Sri Aurobindo Medical College & PG Institute, Indore, India.

5. DOMS, Department of Opthalmology, Sri Aurobindo Medical College & PG Institute, Indore, India.

CORRESPONDING AUTHOR

Dr. Abhishek Singhai, MD Medicine, Assistant Professor, Department of Medicine, Sri Aurobindo Medical College & PG Institute, Indore, India

E-mail: drabhisheksinghai@gmail.com

Ph: 0091 9926597070.
Table 1: Baseline characteristics of subjects in the study

                       Glargine              Human Premix Insulin

Number                  370                   380
Sex (F/M) (%)           58/42                 54/46
Age (years)             45 [+ or -] 9.5       46 [+ or -] 8.9
Duration of diabetes    10 [+ or -] 5         9.0 [+ or -] 6
  (years)
BMI (kg/[m.sup.2])      31.8 [+ or -] 3.63    32.2 [+ or -] 3.85
FBG (mg/dl)             188 [+ or -] 39       184 [+ or -] 47
HbA1c (%)                8.58 [+ or -] 0.7     8.46 [+ or -] 0.8
Prior therapy (%)
SU + metformin          24                    27
SU + metformin+ TZD     76                    73

Table 2:--Weekly insulin titration Table

Start with 10 IU/day bedtime basal insulin and adjust weekly
FBG values       Increase of insulin dosage (IU) day

>180 mg/dl       8
141-180 mg/dl    6
121-140 mg/dl    4
101-120 mg/dl    2
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Title Annotation:ORIGINAL ARTICLE
Author:Singhai, Abhishek; Banzal, Subodh; Joseph, Dolly; Jha, Rajesh Kumar; Jain, Pragya
Publication:Journal of Evolution of Medical and Dental Sciences
Article Type:Report
Geographic Code:9INDI
Date:Jan 14, 2013
Words:2953
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