Vol 7, Suppl 2, 2014 ISSN - 0974-2441
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`Research Article
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`A STUDY ON THE CURRENT PRESCRIBING PATTERNS OF DIPEPTIDYL PEPTIDASE 4
`INHIBITORS IN A MULTI SPECIALITY HOSPITAL OUTPATIENT SETTING
`SUMAYYA MUSHTAQ1, K. RAWHEENA MAYEE1, SANA AMREEN1, V. SATYANARAYANA2, Dr. APARNA
`YERRAMILLI2*, Dr. SANTOSH RAMAKRISHNAN3
`
`1Pharm D Interns, 2Department of Pharmacy Practice, Sri Venkateshwara College of Pharmacy, Osmania University, Hyderabad
`
` 3 Consultant Endocrinologist, Magna Clinics for obesity, diabetes and endocrinology (CODE), Hyderabad.
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` Email: svcppharmd.hod@gmail.com
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`Received: 19 March 2014, Revised and Accepted: 11 April 2014
`
`ABSTRACT
`
`Objective: To evaluate the current prescribing pattern of dipeptidyl peptidase 4 inhibitors in a multi specialty hospital outpatient setting.
`
`Method: The study was a retrospective descriptive analysis of consecutive patients prescribed with DPP4 inhibitors and attending the diabetic
`clinic of the tertiary care hospital. Patient data was collected in relation to drugs prescribed, lab parameters, co morbid conditions and diabetic
`complications. The prescribing pattern of DPP4 inhibitors was studied and evaluated.
`
`Results: During the study, prescription of 74 patients who were initiated with dipeptidyl peptidase 4 inhibitors was reviewed. Sitagliptin (51%)
`was the most prescribed drug. The most commonly prescribed combinations were Metformin and DPP4 inhibitor (62%) as 2nd line agent,
`Metformin + Sulphonylureas + DPP4 inhibitor (44%) as 3rd line agents. In our study DPP4 inhibitors were initiated in patients with higher body
`mass index and Glycated hemoglobin greater than 9%.
`
`Conclusion: Our evaluation revealed the most commonly prescribed DPP4 inhibitor to be Sitagliptin. Initiation of DPP4 inhibitor was more
`commonly seen as a 3rd line agent. As DPP4 inhibitors are recently approved drugs educational intervention regarding their appropriate use is
`required.
`
`Keywords: Diabetes mellitus, Dipeptidyl peptidase 4 inhibitors, Sitagliptin, prescribing patterns, Hyperglycemia.
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`
`INTRODUCTION
`
`is a group of metabolic diseases
`Diabetes mellitus (DM)
`characterized by hyperglycaemia resulting from defects in insulin
`secretion, insulin action, or both. [1] Various agents are available
`which are used as monotherapy, or in combinations for the
`treatment of diabetes mellitus. Several of these agents are also
`associated with adverse effects
`that
`include weight gain,
`hypoglycaemia and gastrointestinal distress. There is a need
`therefore, for alternative therapies that can overcome the limitations
`associated with conventional anti-hyperglycaemic medications. DPP-
`4 inhibitors are relatively new oral hypoglycaemic drugs that have a
`role in effectively reducing blood glucose levels. DPP-4 inhibitors
`increase Glucagon-like peptide-1 (GLP-1) and Gastric inhibitory
`polypeptide (GIP) levels, which inhibit glucagon release, which in
`turn
`increases insulin secretion and
`there by decrease blood
`glucose levels.[14] The American Diabetes Association (ADA),
`American Association of Clinical Endocrinologists (AACE) and
`National Institute
`for Health and Clinical Excellence (NICE)
`guidelines suggests adding a DPP-4 inhibitor as a second line
`treatment to Metformin
`if there
`is a considerable risk for
`hypoglycaemia or if a sulfonylurea is contraindicated or-not-
`tolerated.[2] DPP4 inhibitors possess weight neutral effect without
`causing hypoglycaemia. They are more expensive when compared to
`other agents.The main objective of this study is to review the
`prescribing pattern of DPP -4 inhibitors in the treatment of Diabetes
`mellitus in a tertiary care outpatient centre.
`
`METHODS
`
`A Single-center, retrospective observational study was conducted for
`duration of 6 months with the approval of Institutional Ethics
`Committee (protocol no: SVCP/2012/01). All Adult Outpatients in
`
`
`
`
`
`the diabetic Clinic with a new initiation of DPP -4 inhibitors were
`included in the study. All in-patients, pediatric patients, pregnant
`women, and patients who were already on DPP-4 inhibitors were
`excluded from the study.
`
`Data from Patient data forms (PD) of the diabetic clinic were
`reviewed from June 2010 to July 2012, for the patients with newly
`prescribed DPP-4 Inhibitors. The PD forms were reviewed for the
`newly
`initiated DPP- 4
`inhibitors, dose, frequency, patient’s
`demographics such as age, sex, height, weight, body mass index
`(BMI), family history, duration of DM, co-morbid conditions, diabetic
`complications,
`lab parameters such as Glycated hemoglobin
`(HbA1C), Serum Creatinine (S.Cr), Micro albumin (MicrAL), Fasting
`plasma glucose (FPG), Postprandial glucose (PPG), Serum Glutamic-
`Oxaloacetic Transaminase
`(SGOT), Serum Glutamic Pyruvic
`Transaminase (SGPT) and Self monitoring blood glucose (SMBG).
`Descriptive statistics were used to report the prescribing patterns of
`DPP4 inhibitors.
`
`RESULTS In our study of 74 patients, 54 (72.9%) were males and 20
`(27.1%) were females. A majority of our study population belonged
`to the age group of 41-65years (68%). Co morbidities associated
`with our study population were hypertension (HTN) in 54%
`patients, coronary artery disease (CAD) in 3% patients and
`Dyslipidemia in 6% patients. The average HbA1C was recorded
`between the range 6.5-7.5% in 8(10.8%) patients, 22 (29.7%)
`patients between 7.6-9% and 44 (59.4%) patients >9.1% (Table 1).
`Diabetic complications such as neuropathy were found in 34
`patients (54%), retinopathy in 5 patients (8%); Gastro paresis in 1
`patient (2%), and 23 patients (36%) had no complications. Pre
`prandial glucose of the patients in our study with <130 mg/dl and
`>130 mg/dl were 16% and 84% respectively. The post prandial
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`Yerramilli et al.
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`Asian J Pharm Clin Res, Vol 7, Suppl 2, 2014, 134-136
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`glucose was found to be <180 mg/dl in 5 % and 180-250 mg/dl in 33
`% and >251 mg/dl 62 %.
`
`Table 1: Patient characteristics
`
` Parameters
`
`Ranges
`
`Averages
`
` BMI (kg/m2)
` Duration (years)
` HbA1c
` Creatinine
`(mg/dl)
` MicrAL (mg/dl)
` FPG (mg/dl)
` PPG (mg/dl)
` SGOT (U/L)
` SGPT (U/L)
`
`21.36 - 44.08
`1 week - 30years
`7 - 13.9
`0.6 - 1.8
`
`29.24 ± 4.75
`9.74 ± 7.48
`9.54 ± 1.68
`0.93 ± 0.24
`
`2 - 95
`101 – 339
`168 - 478
`11 - 45
`21 - 108
`
`22 ± 3.56
`182.5 ± 54.26
`279 ± 69.78
`22.8 ± 9.47
`43.6 ± 17.47
`
` S.
`No
`1
`2
`3
`4
`
`5
`6
`7
`8
`9
`
`BMI-Body mass index, HbA1C-Glycated hemoglobin, MicrAL-
`Micro albumin FPG-Fasting plasma glucose, PPG-Postprandial
`glucose, SGOT-Serum Glutamic-Oxaloacetic Transaminase,
`SGPT-Serum Glutamic Pyruvic Transaminase
`
`From our study we could observe that the most commonly
`prescribed DPP4 inhibitor is Sitagliptin (51 %) followed by
`Vildagliptin (32%), Saxagliptin (12%), and Linagliptin (5%). Only
`one patient was found to be on DPP4 I monotherapy with
`Saxagliptin. Most commonly prescribed total daily dose of
`Sitagliptin/Metformin was 50mg/1000 mg (34.4%) followed by
`100mg/1000 mg (34.4%). Similarly, prescribed total daily dose of
`Vildagliptin/Metformin was 100mg/1000 mg (42.8%). Different
`combinations of DPP4 I with other oral hypoglycemics are
`represented in Table 2.
`
`Table 2: Comparison of DPP4 Inhibitors as 1stLine, 2nd Line, 3rd
`Line agents
`
`S.No DPP4I initiated as
`
`1
`
`2
`
`
` 3
`
`4
`
`1st Line agent
`
`2nd Line agent
`Metformin+ DPP4 I
`SU+ DPP4 I
`Pioglitazone+ DPP4 I
`Insulin+ DPP4 I
`
`3rd Line agent
`Metformin+insulin+DPP4 I
`Metformin+ SU+ DPP4 I
`AGI+Insulin+ DPP4 I
`SU+Insulin+ DPP4 I
`Metformin+AGI+ DPP4 I
` Metformin +Pioglitazone+ DPP4 I
`
`4th Line agent
`Metformin +Pioglitazone +AGI+ DPP4 I
`Metformin+AGI+Insulin+DPP4 I
`Metformin+SU+AGI+DPP4 I
`Metformin+SU+Insulin+DPP4 I
`Metformin+Pioglitazone+Insulin+DPP4I
`Metformin+SU+Pioglitazone+DPP4 I
`
`No. Patients (%)
` (n=74)
` 1 (1.35)
`
` 21(28.4)
` 13(17.6)
` 04(5.4)
` 01(1.35)
` 03(4)
`
` 43 (58.05)
` 10(13.5)
` 23(31)
` 01(1.35)
` 02(2.8)
` 04(5.4)
` 03(4)
`
` 9(12.2)
` 01(1.35)
` 01(1.35)
` 01(1.35)
` 03(4)
` 01(1.35)
` 02(2.8)
`
` SU-sulphonyl ureas, AGI-Alpha Glucosidase Inhibitors
`
`DISCUSSION
`
`In our study majority of the population were males. Higher
`percentage of our study population belonged to the age group of 41-
`65 years as it is known that the risk of Diabetes is significantly
`higher in this age group. DPP4 inhibitors were initiated for majority
`of the overweight and obese patients, as it has an advantage of
`weight neutral effect. [4, 5, 6]
`
`About half of our study population had hypertension with lower
`incidence of coronary artery disease (CAD) and dyslipidemia.
`Initiation of DPP 4 inhibitors in Cardiac patients may be influenced
`
`by their cardio-renal protective effects of these drugs, which are still
`under study in various ongoing trials. [3, 5, 7] Family history with
`Diabetes Mellitus (DM) was found in majority of the patients.
`Initiation of DPP4 I was influenced by higher post prandial glucose,
`when compared with their pre prandial glucose levels, as it reduces
`the Post prandial glucose (PPG) primarily. [8, 9, 5, 10]
`
`In our study DPP4 inhibitors were initiated in patients with longer
`duration of diabetes, HbA1C >9% and in whom complications had
`already begun but as per the ADA and AACE guidelines DPP4I must
`be initiated at an early HbA1c level of <9%, reflecting inertia
`towards these newer agents. They may also be used as a rescue drug
`in patients with longer duration of Diabetes, prior to the use of
`insulin.
`
`DPP4I can be used in renal/hepatic impaired patients; with
`appropriate dosage adjustments. In one patient appropriate dose
`adjustment for Sitagliptin was done. Commonly used other anti-
`diabetic drugs are Metformin, sulphonylureas, insulin, Pioglitazone
`and Alpha Glucosidase Inhibitors. From our study we could observe
`that the most commonly prescribed gliptin was Sitagliptin. This can
`be attributed to the fact that it is the first approved DPP4 inhibitor in
`the market and also to the Asian study (China India Korea study),
`which suggests that sitagliptin was more effective in the Indian
`population with greater HbA1c reductions. Linagliptin
`is a
`comparatively recently approved drug and its use in future is
`expected to increase in due course of time, as it’s hepatic clearance is
`an added advantage over the other DPP4 inhibitors[9]
`
`DPP4 inhibitors are known to reduce blood glucose as effective as
`other oral anti diabetics when prescribed as monotherapy when
`HbA1c
`levels are between 6.5-7.5%, with minimal risk of
`hypoglycemia. [4, 11, 12, 13]
`
`CONCLUSION
`
`From our study it was observed that the most commonly prescribed
`gliptin is sitagliptin. Most of our study population initiated on DPP4
`I, have their HbA1c greater than 9%, potentially influenced by the
`BMI levels. However, the duration of DM has no effect on the
`prescriptions of Gliptins. They are initiated as a 3rd line agent in
`patients with higher post prandial glucose as they effectively reduce
`it. The most commonly prescribed anti diabetic agents along with
`Gliptins is Metformin, followed by Sulphonylureas, as a combination
`pill, use of Metformin and Sitagliptin is common. Maximum benefit of
`the gliptins can be achieved when initiated in the earlier stages of
`DM, but it is not being followed so. The compliance of the gliptin use
`may be affected by its cost. Awareness among clinicians is needed
`regarding the time of initiation of DPP4 I in type 2 DM.
`
`ACKNOWLEDGMENTS
`
`It is a pleasant task to express our thanks to all those who
`contributed in many ways to the success of this study. We are also
`extremely indebted to Dr. Afsar and Dr. Sanjeev Sharma, Clinical
`Pharmacologist, Apollo Hospitals. We are thankful to the Principal
`and Management of Sri Venkateshwara College of Pharmacy, Sugar
`clinic, Apollo Hospitals, Jubilee Hills for their support in carrying out
`this project.
`
`REFERENCES
`
`1. Alwin C. Powers Diabetes Mellitus. In: Dan L. Longo, Anthony S.
`Fauci, et al. editors. Harrison's Principles of
`Internal
`Medicine.18th Ed. New York: McGraw-Hill Medical Publishing
`Division; 2008. p. 2968-2979.
`2. Amanda A, Allerdyce C, Doherty T, Farmer A. Type 2 diabetes:
`newer agents. National Institute for Health and Clinical
`Excellence short clinical guideline. 2009; 18-24.
`Tessey J, Pegah Y. Cardiovascular effects of the DPP-4 inhibitors
`Diabetes & Vascular Disease Research. JAMA. 2012; 9(2): 109–
`116.
`4. Karagiannis T, Paschos P, Paletas K, Matthews D R. Dipeptidyl
`peptidase-4 inhibitors for treatment of type2 diabetes mellitus
`in the clinical setting: Systematic review and Meta-analysis.
`BMJ. 2012; 12:1-15.
`
`3.
`
`
`
`135
`
`

`
`Yerramilli et al.
`
`Asian J Pharm Clin Res, Vol 7, Suppl 2, 2014, 134-136
`
`7.
`
`8.
`
`9.
`
`5. Nasser M. Use of Dipeptidyl Peptidase-4 Inhibitors for the
`Treatment of Patients with Type2 Diabetes Mellitus and
`Chronic Kidney Disease. Postgraduate medicine- The rapid
`peer reviewed journal for physicians. 2007; 124: 4-8.
`6. G. Bolli, F. Dotta, Rochotte E, Cohen SE. Efficacy and tolerability
`of vildagliptin vs. pioglitazone when added to metformin: a 24-
`week randomized double-blind study. Diabetes, Obesity and
`Metabolism 2008; 82–90.
`Patil HR, Al Badarin FJ, Al Shami HA, Bhatti SK. Meta-analysis of
`effect of dipeptidyl peptidase-4 inhibitors on cardiovascular
`risk in type 2 diabetes mellitus. Am J Cardiol 2012 Sep 15;
`110(6):826-33.
` Gupta V, Kalra S. Choosing a Gliptin. Indian J Endocr Metab.
`2011; 15: 298-308.
`John A. Welz. Tradjenta (Linagliptin) Tablets A New Type 2
`Diabetes Treatment Option for Patients with Inadequate
`Glycaemic Control. Int J Clin Pharm. 2006; 60:1454-1470.
`J. Garber, A. Schweizer, M. A. Baron, E. Rochotte, S. Dejager.
`Vildagliptin
`in Combination with Pioglitazone
`improves
`glycaemic control in patients with type 2 diabetes failing
`thiazolidinedione monotherapy: A Randomized, Placebo-
`controlled study. Diabetes Obes Metab. 2007; 166–174.
` Rosenstock J. Treatment of elderly patients with type 2
`diabetes mellitus: a systematic review of the benefits and risks
`of dipeptidyl peptidase-4 inhibitors. Diabetes Care 2009 April;
`24: 631-636.
`12. Zachary BG, Drexler A. What role will gliptins play in glycemic
`control? Cleveland Clinic Journal of Medicine 2008; 75:305-
`310.
`13. Tahrani AA, Piya MK, Anthony H. Barnett. Saxagliptin: a new
`DPP-4 inhibitor for the treatment of type 2 diabetes mellitus.
`Advances in Therapy 2009 Mar; 26(3):249-62.
`14. Kothandam H, Umamaheswari P, Wicket SD. Hormone based
`therapy in type 2 diabetes mellitus. AJPCR. 2012; 5(4): 20-24
`
`10.
`
`11.
`
`
`
`
`
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