SECTION 18.5 Comparative Review of Oral Hypoglycemic Agents in Adults Harinder Chahal For WHO Secretariat Table of Contents Acronyms: ............................................................................................................................................................................... 3 I. Background and Rationale for the review: ....................................................................................................................... 4 II. Medications under comparative review: ......................................................................................................................... 4 Table 1 - New oral hypoglycemic agents for comparison with current EML agents .......................................................... 5 III. Literature searches and methodology: ............................................................................................................................ 5 1. Title Search Results: .................................................................................................................................................... 6 2. Statement about quality of evidence: ........................................................................................................................ 6 IV. Clinical efficacy and safety evaluation: ............................................................................................................................ 6 1. DPP-4 Inhibitors (Sitagliptin, Saxagliptin) and Metformin: ......................................................................................... 6 2. Glitazones (Rosiglitazone, Pioglitazone) and Metformin: ........................................................................................... 7 3. Alpha-glucosidase inhibitors (AGIs – Acarbose, Miglitol) and Metformin: ................................................................. 8 4. Meglitinides (Repaglinide, Nateglinide) and Metformin: ........................................................................................... 8 5. DPP-4 Inhibitors (Sitagliptin, Saxagliptin) and Sulfonylureas:..................................................................................... 9 6. Glitazones (Rosiglitazone, Pioglitazone) and Sulfonylureas: ...................................................................................... 9 7. Alpha-glucosidase inhibitors (AGIs – Acarbose, Miglitol) and Sulfonylureas: .......................................................... 10 8. Meglitinides (Repaglinide, Nateglinide) and Sulfonylureas: .................................................................................... 10 9. Statement on Amylin Analogues – Pramlintide: ....................................................................................................... 11 V. Cost, Regulatory and Current NEML Availability Evaluation: ......................................................................................... 11 Table 2: Comparative Cost Chart and Drug Approval by US and Australian Regulatory Agencies ................................... 12 Table 3: Oral hypoglycemics listed on selected NEMLs .................................................................................................... 12 VI. Summary: ....................................................................................................................................................................... 12 Appendix: .............................................................................................................................................................................. 14 Table 4: Summary: Comparative efficacy and safety of oral hypoglycemics .................................................................... 14 Table 5: Chart of systematic reviews used ....................................................................................................................... 15 Table 6: Question: Should Metformin vs DPP-4 Inhibitors be used for Diabetes Mellitus, Type 2? ................................ 16 Table 7: Question: Should Metformin vs Glitazones be used for Diabetes Mellitus Type 2? .......................................... 19 Table 8: Question: Should Acarbose vs Metformin be used for Diabetes Mellitus, Type 2? ........................................... 22 Table 9: Question: Should Metformin vs meglitinides be used for Diabetes Mellitus, Type 2? ....................................... 25 Table 10: Question: Should Glitazones vs SFU be used for Diabetes Mellitus, Type 2? ................................................... 28 Table 11: Question: Should Acarbose vs be used in SFU? ................................................................................................ 31 Table 12: Question: Should SFU vs meglitinides be used for Diabetes Mellitus, Type 2? ................................................ 34 References: ........................................................................................................................................................................... 36 Page 2 of 37 Acronyms: AGI - Alpha-glucosidase inhibitor AHRQ – Agency for Healthcare Research and Quality CHF – Congestive heart failure CI – Confidence interval CV – Cardiovascular DM – Diabetes Mellitus DPP-4 inhibitors – dipeptidylpeptidase-4 inhibitors EC – Expert Committee EML – Essential Medicines List FDA – Food and Drug Administration GRADE – Grading of Recommendations Assessment, Development and Evaluation HbA1c – Glycosylated hemoglobin HDL – High density lipoprotein-cholesterol LDL – Low density lipoprotein-cholesterol LMICs - Low- and Middle-Income Countries MSH – Management Sciences for Health NEML – National Essential Medicines List RCT – Randomized controlled trial SFU – Sulfonylureas TG – Triglycerides TGA – Therapeutics Goods Administration US – United States of America USD – United States dollar WHO – World Health Organization Page 3 of 37 I. Background and Rationale for the review: Diabetes mellitus is a chronic disease that requires life-long pharmacological and non-pharmacological management to prevent complications such as cardiovascular disease, retinopathy, nephropathy, and neuropathy.[1, 2] While type 2 diabetes mellitus is the most common form of diabetes comprising of 90% to 95% of all diabetes cases.[2] An estimated 346 million people worldwide live with diabetes, resulting in 3.4 million deaths in 2004, with more than 80% of these deaths occurring in low- and middle income countries.[3] It is projected that the death burden from diabetes will double by the year 2030.[3] According to the 2010 WHO report on NCDs, the estimated prevalence of diabetes in 2008 was about 8% for men and women in low-income countries and 10% for both sexes in upper-middle-income countries with the highest global prevalence of diabetes in Eastern Mediterranean Region and Region of the Americas.[4] The high prevalence rate is of concern since diabetes in the leading cause of renal failure, visual impairment and blindness and increases the risk of lower limb amputation by at least 10 times.[4] Additionally, patients living with diabetes may need 2 to 3 three times the health-care resources compared to people without diabetes and diabetes care may require allocation of up to 15% of national health care budgets.[4] Furthermore, given the close link between poverty and NCDs, the NCDs impose a disproportionate burden on low and middle income countries.[4] In the United States, 11 classes of medications are approved for management of DM; these include 8 oral agents such as – biguanides, sulfonylureas, meglitinides, thiazolidinediones (glitazones), alpha- glucosidase inhibitors, DPP-4 inhibitors, bile acid sequestrants, dopamine-2 agonists, and 3 injectable agents such as – GLP-1 receptor agonists (incretins), amylin analogues and insulin.[1, 5] The 18th WHO expert committee on the selection and use of essential medicines in 2011 requested a review of the current oral hypoglycemic medicines for use in adult to determine if updates to the EML are needed. [6] Currently, the EML contains two oral hypoglycemics, glibenclamide (sulfonylurea) and metformin. This document will conduct comparative analysis of four oral hypoglycemic agents – glitazones (thiazolidinediones), DPP-4 inhibitors, alpha-glucosidase inhibitors and meglitinides versus sulfonylureas (SFU) and metformin to determine their efficacy and safety, as well as conduct a cost- comparison. This review will also provide an overview of the current availability of the four agents in questions in LMICs by surveying NEMLs of 15 nations at random; as well as provide information on regulatory status of these agents in the US and Australia. The regulatory status in US and Australia was selected as an initial reference point given the stringent review and approval process required for therapeutic approval by these agencies and due to the availability of the databases in English. II. Medications under comparative review: Table 1 lists the medications reviewed by this document and the comparisons made. The 18th EC on the Selection and Use of Essential Medicines had also requested a review on pramlintide – this medication was not reviewed; a statement regarding this therapeutic peptide is made in section IV-9. Page 4 of 37 Table 1 - New oral hypoglycemic agents for comparison with current EML agents Comparison # EML Medication Comparison Medication GRADE Table Comparison 1 Metformin DPP-4 Inhibitors (Sitagliptin) Table 6 Comparison 2 Glitazones (Pioglitazone, Rosiglitazone) Table 7 Comparison