Authors' objectives: Policy Context: This short report is a focused assessment of the effectiveness and safety of glinides (repaglinide and nateglinide), and glitazones (pioglitazone) for treatment of type 2 diabetes mellitus (T2DM) to inform whether their reimbursement should continue or be limited in Switzerland. Technology Description: Glinides and glitazones are oral glycaemic control medications for patients with T2DM. Although evidence suggests that glinides and glitazones are associated with improved glycaemic control, questions remain regarding safety and other clinical benefits, especially with regard to long-term effects on mortality and morbidity. Health Problem: T2DM is a common form of diabetes characterised by insulin resistance, impaired insulin secretion, and other abnormal metabolic or inflammatory changes. T2DM increases risk of microvascular and macrovascular complications. The prevalence of T2DM is rising and is projected to affect more than 500 million adults worldwide by 2030.

Authors' results and conclusions: Key Question 1: What is the comparative effectiveness and safety of repaglinide, alone or in combination with metformin, pioglitazone, or insulin? Evidence for this question comprised eight randomised controlled trials (RCTs). Sample sizes ranged from 100 to 576 patients, and follow up was one year in all studies. All studies compared repaglinide monotherapy using heterogeneous dosing schedules with sulfonylurea or metformin monotherapy. The strength of the evidence for individual outcomes ranged from insufficient to moderate. Evidence does not suggest treatment-related differences in hypoglycaemia, blood pressure, weight changes, cardiovascular morbidity, or adverse events between repaglinide monotherapy and comparators. Evidence regarding mortality was presented in only one study and therefore insufficient to inform conclusions. Limitations include clinical heterogeneity (which precluded quantitative analyses of the findings), and a lack of statistical analyses within studies for many outcomes. Additionally, the evidence was limited because none of the studies were specifically designed to address effectiveness and safety outcomes of interest, and therefore they generally lacked sufficient statistical power and length of follow-up. Key Question 2: What is the comparative effectiveness and safety of nateglinide, alone or in combination with metformin or pioglitazone? Seven RCTs described in eight publications met inclusion criteria. Sample sizes ranged from 78 to 701 patients, and follow-up ranged from 12 weeks to 104 weeks. Nateglinide was administered with or without metformin using a variety of dosing schedules. Comparators varied across studies and included placebo or no treatment, metformin, and metformin plus a sulfonylurea. The strength of the evidence for individual outcomes was very low to moderate. Evidence does not suggest that nateglinide administered with or without metformin is associated with differences in all-cause mortality, episodes of confirmed hypoglycaemia, study drop-out due to adverse events, or substantive changes in weight, compared with comparator groups. Evidence on cardiovascular morbidity was not identified. Limitations include clinical heterogeneity across studies (which precluded quantitative analyses of the findings) and a lack of statistical analyses within studies for many outcomes The evidence was additionally limited because none of the studies were specifically designed to address effectiveness and safety outcomes of interest, and therefore generally lacked sufficient statistical power and length of follow-up. Key Question 3: What is the comparative effectiveness and safety of pioglitazone, alone or in combination with metformin, sulfonylureas, or insulin? The body of included evidence comprised 13 RCTs presented in 28 publications. Sample sizes ranged from 522 to 5238 patients, and follow-up ranged from 1 to 10.7 years. Across studies, pioglitazone was administered differently, including as an add-on to existing treatments, sulfonylureas, and/or metformin. Comparators varied across studies and included placebo or no treatment, sulfonylurea or metformin monotherapy, sulfonylureas and metformin as add-on therapies, and vildagliptin as an add-on to metformin. The strength of the evidence for individual outcomes ranged from low to moderate. Evidence does not suggest that pioglitazone is associated with differences in all-cause mortality or most individual macrovascular events versus comparators. Limited evidence from one large study suggests that major adverse cardiovascular events (MACE) may occur at a lower rate in patients receiving pioglitazone than placebo (in addition to other medications); however, this finding was not replicated in three other placebo-controlled studies and two active controlled studies, which found no treatment-related differences in MACE and other related composite measures. Pioglitazone may be associated with an increased risk of heart failure, oedema, and weight gain compared with controls. Pioglitazone may be associated with fewer episodes of hypoglycaemia compared with sulfonylurea regimens and may be associated with improvements in blood pressure relative to comparators. Limitations include clinical heterogeneity across studies (which precluded quantitative analyses of the findings) and a lack of statistical analyses within studies for many outcomes. The evidence suggests few differences between pioglitazone versus comparators in improving health outcomes, and the apparent risks associated with pioglitazone should be considered in treatment and coverage decisions.

Authors' methods: Methods of systematic review were employed for this short report, including definition of scope by a population, intervention, comparator, and outcomes (PICO) statement and key questions; multimodal systematic literature searches; objective literature selection criteria; narrative synthesis; and critical appraisal of the evidence. The last search for evidence for this report was conducted on December 19, 2019, in PubMed and Embase.

Project Status: Completed

URL for project: https://www.bag.admin.ch/bag/en/home/versicherungen/krankenversicherung/krankenversicherung-leistungen-tarife/hta/hta-projekte/glinide_glitazone.html

Year Published: 2020

URL for published report: https://www.bag.admin.ch/dam/bag/en/dokumente/kuv-leistungen/leistungen-und-tarife/hta/berichte/h0033glnd-h0034gltz-hta-shortreport.pdf.download.pdf/h0033glnd-h0034gltz-hta-shortreport.pdf

URL for additional information: https://www.bag.admin.ch/bag/en/home/versicherungen/krankenversicherung/krankenversicherung-leistungen-tarife/hta/hta-programm.html

English language abstract: An English language summary is available

Publication Type: Rapid Review

Country: Switzerland

Organisation Name: Swiss Federal Office of Public Health (FOPH)

Contact Address: Federal Office of Public Health, Schwarzenburgstrasse 157, CH-3003 Berne, Switzerland

Contact Name: Stephanie Vollenweider

Contact Email: hta@bag.admin.ch

Copyright: Swiss Federal Office of Public Health