Assessment of Safety and Effectiveness of Glaritus ® ( Wockhardt ’ s Insulin Glargine ) in a Prospective , Multi-Centric Post Marketing Observational Study in Nepalese Having Type 2 Diabetes Mellitus

Background: Nepal is one of the fastest urbanizing countries in South Asia and is facing the consequences of urban lifestyle leading to obesity and metabolic syndrome. Type 2 diabetes mellitus (T2DM) is currently a high-burden disease in Nepal with a prevalence of 8.4%. Of these 8% 18% patients are on insulin and 42% patients were reported to have uncontrolled diabetes in the past year. This suggests a need for better therapy options in terms of efficacy and safety. The current study was designed to investigate the effects of Insulin glargine-based therapy in Nepalese with T2DM who could not achieve adequate glycemic control with oral and non-glargine-insulin therapy. Methods: This is a prospective, multi-centric, single arm and post marketing observational study to assess the safety and effectiveness of Glaritus® (Wockhardt’s Insulin Glargine) in 52 T2DM patients from 3 (three) different study sites in Nepal (Bharatpur, Kathmandu and Pokhra) from September 2015 to December 2016. The primary objective of the study was to evaluate the safety of Glaritus®, mainly in terms of hypoglycemia, renal function tests and liver function tests. The secondary objectives were to evaluate the effectiveness of Glaritus® in terms of percentage of patients achieving HbA1c goal of less than 7%, mean changes in HbA1c & fasting plasma glucose (FPG) levels from baseline till the end of study. Results: 3.85% of subjects experienced hypoglycemia during first 3 months of therapy whereas 1.92% had similar expeHow to cite this paper: Joshi, A., Adhikari, B., Tamrakar, B., Puppalwar, G., Shah, A. and Jain, R. (2019) Assessment of Safety and Effectiveness of Glaritus® (Wockhardt’s Insulin Glargine) in a Prospective, MultiCentric Post Marketing Observational Study in Nepalese Having Type 2 Diabetes Mellitus. Open Journal of Endocrine and Metabolic Diseases, 9, 21-33. https://doi.org/10.4236/ojemd.2019.92003 Received: November 5, 2018 Accepted: February 24, 2019 Published: February 27, 2019 Copyright © 2019 by author(s) and Scientific Research Publishing Inc. This work is licensed under the Creative Commons Attribution International License (CC BY 4.0). http://creativecommons.org/licenses/by/4.0/ Open Access


. Rising Burden of T2DM in Nepal
Asia is a home to four of the world's five countries with the largest diabetes burden-India topping the charts at 33 million cases, followed by China having 23 million cases, and Pakistan and Japan having 9 and 7 million cases, respectively [1].The prevalence of diabetes in Nepal is not well characterized due to paucity of studies.But it is logical to assume that epidemiological profile of diabetes in Nepal must be very similar to its neighboring countries as they share lineage, culture and lifestyle profiles [2].Gyawali et al. [3] evaluated the prevalence of diabetes in Nepal in a meta-analysis and systematic review for a 14-year duration (2000)(2001)(2002)(2003)(2004)(2005)(2006)(2007)(2008)(2009)(2010)(2011)(2012)(2013)(2014).Pooled prevalence of type 2 diabetes was 8.4% (95% CI: 6.2% -10.5%) and it differed significantly in urban (8.1%) and rural (1%) populations.
Currently, Nepal is the fastest urbanizing country in South Asia with an average urban population growth rate of about 6 percent per year [4] and is facing the consequences of urban lifestyle leading to obesity and metabolic syndrome.
Amongst the diabetic population in Nepal, 8% -18% are on insulin [5] [6].In a prospective study assessing the drug prescribing trend in 100 patients including 41 diabetic patients, insulin was included only in 2.5% of prescriptions [7].In a study conducted by Sapkota et al. in 200 diabetic patients, 52% patients self-reported not knowing whether their diabetes was well-controlled and 42% had to seek help at least once within the last year for uncontrolled diabetes (in-Open Journal of Endocrine and Metabolic Diseases cluding hypo or hyperglycemia) [6].The situation indicates towards potential for improving diabetes management by enhancing insulin utilization in Nepalese diabetic patients.As the representation from Nepal in global diabetes research and publications is not proportionate to the rising epidemiology, our study is a step forward in contributing to diabetes research representing Nepalese population.

Value of Intensive Glucose Control Early in the Natural Course of Diabetes
The aim of insulin therapy is to mimic the physiological secretion of insulin so that it accommodates both fasting and post-prandial requirements.The UK Prospective Diabetes Study (UKPDS) established that initiating intensive glucose control at the time of diagnosis leads to significant reduction in the risk of cardiovascular and microvascular complications [8].But it must be done with minimal risk of hypoglycemia.Development of long-acting insulin analogs represented a promising step forward in meeting this requirement.Insulin Glargine now represents a reference basal insulin compared to which future developments in long-acting insulin analogs are measured [9] [10] [11].The updated clinical practice is to initiate insulin therapy early as part of "treat-to-target" strategy when ≥2 oral anti-diabetic drugs are not able to meet the individualized glycemic targets currently recommended for T2DM management [12].But in real-world, clinical inertia prevails towards early insulinization due to fear of hypoglycemia [13].Weight gain and the limited flexibility of some insulin regimens [14] may contribute to omission of injections, prolonged continuation of inadequate protocol posing long-term diabetes complications.

The Characteristics of Insulin Glargine
There are several options available for initiating insulin therapy.A basal peak-less insulin supply, offering a long duration of action, is desirable.Long-acting insulin analogs like glargine have been developed in such a way that it releases insulin at a reduced rate from its depot, resulting in flat pharmacokinetic profile for 24 h.Once-daily basal insulin offers the patient practicality and simplicity of use, hence is the most convenient insulin initiation strategy.
Insulin glargine is the most commonly prescribed basal insulin analog [15].
The replacement in the A-chain of asparagine by glycine in position A21 imparts a shift of the isoelectric point (from a pH of 5.4 to 6.7), making it less soluble at physiological pH and prolonging its duration of action up to 24 hours, with no pronounced peak in activity.Following the injection, insulin glargine forms a subcutaneous depot, from which it is slowly absorbed.This provides a relatively uniform concentration for 24 h, which allows mimicking basal endogenous insulin secretion [16].It has been proven that early basal insulin initiation with insulin glargine preserves beta-cell function when compared to prolonged continuation of solely oral therapy [17].As the natural course of diabetes progresses, in-creasing the dose and using combinations of insulins are needed to intensify treatment.Therefore, insulin glargine is suitable for a spectrum of treatment intensities allowing flexibility in regimen which adds to patient convenience.Thus, the early introduction of insulin in patients with type 2 diabetes is to be encouraged [18].

Rationale for Current Study
Insulin glargine brand "Glaritus®" has been registered in Nepal since 2015.The current trial was designed to investigate the effects of glargine-based strategy (Glaritus®) in Nepalese patients with T2DM who could not achieve adequate glycemic control with oral and/or insulin therapy.The approach of the study aimed to more accurately represent the nature of therapy adjustment in routine clinical practice in Nepal.Therefore, Glaritus® initiation and optimization was decided by the treating clinician rather than by a protocol-driven clinical trial setting.Over the last decade, insulin glargine has become a standard of care in diabetes treatment in Nepal due to its well-established safety and efficacy profiles [12].HbA1c is an excellent composite endpoint dependent upon both post-prandial glucose (PPG) and fasting plasma glucose (FPG) levels.Since we used a "treat-to-target" design of the study, we evaluated parameters FPG and HbA1c.

Study Design
This is a prospective, multi-centric, single arm, post marketing, observational, phase IV study to assess the safety and effectiveness of Glaritus® in Nepalese patients with T2DM.

Study Objectives
This being a post-marketing surveillance, the primary objective of the study was to evaluate the safety of Glaritus® in Nepalese patients at 3 centers from September 2015 to December 2016.The secondary objectives were to evaluate the efficacy of Glaritus® in terms of percentage of patients achieving HbA1c goal of less than 7% at the end of study and mean changes in HbA1c & FPG levels from baseline at 6 months of therapy.

Patients
52 patients were included from 3 different study sites in Nepal (Bharatpur, Kathmandu and Pokhra).All patients were enrolled after obtaining written informed consent.Local ethics committee approval was not required for post-marketing surveillance as per the Department of Drug Administration (DDA), Nepal.Relevant medical history, vital signs evaluation and thorough clinical examination were carried out before inclusion of the patient into the surveillance.The lab parameters included determination of FPG and HbA1c.Renal function tests and liver function tests were also carried out for safety as-Open Journal of Endocrine and Metabolic Diseases sessment.Follow up visits were conducted at 3 month and at 6 months of therapy when the safety and clinical assessment were repeated as per protocol requirements.
The main inclusion criteria were patients aged 18 to 65 years with T2DM diagnosed at least 1 year ago, not responding to/uncontrolled on the current therapy of oral antidiabetic medications (Insulin-naïve patients) or on insulin (basal/bolus), with HbA1c levels > 7% and ≤11%, having BMI < 40 kg/m 2 , and no history of ketonemia.Patients were excluded from study if they had history of known hypersensitivity to glargine, had history of ketonemia, were pregnant or lactating females, were suffering from either hepatic or renal dysfunction, had active cardiovascular disease or had history of recurrent severe hypoglycemia.

Medication
Glaritus® cartridge to be used with My Pen insulin delivery device (manufactured by Wockhardt Limited, India) was the surveillance medication.This was a post-marketing, observational study, hence no free medication was provided to the patients.The mode of administration was subcutaneous, once daily injection and dose of administration was as per the discretion of the investigator.Oral hypoglycemic agents and other insulin were allowed as concomitant medication.
The titration of dosage of Glaritus®, other insulin and oral hypoglycemic agents was determined on the basis of blood glucose levels.The total duration of study was 6 months.

Safety and Efficacy Variables
Safety assessment was done by evaluating occurrence of hypoglycemia, renal function tests and liver function tests any other adverse events reported.
The primary efficacy variable was HbA1c.Final evaluation on efficacy was based on the percent patients achieving HbA1c goal of less than 7% and mean change in HbA1c level (from baseline to final visit i.e., post treatment with surveillance medication for 6 months).The secondary efficacy variable was FPG.
The mean changes of FPG from baseline visit to final visit were evaluated.

Statistical Analysis
Since the study was designed as "proof-of-concept" in Nepal, sample size was not estimated using statistical tests.It was determined arbitrarily as per investigator's clinical judgment.The data was subject to descriptive statistics.Paired t-test was used to evaluate the statistical significance of differences in HbA1c and FPG values.Demographic data such as age, gender, weight, height and BMI were summarized overall and by study-sites.Occurrence of adverse events (hypoglycemia) at each assessment visit was recorded and summarized using count and percentage.Age, weight, height and BMI are summarized using statistical measures of mean and standard deviation.Gender is summarized using frequency and percentages.Open Journal of Endocrine and Metabolic Diseases

Results
52 patients were enrolled in this study at 3 centers.Figure 1 depicts the percentage contribution of data from each site.Table 1 shows the summary statistics of demography parameters age, height, weight, BMI, gender and study-site wise distribution.The mean (range) age of patients was 52.79 years (19 -65) and mean (range) BMI was 26.55 (16.9 -35.5).
Table 2 shows visit-wise mean HbA1c and FPG values.The mean HbA1c values reduced from 9.16% to 7.15% at the end of study.The mean FPG value of entire group reduced from 239.94 mg/dL to 151.31 mg/dL towards the end of study.
Figure 2 shows the frequency and percentage of patients achieving HbA1c goal of less than 7% at various assessment visits.
Twenty one point zero five (21.05)% of the enrolled subjects achieved the goal of HbA1c < 7% at 3 months of therapy, whereas 52.50% achieved the goal at the end of 6 months of therapy.Paired t-test was used to compare change in HbA1c values from baseline to end of visit (Visit 3 and Visit 4).The hypothesis testing was performed at 5% LOS.P value was highly significant < 0.0001.
Figure 4 shows the change in FPG values from baseline to the end of visit (Visit 3 and Visit 4).
Paired t-test was used to compare change in FPG values from baseline to end of visit (Visit 3 and Visit 4).The hypothesis testing was performed at 5% LOS.P value was highly significant < 0.0001 at the end of Visit 3 and 4.
Table 3 depicts the percentage of patients experiencing hypoglycemia.3.85% subjects were recorded to experience hypoglycemia in Visit 3 whereas 1.92% subjects were recorded in Visit 4. No significant change in renal or liver functions occurred during the treatment.
There was no significant change in renal or liver functions during treatment in terms of serum creatinine and liver enzymes.None of the subjects experienced any other AE, thus indicating that Glaritus® was well tolerated by the study subjects.

Discussion
Glargine was the first-to-be-introduced once-daily, long-acting insulin analog efficacious for 24 hours.It has now been in clinical use for more than 10 years   The most common approach to initiate pharmacotherapy in T2DM is met- formin, which can be further intensified by adding and replacing oral antidiabetic drugs of other classes or injectable GLP-1 agonists.Given the natural clinical course of T2DM, many patients will eventually require insulin, usually beginning from one injection of basal insulin preparation [12] [21] [22].Even though, many insulin analogues have been developed so far, insulin glargine has favorable pharmacokinetic properties that allow consistent insulin activity over 24 h with only a single injection.This makes insulin glargine the most widely prescribed long acting insulin analogue [11].
In our study only 3.85% and 1.92% subjects experienced hypoglycemia at 3 months and 6 months of Glaritus® therapy, respectively.The improvement in the HbA1c values from baseline to the end of study is statistically significant at 5% LOS (p-value < 0.05).Similarly, the change in the FPG values from baseline to the end of study is statistically significant at 5% LOS (p-value < 0.05).The reduced risk of hypoglycaemia and better FPG observed with Glaritus® offers additional positive features, including greater flexibility.The flexibility in timing the insulin glargine dose, although requiring dosing at the same time each day, may provide patients with some respite from the strict insulin regimens, especially in insulin initiators.
The lower incidence of hypoglycemia can be explained by the flat time-action profile of insulin glargine with no pronounced peak, which would facilitate maintenance of euglycemia with reduced blood glucose excursions.There was no significant change in renal or liver functions during treatment.None of the subjects experienced any other AE.
Glaritus® offers both increased convenience (once-daily administration) and safety (reduced risk of hypoglycemia) when attempting to reach the target HbA1c level of 7.0%.HbA1c target was achieved in more than 52.54% of subjects, similar to other previous studies [23].
Our results are in line with previous studies conducted in other geographies.
Freemantle et al. [24] conducted a network meta-analysis comparing the efficacy and safety of insulin glargine with other basal insulin therapies in patients with T2DM.Change in HbA1c was comparable with other insulins (detemir, NPH, premixed etc.) and incidence of hypoglycemia was significantly lower with glargine.Similarly, Pandya et al. [25] conducted a pooled analysis of 24-week data from nine prospective open-label, multicenter, phase 3/4, two-arm, parallel-group, randomized controlled trials, where patients with T2DM aged 18 -80 years received insulin glargine (used as a basal insulin regimen) or comparators (including OADs, insulin lispro, insulin lispro 75/25, NPH insulin, NPH insulin 30/70, and lifestyle/dietary measures).They concluded in favor of insulin glargine, which was associated with better glycemic control and a reduced incidence of hypoglycemia versus comparator interventions in both younger and older T2DM patients.Pscherer et al. [26] reported the results of their study performed on 20 diabetic patients with end stage renal disease on hemodialysis treated with insulin glargine.In this nine-month study, mean HbA1c reduced by 0.9% (p < 0.01) and severe hypoglycemic events were not reported.In the present study, Open Journal of Endocrine and Metabolic Diseases the target HbA1c level of 7.0% or less was achieved for over half of study subjects within the short study duration.Most of the clinical practice guidelines recommend the target glucose level to prevent diabetes related vascular complications and glycemic goals of HbA1c ≤ 7.0% (53 mmol/mol) [27].However, a new perspective was introduced by three recently published large RCT studies (ACCORD, ADVANCE, VADT).They have demonstrated no significant benefits in cardiovascular outcome with intensive glycemic control [28] in participants who had T2DM for 8 to 11.5 years.These studies depict that the glycemic target should be individualized according to age, comorbidities, duration of T2DM, presence of macro-and micro-vascular complications and propensity for hypoglycemia.

Limitations and Strengths of the Study
The limitations of the present study include its single-arm, open-label design, which could have introduced physicians' and patients' bias, however, it would have been difficult to use a double-blind design in the real-world practice.The sample size of the study was small which must be considered before interpreting the results.
Although the length of the study was fairly short in view of the chronic nature of T2D, but the duration was sufficient for treatment to reach a steady state and insulin glargine treatment optimization process to be completed.The study duration was also adequate to assess treatment effect.This study's strength is that it is the only study to our knowledge which evaluates insulin glargine-based treatment with/without OAD combination in Nepalese patients with uncontrolled type 2 diabetes.

Conclusion
In patients with type 2 diabetes mellitus inadequately controlled on OADs and/or insulin, initiation with Glaritus® significantly improved glycemic control with good tolerability and acceptability.The results of our study support current guidelines and add to the body of evidence supporting the use of insulin glargine, but from a Nepalese T2DM population perspective.This analysis in T2DM Nepalese patients shows that Glaritus® helps to improve glycemic control and, at the same time avoid severe and nocturnal hypoglycemia.Insulin glargine offers a safer peak-less glycemic profile, hence suited to aggressive treatment regimens.
From a societal perspective, it can help more patients achieve tight glycemic control as recommended by current treatment guidelines.Further carefully designed, long-term and prospective studies are needed to evaluate the overall benefits and clinical efficacy of Glaritus® injection in Nepalese diabetic population.

Figure 3
Figure 3 shows the change in HbA1c values from baseline to the end of visit (Visit 3 and Visit 4).Paired t-test was used to compare change in HbA1c values from baseline to end of visit (Visit 3 and Visit 4).The hypothesis testing was performed at 5% LOS.P value was highly significant < 0.0001.Figure4shows the change in FPG values from baseline to the end of visit (Visit 3 and Visit 4).Paired t-test was used to compare change in FPG values from baseline to end of visit (Visit 3 and Visit 4).The hypothesis testing was performed at 5% LOS.P value was highly significant < 0.0001 at the end of Visit 3 and 4.Table3depicts the percentage of patients experiencing hypoglycemia.3.85% subjects were recorded to experience hypoglycemia in Visit 3 whereas 1.92% subjects were recorded in Visit 4. No significant change in renal or liver functions occurred during the treatment.There was no significant change in renal or liver functions during treatment in terms of serum creatinine and liver enzymes.None of the subjects experienced any other AE, thus indicating that Glaritus® was well tolerated by the study subjects.

Figure 1 .
Figure 1.Percentage contribution of data from each site.
Open Journal of Endocrine and Metabolic Diseases

Figure 4 .
Figure 4. Mean change in FPG values (mg/dL) from baseline to Visit 3 and 4.
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Table 2 .
Visit wise mean HbA1c and FP values.

Table 3 .
Percentage of subjects experiencing hypoglycemia.