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Comparative Evaluation of DPP-IV Inhibitors and other Oral Hypoglycaemic Agents used Either Alone or in Combination with Reference to Glycemic Targets in Patients with Type 2 Diabetes Mellitus

Introduction: This study assumes significance as it compares head on DPP-IV inhibitors along with other oral hypoglycemic agents with respect to glycemic and non-glycemic targets. Study was done to evaluate the DPP-IV inhibitors and other oral hypoglycemic agents (OHA) either alone or in combination, with reference to glycemic targets like fasting plasma glucose (FPG), post prandial glucose (PPG) and glycosylated hemoglobin (HbA1c) in type 2 diabetes mellitus. Material and Methods: This was an open labelled comparative study and included 90 patients with Type 2 DM. These patients were divided into 3groups: Each group was containing 30 patients i.e. Group A: DPP-IV inhibitors (n= 30); Group B: Oral hypoglycemic agents other than DPP-IV inhibitors (n= 30) and Group C: DPP-IV inhibitors + other oral hypoglycemic agents (n= 30). The patients were given drugs on the basis of physician’s discretion, depending upon the glycemic of the patients at the time of presentation. A detailed history regarding age, sex, profession, duration of disease, treatment history, family history and personal history was taken for each patient. After stabilization patients observed at 0 weeks, 6 weeks, 12 weeks and 24 weeks. Results: Mean duration of diabetes was 5.35±0.53 years, and the mean age of onset of diabetes was 46.98±0.91years. There was no significant difference between the study groups with respect to FPG, PPG, and HbA1c levels. The HbA1c showed significant improvement in each group at the end of study period. Conclusion: In summary, this study showed that treatment with sitagliptin, either alone or in combination with other oral hypoglycemic agent led to clinically meaningful reductions in HbA1c, FPG and PPG over a 24 week period. Sitagliptin presents an alternative therapeutic strategy for patients with type 2 diabetes and, in general, showed significant improvements in glycemic control and is well tolerated, particularly with regard to weight change and hypoglycemia.


INTRODUCTION
Diabetes mellitus is a metabolic disorder with common denominator of hyperglycemia, arising from a variety of pathogenic mechanisms. It has emerged as an epidemic both in the developing and developed countries and shows no signs of regression. 1 India, the world's second most populous country, is also world's second most populous with reference to type 2 diabetes (≈61.3 million), first being China. Type 2 Diabetes mellitus is rapidly increasing and is a major public health problem globally with a prevalence of 6 % in 2007 which is expected to rise to 7.3% in 2025.This means there would be near 80 million diabetics by 2025. It poses a major health, social and economic burden on the society. 2 Glycaemic management in type-2 diabetes mellitus has become increasingly complex and, to some extent, controversial, with a widening array of pharmacological agents now available. 3,4 It mounts concerns about their potential adverse effects and new uncertainties regarding the benefits of intensive glycaemic control on macrovascular complications. 5,6 The strict glycemic control is necessary to prevent diabetic complications. However strict glycemic control is associated with frequent hypoglycemic effects. It is even observed that it does not produce any cardiovascular benefits. This forms the rationale of using more than one pharmaco-therapeutic agent with varied mechanisms of action to not only target hyperglycemia but also non glycemic parameters. 7 Treatment of type 2 diabetes is based on interplay of patient characteristics, severity of hyperglycemia and available therapeutic options. Metformin, sulfonylureas (SU) and thiazolidinediones (TZD) are the most studied of the oral Section: Pharmacology medications used worldwide. They play a prominent initial role in the type 2 diabetes treatment algorithm recommended by the American Diabetes Association (ADA) and the European Diabetes Association for the Study of Diabetes (EASD). 8 Metformin is considered first-line therapy unless not tolerated or contraindicated. Second-line therapy then includes SUs, TZDs, dipeptidyl peptidase-IV (DPP-4) inhibitors, glucagon-like polypeptide-1 (GLP-1) agonists or insulin. DPP-4 inhibitors are relatively newer and are the only oral agent in the incretin family of therapeutic targets. In addition, multiple oral medications have been approved for the treatment of type 2 diabetes that is less widely used. 9 The American Diabetes Association / European Society for the Study of Diabetes consensus algorithm for the treatment of type 2 Diabetes mellitus endorses the use of newer class of drugs, the incretins or incretin based therapies, either alone or in combination. Incretin based therapy, specially DPP-IV inhibitors is a unique class of drugs, which prevent the rapid degradation of endogenous Glucagon like Peptide-1(GLP-1) and Glucose dependent insulinotropic polypeptide (GIP) and increase the level of intact active form of endogenous GLP-1. 10 The DPP-IV (Dipeptidyl peptidase) inhibitors increase insulin concentrations in a glucose dependent fashion. Other advantages are little or no hypoglycemia, improvement in Fasting and Post Prandial hyperglycemia, no weight gain, decrease in appetite, reduced HbA1C level by an average of 0.8% and an improved β-cell function. 1 For anti-hyperglycaemic management of type 2 diabetes, the comparative evidence basis to date is relatively lean, especially beyond metformin monotherapy. 11 There is a significant need for high-quality comparative effectiveness research, not only regarding glycaemic control, but also regarding non glycaemic parameters. As new medications are introduced for type 2 diabetes, their benefit and safety should be demonstrated in studies to provide meaningful data on meaningful outcomes. This study assumes significance as it compares head on DPP-IV inhibitors along with other oral hypoglycemic agents with respect to glycemic.

MATERIAL AND METHODS
This study was carried out in the departments of Pharmacology and Medicine at Shri Guru Ram Rai Institute of Medical and Health Sciences (SGRRIM and HS), Dehradun, Uttarakhand, India. Prior to initiation of study approval of institutional ethics/research committee and written informed consent from the patient/legal guardian of the patient were obtained after full explanation of elements contained in the research protocol. All Type-2 DM patients diagnosed as per ADA criteria, attending the medicine outpatient department and inpatient department were included in the study. The duration of the study was one year from January 2013 to December 2013.  Table 4]. There was an extremely significant improvement in all the groups with respect to FPG and PPG at the end of the study period. At the end of the study period, the three groups were compared for changes in FPG and PPG values. At 24 weeks FPG was in group A, B and C were 136.90±1.25mg/dl, 127.30±2.31mg/ dl and 125.16±2.48 mg/dl. ANOVA test was used for intergroup comparison. There was a significant difference between the three groups (p< 0.001). The difference between group A and group B was highly significant (p< 0.01). The difference between group B and group C was insignificant (p>0.05) and between group A and group C was extremely significant (p <0.001) [ Table 5]. PPG in groups A, B and C at 24 weeks were 164.43±2.34 mg/ dl, 160.83±4.40mg/dl and 156.93±2.10 mg/dl respectively. There was a significant difference between the three groups (p< 0.001). The difference between group A and group B was highly significant (p< 0.01). The difference between group B and group C was significant (p< 0.05) and between group A and group C was extremely significant (p < 0.001) [ Table 5]. The HbA1c showed significant improvement in each group at the end of study period. At the end of study period comparison was made in HbA1c values between -2 weeks and 24 weeks. In group A the HbA1c at -2 weeks was 8.91±0.1 and at 24 weeks was7.93±0.10 (p< 0.001). In group B at -2 and 24 weeks it was 8.79±0.11and 7.32± 0.11(p< 0.001) and in group C 8.97±0.13 and 7.09±0.13 (p< 0.001). Intergroup comparison of HbA1c was done at 24 weeks using ANOVA test and it was highly significant (p <0.001). In group A and B it was highly significant (p <0.01), between group A and C extremely significant (p <0.001) and between group B and C it was insignificant (p> 0.05) [ Table 6]. All the patients were enquired for any adverse reactions due to study drugs throughout the study period. A total of 36 adverse drug reactions were observed during the study period (09 in group A, 12 in group B and 15 in group C. The predominant  Table 7]. All the adverse drug reactions were mild and transient and did not require alteration or discontinuation of study drugs.

DISCUSSION
The prevalence of type 2 diabetes particularly in the Indian subcontinent is increasing enormously over the recent years. For the physicians to be able to use these new drugs for pharmacotherapy, clinical trials which evaluate the efficacy and safety of these drugs are important. Metformin is the most commonly used oral antihyperglycemic agent both as monotherapy and in combination with other agents. Combination of glimepiride with metformin is a wellestablished therapy for type 2 diabetes mellitus. In India there is a dearth of data regarding results of use of DPP-4 inhibitors in the Indian population. 12 15 Additional studies comparing sitagliptin or sulfonylurea add-on therapy to metformin have shown similar results for reduction of HbA1c, but not favouring either agent. 16,17 On the basis of previous observations, we compared DPP-4 inhibitors either alone or in combination with other oral hypoglycaemic agents with reference to glycemic and nonglycemic targets in patients with type 2 diabetes mellitus. A total of 90 patients suffering from type 2 diabetes mellitus were included in the study which were randomly divided into three groups each consisting of 30 patients at the time of enrolment: Group A patients were put on sitagliptin, Group B were put on metformin + glimepiride and Group C patients were given a combination of sitagliptin and metformin. The efficacy of oral hypoglycemic agents used in our study was assessed in terms of glycemic control using various tests like fasting and post prandial glucose levels and glycosylated hemoglobin. In addition the non-glycemic parameters like lipid profile and anthropometric changes were also measured. Type 2 diabetes mellitus is commonly seen in middle age individuals especially after 50 years of age (Table 1). 18 The mean age in our study was 52.3 years which was seen in collaboration with previous studies where the average age was 53.51 years and 58.3 years respectively. In this study the male: female ratio was 43:47. Females outnumber males which may be due to their more sedentary and diabetogenic lifestyle. This was similar to previous studies by Bennett P et al and Howteerakul et al which showed higher prevalence of type-2 diabetes in women than in men. 19,20 In the present study 35 patients had a positive family history indicating either one or both the parents had type 2 diabetes which was at one stage or the other transferred from one generation to another. 21 The average duration of diabetes mellitus in the present study was 5. Section: Pharmacology noted during the entire study period. The most common reactions were hypoglycemia, abdominal discomfort, weight loss, weight gain, nausea/vomiting, upper respiratory tract infections and weakness/fatigue. Abdominal discomfort was commonly seen with most of the antidiabetic drugs which has been well documented in previous studies. 25 Hypoglycemia was seen in 3 patients in group B and 4 patients in group C. No patients complained of hypoglycemia in the group which received DPP-4 inhibitors alone. Hypoglycemia is an uncommon complication of DPP-4 inhibitors. In a metaanalysis of clinical trials by Drucker DJ et al 27 and Amori RE et al 28 there were lower incidences of hypoglycemia with DPP-4 inhibitors. The incidence of hypoglycemia with other oral hypoglycemicshas been proven in many previous studies. Other adverse drug reactions were similar in all the study groups which were similar to the study by Goldstein et al. 25 The efficacy and safety of Sitagliptin either alone or in combination with other oral hypoglycemics was assessed in his 24 week study in patients with type 2 diabetes mellitus. By inhibiting the degradation of active incretins, sitagliptin increases active incretin concentrations, thereby enhancing their glucoregulatory effects. 29 In the present study all the three groups showed improvement in HbA1c, FPG, PPG and Lipid profile at the end of study period. The group with a combination of Sitagliptin and Metformin provided a greater reduction in all glycemic targets relative to other groups. DPP-4 inhibitors and other oral hypoglycemics have different mechanisms, thus predicting a potential complementary effect on lowering glucose levels. 30

Study limitations:
This was an open label study. The patients and the doctor were aware of the prescribed drugs. Hence there are more chances of errors. Secondly the sample size was small. Only 90 patients were included in the study which may not be sufficient enough to demonstrate intergroup differences in efficacy of study drugs. Thirdly the duration of follow up was just upto 24weeks. A longer follow up period may have yielded different results. Hence keeping these limitations in view, further studies with larger sample size and longer duration are needed to evaluate the magnitude of the antidiabetic effects of DPP-4 inhibitors.

CONCLUSION
Type 2 Diabetes mellitus affects middle aged patients and is more prevalent in males than females. There was an improvement in FPG, PPG and HbA1c in all the study drug groups at the end of study period. At the end of study period, the intergroup comparison showed highly significant improvement in FPG, PPG and HbA1c, indicating that the patients receiving DPP-4 inhibitors+ other oral hypoglycemic agents had a better glycemic control than the patients receiving DPP-4 inhibitors alone or other oral hypoglycemic agents. The study drug groups were similar with respect to the safety profiles. No patient discontinued the study or changed the treatment because of the adverse effects.
To conclude, all the patients showed improvement in glycemic parameters like FPG, PPG and HbA1c at the end of study period. Intergroup comparison revealed better glycemic control in patients receiving DPP-4 inhibitors+ other oral hypoglycemic agents. But further larger studies with more number of patients are needed to evaluate the magnitude of antidiabetic effects of DPP-4 inhibitors.