Comparative Review of Oral Hypoglycemic Agents in Adults

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1 SECTION 18.5 Comparative Review of Oral Hypoglycemic Agents in Adults Harinder Chahal For WHO Secretariat

2 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: Title Search Results: Statement about quality of evidence:... 6 IV. Clinical efficacy and safety evaluation: DPP-4 Inhibitors (Sitagliptin, Saxagliptin) and Metformin: Glitazones (Rosiglitazone, Pioglitazone) and Metformin: Alpha-glucosidase inhibitors (AGIs Acarbose, Miglitol) and Metformin: Meglitinides (Repaglinide, Nateglinide) and Metformin: DPP-4 Inhibitors (Sitagliptin, Saxagliptin) and Sulfonylureas: Glitazones (Rosiglitazone, Pioglitazone) and Sulfonylureas: Alpha-glucosidase inhibitors (AGIs Acarbose, Miglitol) and Sulfonylureas: Meglitinides (Repaglinide, Nateglinide) and Sulfonylureas: Statement on Amylin Analogues Pramlintide: V. Cost, Regulatory and Current NEML Availability Evaluation: Table 2: Comparative Cost Chart and Drug Approval by US and Australian Regulatory Agencies Table 3: Oral hypoglycemics listed on selected NEMLs VI. Summary: Appendix: Table 4: Summary: Comparative efficacy and safety of oral hypoglycemics Table 5: Chart of systematic reviews used Table 6: Question: Should Metformin vs DPP-4 Inhibitors be used for Diabetes Mellitus, Type 2? Table 7: Question: Should Metformin vs Glitazones be used for Diabetes Mellitus Type 2? Table 8: Question: Should Acarbose vs Metformin be used for Diabetes Mellitus, Type 2? Table 9: Question: Should Metformin vs meglitinides be used for Diabetes Mellitus, Type 2? Table 10: Question: Should Glitazones vs SFU be used for Diabetes Mellitus, Type 2? Table 11: Question: Should Acarbose vs be used in SFU? Table 12: Question: Should SFU vs meglitinides be used for Diabetes Mellitus, Type 2? References: Page 2 of 37

3 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

4 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 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), alphaglucosidase 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 18 th 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 costcomparison. 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 18 th 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

5 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 3 Alpha-glucosidase inhibitors (Acarbose) Table 8 Comparison 4 Meglitinides (Repaglinide, Nateglinide) Table 9 Comparison 5 Sulfonylureas DPP-4 Inhibitors (Sitagliptin) None Comparison 6 Glitazones (Pioglitazone, Rosiglitazone) Table 10 Comparison 7 Alpha-glucosidase inhibitors (Acarbose) Table 11 Comparison 8 Meglitinides (Repaglinide, Nateglinide) Table 12 Comparison 9 Pramlintide acetate Not reviewed None III. Literature searches and methodology: The purpose of this review is to present evidence for safety, efficacy and cost for DPP-4 inhibitors, glitazones, alpha-glucosidase inhibitors and meglitinides as compared to the current EML oral hypoglycemics, metformin (biguanide) and glibenclamide (sulfonylurea). Literature search was focused to answer this question. The Cochrane library and PubMed databases were searched for existing systematic reviews on hypoglycemic medications up to July 2012 using the following terms: sitagliptin, saxagliptin, DPP-4 inhibitors, dipeptidylpeptidase-4 inhibitors; alpha-glucosidase inhibitors, acarbose; sulfonylureas, glibenclamide, glyburide, glimepiride, gliclazide; thiazolidinediones, glitazones, pioglitazone, rosiglitazone; biguanides, metformin; meglitinides, nateglinide, repaglinide, mitiglinide. Eight (8) reviews were identified relevant to topic of this review (Table 4); 6 reviews from Cochrane and 2 from AHRQ.[7-14] The primary reviews used for this report were by Bennett et al and Bolen et al due to their most recent publication dates and review of medications of interest.[7, 9] However, other reviews as shown in Table 4, were used and referenced as needed to clarify and to add to the body of evidence. Bennett et al reviewed literature up to April 2010 on all anti-diabetic medications except alpha-glucosidase inhibitors.[7] Bolen et al reviewed literature up to January 2006 on all anti-diabetic medications of interest.[9] New, English-language literature beyond the periods covered by the systematic reviews was searched using Cochrane Central Register for Controlled Trials for titles addressing comparative safety and efficacy of monotherapy with medications for whom a paucity of data was determined. For alphaglucosidase inhibitors the databases for searched from February 2006 up to July For meglitinides and DPP-4 inhibitors the databases were searched from June 2010 up to July The following search terms were used: sitagliptin, saxagliptin, DPP-4 inhibitors, dipeptidylpeptidase-4 inhibitors; alphaglucosidase inhibitors, acarbose; sulfonylureas, glibenclamide, glyburide, glimepiride, gliclazide, glipizide; biguanides, metformin; meglitinides, nateglinide, repaglinide, mitiglinide. No additional search was conducted on glitazones or DPP-4 inhibitors versus metformin because it was determined the evidence available in the systematic reviews used on these comparisons was sufficient for review of efficacy and safety. The results of these searches are provided under section III-1 Title Search Results. Page 5 of 37

6 Since our search focused on comparative literature for the classes of medications in question, this review does not include many of the placebo-controlled studies conducted for safety and efficacy of these agents. The WHO Essential Medicines website was used to reference NEMLs of 15 nations at random to determine how many of the surveyed nations had four classes of drugs in question on their NEML.[15] (Table 3) MSH 2010 International Drug Price Indicator Guide was referenced first to obtain median buyer price per unit.[16] However, for majority of the medications of interest, prices were not available in MSH 2010 guide, Lexi-Comp online database was used for price and maximum daily dose of all medications as a reference source for pricing.[17] 1. Title Search Results: a. DPP-4 Inhibitors versus SFU: 80 trials resulted in the search; 6 studies were identified as relevant to the question from title review. Two were duplicates from the Bennett et al review. None of the 4 new studies identified compared DPP-4 monotherapy with SFU monotherapy.[18-21] These studies were included in this review due to their relevance to efficacy and safety outcomes. b. Meglitinides versus Metformin: The search resulted in 3 trials. The trials did not address the question of comparative efficacy and safety of these agents. No new trials of interest were identified. c. Meglitinides versus SFU: The search resulted in 38 trials. 2 new trials of interest were identified. These trials did not address all outcomes of interest; however, they were included in this review due to their relevance to the safety outcome data.[22, 23] d. Alpha-glucosidase inhibitors versus metformin: The search resulted in 17 trials. The trials did not address the question of comparative efficacy and safety of these agents. No new trials of interest were identified. e. Alpha-glucosidase inhibitors versus SFU: The search resulted in 11 trials. The trials did not address the question of comparative efficacy and safety of these agents. No new trials of interest were identified. 2. Statement about quality of evidence: The quality evidence presented in the systematic reviews and other clinical trials used in this review were evaluated using the GRADE methodology. GRADE tables were prepared for efficacy and safety outcomes, whenever possible, based on the evidence presented in the referenced reviews; other GRADE assessments were at the judgment of the author of this review. When necessary, the primary publication was referenced to determine GRADE rating. The strength of evidence evaluations are presented in Tables 6 through 12 in the appendix. IV. Clinical efficacy and safety evaluation: 1. DPP-4 Inhibitors (Sitagliptin, Saxagliptin) and Metformin: Page 6 of 37

7 Efficacy: Bennett et al reviewed three RCTs that compared metformin with DPP-4 inhibitors, and found greater reductions in HbA1c with metformin.[7] The between-group difference of -0.4 percent (95 percent CI -0.5 percent to -0.2 percent) were observed, favoring metformin.[7] For weight loss, 3 short duration RCTs comparing these 2 agents found greater reduction in weight with metformin.[7] Although evidence favors a greater reduction in LDL and a greater increase in HDL with metformin compared to DPP-4 inhibitors, no statistical significance is seen.[7] While a greater reduction in triglycerides is seen with DPP-4 inhibitors, these results are also not statistically significant.[7] Bennett et al, found insufficient data to make a determination regarding all-cause mortality and cardiovascular mortality benefits between DPP-4 inhibitors and metformin.[7] Safety: DPP-4 inhibitors have a better safety profile in terms of mild to moderate hypoglycemia symptoms and gastrointestinal side effects.[7] In one 24-week RCT mild to moderate hypoglycemic symptoms were observed at a rate of 3.3% for metformin and 1.7% with DPP-4 inhibitors, however, the results were not statistically significant (p=0.12).[7, 24] One RCT showed an occurrence of adverse GI events (nausea/vomiting/diarrhea/abdominal discomfort) in metformin group at a rate of 20.7% and 11.5% in DPP-4 inhibitor group, in which diarrhea accounted for majority of the difference at 10.9% with metformin and 3.6% for sitagliptin.[7] The high incidence of diarrhea with metformin is consistent with published literature as a common side-effect of therapy and usually subsides with continued therapy.[25] GRADE evidence is summarized in Table Glitazones (Rosiglitazone, Pioglitazone) and Metformin: Efficacy: From the 14 RCTs comparing glitazones and metformin reviewed by Bennett et al, no between-group differences in reduction of HbA1c was observed.[7] A review of 8 RCTs comparing weight loss between therapy with metformin and glitazones, found weight loss with metformin and mild increases in weight with glitazone treatment.[7] A four-year RCT observed a between-group reduction in weight of 6.9kg favoring metformin over rosiglitazone.[7, 26] A review of 6 RCTs favors metformin for reduction in LDL and TG over rosiglitazone, with pooled between-group difference of -12.8mg/dL for LDL and -26.9mg/dL for TG.[7] However, an evaluation of 6 RCTs found no HDL benefit with either metformin or rosiglitazone.[7] There was no all-cause mortality or cardiovascular mortality benefit with either treatment.[7, 26] Safety: A large 4-year double-blind RCT (ADOPT) with over 1400 participants in each arm found no significant differences in the occurrence of self-reported hypoglycemic events in patient assigned to the rosiglitazone or the metformin group, with one serious hypoglycemic event in each group.[7, 26] Bennett et al notes conflicting evidence for rate of CHF with metformin and glitazones.[7] Three RCTs and four observational studies provide a low grade evidence for increased CHF with glitazones.[7] However, the ADOPT study notes no difference in CHF adverse events between either treatment group.[7, 26] It is important note that the FDA has placed a boxed warning for all thiazolidinedione agents, including rosiglitazone and pioglitazone for congestive heart failure.[27-29] Metformin has been consistently shown to have a greater occurrence of GI adverse events over glitazones.[7] Page 7 of 37

8 GRADE evidence is summarized in Table Alpha-glucosidase inhibitors (AGIs Acarbose, Miglitol) and Metformin: Efficacy: Van de Laar et al. and Bolen et al. reviewed 2 RCTs comparing submaximal dosed metformin and maximally dosed acarbose showing no significant differences in HbA1c reduction between the two treatment groups.[9, 14] No statistically significant differences were observed for weight reduction with either AGIs or metformin.[9, 14] Reviews by Van de Laar et al and Bolen et al, found no benefits to HDL or TG with either therapy. [9, 14] One study, using submaximal doses of metformin and maximum doses of acarbose showed a reduction in LDL favoring acarbose.[14] No evidence is available to determine all-cause or CV mortality benefits with either treatment. Safety: One RCT reported a low incidence of hypoglycemia risk with both agents, however, provided no statistical analysis.[30] Van de Laar et al and Bolen et al reviews based on two trials, report higher rate of side effects for acarbose, favoring metformin.[9, 14] For total adverse events, one study reported an odds ratio of 15 in favor of metformin.[14] Van de Laar et al, reviewed one RCT comparing miglitol (AGI) and metformin, in which no statistically significant differences in GI adverse events were observed.[14] Another study reports the incidence of withdrawal from the study due to GI adverse effects was 58% for acarbose arm and 14.8% for metformin.[9, 30] GRADE evidence is summarized in Table Meglitinides (Repaglinide, Nateglinide) and Metformin: Efficacy: Bennett et al reviewed 3 RCTs comparing metformin with meglitinides, which found similar effects on HbA1c with both treatments.[7] Two studies compared metformin and repaglinide at comparable doses showing non-significant HbA1c differences between treatment groups.[7] Evidence regarding benefits of weight reduction with meglitinides or metformin is low, however, indicates generally non-significant weight differences, with a slight trend that may favor metformin.[7] Similarly, evidence suggests a reduction in LDL and TG that may favor metformin over meglitinides, however is non-significant.[7] For HDL, their maybe a benefit with repaglinide over metformin, however the results are non-significant.[7] Overall, the evidence for benefits to lipid profile with meglitinides versus metformin is low.[7] There is low level of evidence to determine all-cause mortality or CV mortality benefits, however, one 24-week trial found one death in the metformin group and no deaths in the nateglinide treatment group.[7, 31] The one death in the metformin group was judged by investigators to be unlikely to be associated with therapy.[31] A recent nationwide study of over 100,000 Danish residents >20years of age, determined no statistical difference in all-cause mortality between patients taking repaglinide versus metformin.[32] Safety: In Bennett et al review, 5 RCTs determined a favorable side effect profile for mild or moderate hypoglycemic events for metformin over meglitinides with an OR of 3.01.[7] Comparatively, meglitinides present with a favorable GI adverse effect profile over metformin.[7, 33] In one double- Page 8 of 37

9 blind, RCT combined GI side-effects were 70% and 47% for metformin and repaglinide, respectively.[33] GRADE evidence is summarized in Table DPP-4 Inhibitors (Sitagliptin, Saxagliptin) and Sulfonylureas: Efficacy: Bennett et al reviewed one 12-week moderately-sized double-blind RCT compared high dose sitagliptin with maximum dose glipizide and found similar reductions in HbA1c, -0.77% versus -1.00%, for DPP-4 inhibitor and SFU, respectively.[7] Additional studies comparing DPP-4 inhibitor or SFU add-on therapy to metformin have shown similar results for reduction of HbA1c, not favoring either agent.[7, 19, 20, 34] Evidence indicates a benefit for weight reduction with a DPP-4 inhibitor over SFU, either as monotherapy and as combination therapy with metformin.[7, 19, 20, 34] However, due to lack of direct monotherapy comparative data, unable to determine true effect. Bennett et al review of lipid profile indicated an increase in LDL and HDL with sitagliptin over SFU, while the increase in TG with sitagliptin was less than the increase with SFU (3.6% versus 7.0%).[7] However, in all lipid measures reviewers found an overlapping CI after placebo-subtracted change from baseline in each group.[7] There is insufficient data to determine all-cause mortality benefits for this comparison.[7] Safety: Sitagliptin consistently has a better hypoglycemic profile compared to SFUs as monotherapy and as combination therapy with metformin.[7, 18-20] Additionally, reduced incidence of hypoglycemia with sitagliptin versus glipizide or glimepiride was observed during Ramadan in a multi-center study.[18] This is a specialized patient population since observers of Ramadan abstain from food or water from dawn until dusk for the duration of the month of Ramadan.[18] No differences in GI sideeffects have been observed with DPP-4 inhibitors and SFU as monotherapy or combination therapy.[7, 20, 35] GRADE evidence: For all outcomes, the evidence strength for DPP-4 inhibitor comparison with SFUs is Low, with the exception of hypoglycemia and GI adverse events, for which the evidence strength is Moderate. One short term RCT evaluating direct comparison of DPP-4 inhibitor with SFU was identified [35]; this trial is reviewed in Bennett et al.[7] Low is detected, the outcomes observed were direct, however, it is not possible to determine consistency (due to only one study) and there is concern for precision since the trial moderately sized and no statistical analysis was provided for some outcomes (such as GI side effects), and differing doses on sitagliptin and glipizide (based on titration protocol) were compared leading to uncertainty in results. 6. Glitazones (Rosiglitazone, Pioglitazone) and Sulfonylureas: Efficacy: Bennett et al reviewed 13 RCTs comparing glitazones or thiazolidinediones (TZDs) (pioglitazone and rosiglitazone) and second-generation sulfonylureas (glibenclamide, glimepiride, and glyburide). The review found both treatments had similar effects on HbA1c.[7] Five RCTs with up to 1 year or less in duration, compared glitazones and a SFU, showing greater weight gain with glitazones, favoring SFUs.[7] Five RCTs compared rosiglitazone or pioglitazone with a SFU, indicating a greater increase in LDL with glitazones relative to a SFU.[7] Eight RCTs compared rosiglitazone or Page 9 of 37

10 pioglitazone with a SFU, indicating a favorable increase in HDL with glitazones relative to a SFU.[7] Pioglitazone is favored for a greater decrease in TG over SFUs in 6 RCTs.[7] However, when comparing rosiglitazone and SFUs, Bennett et al found conflicting evidence for benefits of TG lowering. In one RCT, while both rosiglitazone (at 8mg dose) and a SFU were associated with a decrease in TG, the differences were non-significant; in another RCT a lower dose (4mg) of rosiglitazone lowered TG relative to a SFU, however, at a dose of 8mg, rosiglitazone increased TG relative to SFU with no statistical significance reported.[7] The ADOPT study showed all-cause mortality and cardiovascular mortality to be similar for rosiglitazone and glyburide at 2.3% and 2.2%, respectively.[7, 26] As above, it should be noted that the FDA has placed a boxed warning for all thiazolidinedione agents, including rosiglitazone and pioglitazone for congestive heart failure.[27-29] Safety: Five RCTs determined a greater mild to moderate hypoglycemia with SFUs over glitazones with an OR of 3.9.[7] Although the ADOPT study with over 1300 participants in each arm reported no statistical significance for outcome of hypoglycemia between rosiglitazone and glyburide.[7] Bennett et al reviewed 4 RCTs looking at outcome of CHF with glitazones versus SFU and found an increase of CHF incidence with glitazones over SFUs with an OR of 1.68.[7] While the review did not show statistical significance, clinical significance could not be ruled out.[7] Three RCTs did not show a consistent difference in the occurrence of diarrhea between groups treated with pioglitazone or rosiglitazone and glyburide.[7] GRADE evidence is summarized in Table Alpha-glucosidase inhibitors (AGIs Acarbose, Miglitol) and Sulfonylureas: Efficacy: Van de Laar et al reviewed 8 RCTs comparing SFU and acarbose showing a non-significant trend for reduction in HbA1c in favor of SFU.[14] However, for most comparisons the review found that the SFU was dosed sub-maximally.[14] Van de Laar et al review found no statistically significant differences in weight between AGIs and SU.[14] Five RCTs show Reviews of RCTs by Van de Laar et al and Bolen et al, found no benefit for lipid profile (LDL, HDL or TG) when comparing acarbose versus a SFU.[9, 14] All-cause mortality and cardiovascular mortality evidence is limited to allow for determination of mortality benefit between SFU and acarbose.[9] One small RCT comparing acarbose and tolbutamide showed no statistical difference in mortality benefit between the two treatments.[9, 14] Safety: SFUs are favored for their overall and GI side effect profile. One RCT favors SFU over acarbose for GI side effects with an OR of 7.70.[14] However, in contrast, in terms hypoglycemic risks acarbose is favored over SFU.[9, 36] GRADE evidence is summarized in Table Meglitinides (Repaglinide, Nateglinide) and Sulfonylureas: Efficacy: Bennett et al reviewed 7 RCTs comparing a second-generation sulfonylurea with repaglinide, showing a pooled between-group difference of 0.1 percent (95 percent CI -0.2 percent to 0.3 percent) slightly favoring meglitinides.[7] However, when only studies using comparable doses of the two agents Page 10 of 37

11 were evaluated (3 out 7 studies), no differences in HbA1c reduction were observed.[7] The review found that no single study significantly influenced the results.[7] A review of 6 RCTs comparing meglitinides with SFUs showed no benefit for reduction in weight.[7] No statistically significant differences have been observed for improvement of lipid profile (LDL, HDL, TG) when comparing SFUs and meglitinides.[7] Evidence is limited to for mortality benefits when comparing these two classes of drugs. Bennett et al reviewed one, 1-year long RCT that looked at the all-cause mortality between repaglinide and glyburide and observed 3 deaths out of 362 participants in the repaglinide group and 1 death out of 182 participants in the glyburide group.[7] Each treatment group had one CV related death.[7] To note, the reviewers identified the strength of the evidence for all-cause mortality and CV mortality outcomes as low.[7] Safety: Six studies reviewed by Bennett et al showed a lower incidence of hypoglycemia with meglitinides when compared with a SFU, however, the pooled results were not statistically significant.[7] The lower incidence of hypoglycemia is supported by 2 RCTs since the Bennett review.[22, 32] Additionally, a high-quality trial comparing repaglinide versus glibenclamide in patients observing Ramadan, showed statistically significant lower incidence of hypoglycemia with repaglinide than with glibenclamide (p<0.001).[7, 37] As mentioned above, Ramadan is a period during which the practitioners do not drink or eat from sunrise to sunset, so this study applies to a specific subset of patient population.[18, 37] The same study and two others have found that apart from incidence of hypoglycemia, both treatments were equally well tolerated.[37-39] However, there is paucity of data for evaluation of comparative GI side-effects between these agents. GRADE evidence is summarized in Table Statement on Amylin Analogues Pramlintide: The 18 th EC on Essential Medicines had also requested a comparative review of pramlintide, an amylin analogue.[6] However, a detailed review on this medication was not prepared because it was determined to be not appropriate for a comparison with oral hypoglycemics, the primary focus of this review. Pramlintide is a subcutaneous injectable synthetic analog of the human amylin peptide, a hormone produced by the pancreas for glycemic control during postprandial period.[40] Pramlintide works by delaying gastric emptying to reduce the initial postprandial increase in glucose, preventing a rise in plasma glucagon during postprandial period and causes satiety to decrease caloric intake.[40] Pramlintide is indicated for use prior to meals as an adjunct to insulin with or without SFU or metformin.[40] V. Cost, Regulatory and Current NEML Availability Evaluation: Table 2 provides an overview of the cost per unit, per 30 units and estimated monthly cost of treatment with medications under review in US dollars. Metformin and glibenclamide prices are from MSH and Lexi-Comp online; however, the cost of other agents was not available from MSH, therefore, Lexi- Comp online was used to evaluation this provides costs of medications as they pertain to US markets.[16, 17] Regulatory status of medications in the US (FDA) and Australia (TGA) is also Page 11 of 37

12 shown.[27, 41] As mentioned above, 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. Table 3 evaluates the availability of DPP-4 inhibitors, glitazones, acarbose and meglitinides across 15 low and middle-income countries based on the NEML for each nation. The countries for this review were selected at random from the WHO website hosting NEMLs.[15] Table 2: Comparative Cost Chart and Drug Approval by US and Australian Regulatory Agencies Medication (Name and Strength) Cost per unit (USD) Cost/30 tablets (USD) Daily Maximum Dose[17] Monthly cost based on maximum dosing (USD) FDA Approved TGA Approved Metformin 500mg* [16] mg/day 1.30 Yes Yes Glibenclamide 5mg* [16] mg/day 0.52 Yes Yes Prices from Lexi-Comp Online (US based prices) [17] Metformin 500mg* mg/day Yes Yes Metformin 1000mg* mg/day Yes Yes Glibenclamide 5mg* mg/day Yes Yes Sitagliptin 25mg mg daily Yes Yes Sitagliptin 100mg mg daily Yes Yes Rosiglitazone 2mg mg once or BID Yes Yes Rosiglitazone 8mg mg once or BID Yes Yes Pioglitazone 15mg mg/day Yes Yes Pioglitazone 45mg mg/day Yes Yes Acarbose 25mg* mg TID Yes Yes Acarbose 100mg* mg TID Yes Yes Nateglinide 60mg* mg TID Yes No Repaglinide 0.5mg mg daily Yes Yes Repaglinide 2mg mg daily Yes Yes *Denotes generic price Table 3: Oral hypoglycemics listed on selected NEMLs # Country DPP-4 Inhibitors (Sitagliptin) Glitazones (Pioglitazone and Rosiglitazone) Alpha-glucosidase inhibitors (Acarbose) Meglitinides (Repaglinide and Nateglinide) 1 Bangladesh No No No No 2 China No No No No 3 Dominican Republic No No No No 4 Ecuador No No No No 5 Fiji No No No No 6 Ghana No No No No 7 India No No No No 8 Iran No Yes (pioglitazone) Yes (acarbose) Yes (repaglinide) 9 Kyrgyzstan No Yes (Rosiglitazone) No No 10 Malta No No Yes (acarbose) Yes (repaglinide) 11 Morocco No No Yes (acarbose) No 12 Malaysia No No No No 13 Namibia No No No No 14 Nigeria No No No No 15 Oman No Yes (rosiglitazone) No No Total # of surveyed countries with identified medications on the NEML VI. Summary: Page 12 of 37

13 This document provides a comprehensive comparative efficacy, safety and cost profile of four classes of oral hypoglycemic agents glitazones, DPP-4 inhibitors, alpha-glucosidase inhibitors and meglitinides versus sulfonylureas and metformin using GRADE methodology in Section IV and in Tables 6 through 12. Table 4 provides a summary of the key efficacy and safety outcomes alongside the strength of evidence. The summary table also provides a relative comparison of cost for the agents in review compared to metformin and glibenclamide as baseline agents. The cost comparison is based on US market as referenced from Lexi-Comp online database for the recommended maximum daily dose. Costs for metformin 500mg strength and glibenclamide 5mg strength was used as these dosage strengths are on the EML and compared to maximum available strength for the comparative agents. Additionally this review has shown the limited availability of these agents on NEMLs from a survey of 15 LMICs in Table 3 and provided information on regulatory status of these agents in the US and Australia in Table 2. Evidence on efficacy, safety, cost and availability on selected NEMLs does not support the addition of any agent from the four classes of oral hypoglycemics reviewed glitazones, DPP-4 inhibitors, alphaglucosidase inhibitors and meglitinides to the EML at this time. Page 13 of 37

14 Appendix: Table 4: Summary: Comparative efficacy and safety of oral hypoglycemics Comparison HbA1c Weight LDL HDL TG Hypoglycemia Adverse events (GI) Metformin versus (outcome and strength of evidence) Relative Cost: Metformin Baseline [US$26.00/month for 500mg tablets (strength on EML)] 1 DPP-4 inhibitors (Sitagliptin, Saxagliptin) Favors Metformin Favors Metformin (Low) (Very Low) (Low) (High) Favors DPP-4-I (Very Low) 2 Glitazones (Rosiglitazone, Pioglitazone) 3 AGIs (Acarbose, Miglitol) 4 Meglitinides (Nateglinide, Repaglinide) Favors Metformin (High) (Low) Favors Metformin Favors Acarbose Favors Metformin (Low) (High) Unclear (Low) Favors Metformin (Low) Favors Glitazones (High) Favors Metformin Favors Meglitinides (High) Sulfonylureas versus (outcome and strength of evidence) Relative Cost: Glibenclamide Baseline [US$ 15.99/month for 5mg tablets (strength on EML)] 5 DPP-4 inhibitors (Sitagliptin, Saxagliptin) (Low) Unclear (Low) (Low) (Low) (Low) Favors DPP-4-I 6 Glitazones (Rosiglitazone, Pioglitazone) 7 AGIs (Acarbose, Miglitol) 8 Meglitinides (Nateglinide, Repaglinide) (High) Favors SFU (Low) (High) Favors SFU (Low) (High) (Low) Favors Glitazones (Low) (High) Unclear (Low) (High) (Low) (High) Favors AGI (High) Favors Meglitinides (High) Favors SFU (High) Unknown (n/a) Relative Cost (cost for maximum monthly dose) Sitagliptin 100mg: 9x greater than Metformin Rosiglitazone 8mg: 9.6x greater Pioglitazone 45mg: 11.9x greater Acarbose 100mg: 3.11x greater Nateglinide 60mg: 11x greater Repaglinide 2mg: 27x greater Sitagliptin 100mg: 14.6x greater than Glibenclamide Rosiglitazone 8mg: 15.6x greater Pioglitazone 45mg: 19x greater Acarbose 100mg: 5x greater Nateglinide 60mg: 18x greater Repaglinide 2mg: 43x greater Page 14 of 37

15 Table 5: Chart of systematic reviews used Drug Class Drugs Review Period Reviewed Alpha-glucosidase inhibitors 1. Acarbose 2. Miglitol 3. Voglibose 1. Sitagliptin 2. Saxagliptin 1. Repaglinide 2. Nateglinide Alpha-glucosidase inhibitors for type 2 diabetes mellitus (Van de Laar FA)[14] Up to: 29 April 2003 DPP-4 Inhibitors Dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes Up to: 30 January 2008 Mellitus (Richter B)[12] Meglitinide Meglitinide analogues for type 2 diabetes mellitus (Black C)[8] Up to : 30 October 2006 Analogues Biguanides 1. Metformin Metformin monotherapy for type 2 diabetes mellitus (Saenz Up to: 29 September A)[13] Glitazones 1. Rosiglitazone Rosiglitazone for type 2 diabetes mellitus (Richter B)[11] Up to: 29 April Pioglitazone Pioglitazone for type 2 diabetes mellitus (Richter B)[10] Up to: 30 August All above All above Comparative Effectiveness and Safety of Oral Diabetes Up to: January 2006 Medications for Adults with Type 2 Diabetes. Comparative Effectiveness (Bolen et al.)[9] All above except Alpha-glucosidase inhibitors All above except Alpha-glucosidase inhibitors Oral Diabetes Medications for Adults With Type 2 Diabetes: An Update (Bennett et al.)[7] Up to: April 2010 Page 15 of 37

16 Table 6: Question: Should Metformin vs DPP-4 Inhibitors be used for Diabetes Mellitus, Type 2? Bibliography: Oral diabetes medications for adults with type 2 diabetes: An update. Bennett W. et al. Quality assessment Summary of Findings Participants (studies) Follow up Risk of Inconsistency Indirectness Imprecision Publication Overall quality of evidence Study event rates (%) Relative effect (95% CI) Anticipated absolute effects With DPP-4 Inhibitors With Metformin Risk with DPP-4 Inhibitors Risk difference with Metformin (95% CI) Mean difference in HbA1c for Metformin vs DPP-4 Inhibitors (CRITICAL OUTCOME; measured with: %; Better indicated by lower values) 1921 (3 studies) 24 serious 1 MODERATE 1 due to in hba1c for metformin vs dpp-4 inhibitors in the control -0.7 % in hba1c for metformin vs dpp-4 inhibitors in the intervention 0.37 lower (0.54 to 0.2 lower) Mean difference in weight for Metformin vs DPP-4 Inhibitors (NOT IMPORTANT OUTCOME; measured with: Kg; Better indicated by lower values) 1918 (3 studies) 24 to 54 serious 1 MODERATE 1 due to in weight for metformin vs dpp-4 inhibitors in the control -0.6 Kg in weight for metformin vs dpp-4 inhibitors in the intervention 1.40 lower (1.8 to 1 lower) Mean difference in LDL for Metformin vs DPP-4 Inhibitors (NOT IMPORTANT OUTCOME; measured with: mg/dl; Better indicated by lower values) 1918 (3 studies) 24 to 54 serious 2 serious 2 LOW 2 due to, in ldl for metformin vs dpp- 4 inhibitors in the control -0.5 mg/dl in ldl for metformin vs dpp-4 inhibitors in the intervention 5.85 lower (9.65 to 2.05 lower) Mean difference in HDL for Metformin vs DPP-4 Inhibitors (NOT IMPORTANT OUTCOME; measured with: mg/dl; Better indicated by higher values) 1918 (3 studies) 24 to 54 serious 3 serious 3 serious 3 VERY LOW 3 due to, in hdl for metformin vs dpp- 4 inhibitors in the control in hdl for metformin vs dpp- 4 inhibitors in the Page 16 of 37

17 , 3.9 mg/dl intervention 2.30 higher (0.28 lower to 4.88 higher) Mean difference in triglycerides for Metformin vs DPP-4 Inhibitors (NOT IMPORTANT OUTCOME; measured with: mg/dl; Better indicated by lower values) 1918 (3 studies) 24 to 54 serious 4 serious 4 LOW 4 due to, in triglycerides for metformin vs dpp-4 inhibitors in the control -3 mg/dl in triglycerides for metformin vs dpp-4 inhibitors in the intervention 3.4 higher (0.39 lower to 7.19 higher) All-cause mortality for Metformin vs DPP-4 Inhibitor 5 (CRITICAL OUTCOME; measured with: Number of events; Better indicated by lower values) 0 (0) See comment See comment See comment Cardiovascular mortality for Metformin vs DPP-4 Inhibitor 5 (CRITICAL OUTCOME; assessed with: Number of events) 0 (0) See comment - - not pooled 5 See comment See comment Hypoglycemia for Metformin vs DPP-4 Inhibitor (CRITICAL OUTCOME; assessed with: Number of events) 1050 (1 study) /528 HIGH 6 (1.7%) 17/522 (3.3%) RR per more per 1000 (0 to 0) 7 (from 17 fewer to 17 fewer) Combined GI adverse effects for Metformin vs DPP-4 Inhibitor (Nausea/Vomiting/Diarrhea/Abdominal discomfort) (IMPORTANT OUTCOME; assessed with: Number of events) 1155 (2 studies) 24 very serious 8 8 serious 8 VERY LOW 8 due to, 88/534 (16.5%) 146/621 (23.5%) RR 1.42 (0 to 0) 165 per more per 1000 (from 165 fewer to 165 fewer) 1 Bennett et al reviewers rated 3 RCTs as Moderate due to medium. No identification for the source of was provided. 2 Bennett et al reviewers rated 3 RCTs as Moderate due to medium and. No identification for the source of was provided. Possible reason for the rating of may be the MD of -5.85mg/dL with a somewhat wide CI [-9.65, -2,.05]. However, using the GRADE criteria, the rating for this evidence has been decreased to Low. 3 Bennett et al reviewers rated 3 RCTs as Low due to medium, and. No identification for the source of was provided. Possible reason for the rating of may be the MD of 2.30mg/dL with a CI [-0.28, 4.88] that cross the line of no difference. A possible reason for may be due to the I-squared value of 49%. However, using the GRADE criteria, the rating for this evidence has been decreased to Very Low. Page 17 of 37

18 4 Bennett et al reviewers rated 3 RCTs as Low due to medium and. No identification for the source of was provided. Possible reason for the rating of may be the MD of 3.40mg/dL with a relatively wide CI [-0.39, 7.19] that crosses the line of no difference. 5 Insufficient data 6 Bennett et al reviewers rated 3 RCTs as High with medium. No identification for the source of was provided. This table is based on 1 double-blind, multi-center RCT with over 500 participants in each treatmentment group. No points were deducted for. The overall rating of the evidence remains consistent with that of the reveiwers as High. 7 No statistically significant (p=0.12) 8 Bennett et al reviewers rated 2 RCTs as Low due to high, unknown and. No source of was identified. The review did not provide a meta-analysis of these trial, therefore, the reveiwers determination of and is accepted, however, the no points will be deducted for. Further, using the GRADE criteria, the rating for this evidence has been decreased to Very Low. Page 18 of 37

19 Table 7: Question: Should Metformin vs Glitazones be used for Diabetes Mellitus Type 2? Bibliography: Oral Diabetes Medications for Adults With Type 2 Diabetes: An Update (Bennett et al) Quality assessment Summary of Findings Participants (studies) Follow up Risk of Inconsistency Indirectness Imprecision Publication Overall quality of evidence Study event rates (%) Relative effect (95% CI) Anticipated absolute effects With Glitazones With Metformin Risk with Glitazones Risk difference with Metformin (95% CI) Mean difference in HbA1c for Metformin vs Glitazones (CRITICAL OUTCOME; measured with: %; Better indicated by lower values) 2662 (14 studies) 12 to 52 serious 1 2 MODERATE 1,2 due to in hba1c for metformin vs glitazones ranged across control groups from -2.6 to -0.3 % The mean mean difference in hba1c for metformin vs glitazones in the intervention groups was 0.07 lower (0.18 lower to 0.04 higher) Mean weight difference for Metformin vs Glitazones (NOT IMPORTANT OUTCOME; measured with: Kg; Better indicated by lower values) 1914 (8 studies) 16 to 52 HIGH The mean mean weight difference for metformin vs glitazones in the control -0.3 Kg The mean mean weight difference for metformin vs glitazones in the intervention 2.61 lower (4.06 to 1.16 lower) Mean difference in LDL for Metformin vs Rosiglitazone (NOT IMPORTANT OUTCOME; measured with: mg/dl; Better indicated by lower values) 482 (6 studies) 16 to 52 serious 3 1 MODERATE 1,3 due to in ldl for metformin vs rosiglitazone in the control 5.1 mg/dl The mean mean difference in ldl for metformin vs rosiglitazone in the intervention groups was lower (23.96 to 1.56 lower) Mean difference in HDL for Metformin vs. Rosiglitazone (NOT IMPORTANT OUTCOME; measured with: mg/dl; Better indicated by higher values) Page 19 of 37

20 482 (6 studies) 16 to 52 serious 4 MODERATE 4 due to in hdl for metformin vs. rosiglitazone in the control 3.5 mg/dl The mean mean difference in hdl for metformin vs. rosiglitazone in the intervention 0.45 lower (2.34 lower to 1.43 higher) Mean difference in TG for Metformin vs. Rosiglitazone (NOT IMPORTANT OUTCOME; measured with: mg/dl; Better indicated by lower values) 482 (6 studies) 16 to 52 serious 5 serious 5 serious 5 LOW 5 due to,,, large effect in tg for metformin vs. rosiglitazone in the control -4.2 mg/dl The mean mean difference in tg for metformin vs. rosiglitazone in the intervention lower (49.26 to 4.47 lower) All-cause mortality for Metformin vs Rosiglitazone (CRITICAL OUTCOME 6 ; assessed with: Number of events) 2910 (1 study 6 ) 4 years 34/ HIGH 6 (2.3%) 31/1454 (2.1%) RR 0.91 (0 to 0) 23 per fewer per 1000 (from 23 fewer to 23 fewer) Cardiovascular mortality for Metformin vs Rosiglitazone (CRITICAL OUTCOME; assessed with: Number of events) 2910 (1 study 7 ) 4 years 7 2/ HIGH 7 (0.14%) 2/1454 (0.14%) RR 1 (0 to 0) 1 per fewer per 1000 (from 1 fewer to 1 fewer) Hypoglycemia for Metformin vs Glitazones (CRITICAL OUTCOME; assessed with: Number of events) 2910 (1 study) 4 years 1,8 141/1456 HIGH 1,8 (9.7%) 167/1454 (11.5%) RR 0.9 (0.8 to 1) 97 per fewer per 1000 (from 19 fewer to 0 more) Incidence of Heart Failure for Metformin vs Rosiglitazone (IMPORTANT OUTCOME; assessed with: Number of events) 2910 (1 study 9 ) 4 years HIGH 22/1456 (1.5%) 19/1454 (1.3%) RR 0.86 (0 to 0) 15 per fewer per 1000 (from 15 fewer to 15 fewer) Page 20 of 37

21 Combined GI adverse effects for Metformin vs Rosiglitazone (Nausea/Vomiting/Diarrhea/Abdominal discomfort) (IMPORTANT OUTCOME; assessed with: Number of events) 2910 (1 study 10 ) 4 years HIGH 335/1456 (23%) 557/1454 (38.3%) RR 1.66 (0 to 0) 230 per more per 1000 (from 230 fewer to 230 fewer) 1 1 Rating based on documentation by Bennett et al reviewers for 16 studies. No reason for down-grading of evidence was provided. 2 Rating based on documentation by Bennett et al reviewers for 16 studies. Consistent for short-duration studies. One long-term study inconsistent. No points were deducted. 3 Rating based on documentation by Bennett et al reviewers for 7 studies. No reason for down-grading of evidence was provided. However, a MD of is reported with a wide CI [-23.96, -1.56], which may account for of evidence. 4 Rating based on documentation by Bennett et al reviewers for 6 studies. No reason for down-grading of evidence was provided. However, a modest MD of is reported with a CI crossing the line of no difference [-2.34, 1.43], which may account for of evidence. 5 Rating based on documentation by Bennett et al reviewers for 7 studies. No reason for down-grading of evidence was provided. An I-squared value of 70% is reported, which could account for the rating. A wide CI [-49.26, -4.47] with a mean difference of mg/dL favoring metformin is reported, which could account for the rating. The median change for rosiglitazone was -4.2mg/dL versus mg/dL for metformin, which could account for the large effect reported by the authors. 6 Bennett et al reviewers report Low strength of evidence based of 4 RCTs for all-cause mortality due to, however, no further explanation was provided. The all-cause mortality outcome on this table is based on the ADOPT study, a large double-blind, RCT; the strength of this evidence is ranked as High. 7 Bennett et al reviewers report Low strength of evidence based of 2 RCTs for CV mortality due to and moderate level of, however, no further explanation was provided. The CV mortality outcome on this table is based on the ADOPT study, a large double-blind RCT; the strength of this evidence is ranked as High. 8 Bennett et al reviewers report Moderate strength of evidence based on ADOPT study for hypoglycemia due to moderate level of and unknown consistency, however, no further explanation was provided. Given only 1 RCT, the consistency of this evidence can be classified as unknown. The hypoglycemia outcome on this table is based on the ADOPT study, a large double-blind RCT; we are classifying the strength of this evidence as High. 9 Bennett et al reviewers report Moderate strength of evidence based of 3 RCTs and 4 observational studies for CHF due to moderate level of, and, however, no further explanation was provided. The reviewers note low-grade evidence showing increased HF with glitazones, which could explain the Moderate strength of evidence. The CHF outcome on this table is based on the ADOPT study, a large double-blind, RCT; the strength of this evidence is ranked as High. 10 Bennett et al reviewers report High strength of evidence based of 5 RCTs for GI side-effects. The GI side-effects outcome on this table is based on the ADOPT study, a large double-blind RCT; the strength of this evidence is ranked as High. Page 21 of 37

22 Table 8: Question: Should Acarbose vs Metformin be used for Diabetes Mellitus, Type 2? Bibliography: 1. Alpha-glucosidase inhibitors for type 2 diabetes mellitus. Van de Laar FA, et al. 2. Comparative Effectiveness and Safety of Oral Diabetes Medications for Adults with Type 2 Diabetes. Bolen, et al. 3. Comparison of acarbose and metformin in patients with Type 2 diabetes mellitus insufficiently controlled with diet and sulphonylureas: a randomized, placebo-controlled study. Willms B. et al. Quality assessment Summary of Findings Participants (studies) Follow up Risk of Inconsistency Indirectness Imprecision Publication Overall quality of evidence Study event rates (%) Relative effect (95% CI) Anticipated absolute effects With Metformin With Acarbose Risk with Metformin Risk difference with Acarbose (95% CI) Mean difference in HbA1c for Acarbose vs. Placebo (IMPORTANT OUTCOME; measured with: %; Better indicated by lower values) 2831 (28 studies 1 ) 16 to 52 no serious HIGH in hba1c for acarbose vs. placebo ranged across control groups from to 1.6 % in hba1c for acarbose vs. placebo in the intervention 0.77 lower (0.9 to 0.64 lower) Mean difference in HbA1c for Acarbose vs Metformin (CRITICAL OUTCOME; measured with: %; Better indicated by lower values) 62 (1 study 3 ) 24 no serious serious 2 MODERATE 2 due to in hba1c for acarbose vs metformin in the control in hba1c for acarbose vs metformin in the intervention 0.25 lower (0.61 lower to 0.11 higher) Mean difference in LDL for Acarbose vs Metformin (NOT IMPORTANT OUTCOME; measured with: mg/dl; Better indicated by lower values) 62 (1 study) 24 no serious serious 2 MODERATE 2 due to in ldl for acarbose vs metformin in the control 0.05 mg/dl in ldl for acarbose vs metformin in the intervention groups was 0.94 lower (1.52 to 0.36 lower) Mean difference in HDL for Acarbose vs Metformin (NOT IMPORTANT OUTCOME; measured with: mg/dl; Better indicated by higher values) Page 22 of 37

23 62 (1 study) 24 no serious serious 2 MODERATE 2 due to in hdl for acarbose vs metformin in the control mg/dl in hdl for acarbose vs metformin in the intervention 0.24 higher (0.02 lower to 0.5 higher) Mean difference in triglycerides for Acarbose vs Metformin (measured with: mg/dl; Better indicated by lower values) 62 (1 study) 24 no serious serious 2 MODERATE 2 due to in triglycerides for acarbose vs metformin in the control mg/dl in triglycerides for acarbose vs metformin in the intervention 0.28 lower (0.8 lower to 0.24 higher) Mean difference in weight for Acarbose vs Metformin (NOT IMPORTANT OUTCOME; measured with: Kg; Better indicated by lower values) 62 (1 study) 24 no serious serious 2 serious 2,4 LOW 2,4 due to, in weight for acarbose vs metformin in the control -0.5 mg/dl in weight for acarbose vs metformin in the intervention 0.30 lower (5.45 lower to 4.85 higher) Adverse effects for Acarbose vs Metformin (Total) (IMPORTANT OUTCOME; assessed with: Number of events) 64 (1 study) 24 no serious serious 2 serious 5 LOW 2,5 due to, 2/32 (6.3%) 16/32 (50%) OR 15 (3.06 to 73.58) 62 per more per 1000 (from 107 more to 768 more) Hypoglycemia Acarbose vs Metformin (CRITICAL OUTCOME; assessed with: Number of events) 60 (1 study 8 ) 12 no serious serious 6 serious 7 LOW 6,7 due to, 5/29 (17.2%) 3/31 (9.7%) RR 0.5 (0 to 0) 172 per fewer per 1000 (from 172 fewer to 172 fewer) 1 Bases on the review by Van De Laar, et al. Review by Bolen et al. found 4 additional trials comparing alpha-glucosidase inhibitors with placebo that showed similar results. 2 The trial compared maximal doses of acarbose with submaximal doses of metformin. 3 Bases on the review by Van De Laar, et al. Review by Bolen et al. found 1 additional review that "compared submaximal doses of metformin to maximal doses of acarbose and showed no meaningful or consistent effects on HbA1c." Page 23 of 37

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