Dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes mellitus.

BACKGROUND: In type 2 diabetes mellitus there is a progressive loss of beta-cell function. One new approach yielding promising results is the use of the orally active dipeptidyl peptidase-4 (DPP-4) inhibitors like sitagliptin and vildagliptin. OBJECTIVES: To assess the effects of dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes mellitus. SEARCH STRATEGY: Studies were obtained from computerised searches of MEDLINE, EMBASE and The Cochrane Library. SELECTION CRITERIA: Studies were included if they were randomised controlled trials in adult people with type 2 diabetes mellitus and had a trial duration of at least 12 weeks. DATA COLLECTION AND ANALYSIS: Two authors independently assessed risk of bias and extracted data. Pooling of studies was performed by means of fixed-effect meta-analysis. MAIN RESULTS: Twenty-five studies of good quality were identified, 11 trials evaluated sitagliptin and 14 trials vildagliptin treatment. Altogether, 6743 patients were randomised in sitagliptin and 6121 patients in vildagliptin studies, respectively. Sitagliptin and vildagliptin studies ranged from 12 to 52 weeks duration. No data were published on mortality, diabetic complications, costs of treatment and health-related quality of life. Sitagliptin and vildagliptin therapy in comparison with placebo resulted in an HbA1c reduction of approximately 0.7% and 0.6%, respectively. Data on comparisons with active comparators were limited but indicated no improved metabolic control following DPP-4 intervention in contrast to other hypoglycaemic agents. Sitagliptin and vildagliptin therapy did not result in weight gain but weight loss was more pronounced following placebo interventions. No definite conclusions could be drawn from published data on sitagliptin and vildagliptin effects on measurements of beta-cell function. Overall, sitagliptin and vildagliptin were well tolerated, no severe hypoglycaemia was reported in patients taking sitagliptin or vildagliptin. All-cause infections increased significantly after sitagliptin treatment but did not reach statistical significance following vildagliptin therapy. All published randomised controlled trials of at least 12 weeks treatment with sitagliptin and vildagliptin only reported routine laboratory safety measurements AUTHORS' CONCLUSIONS: DPP-4 inhibitors have some theoretical advantages over existing therapies with oral antidiabetic compounds but should currently be restricted to individual patients. Long-term data especially on cardiovascular outcomes and safety are urgently needed before widespread use of these new agents. More information on the benefit-risk ratio of DPP-4 inhibitor treatment is necessary especially analysing adverse effects on parameters of immune function. Also, long-term data are needed investigating patient-oriented parameters like health-related quality of life, diabetic complications and all-cause mortality.

Rosiglitazone for type 2 diabetes mellitus.

BACKGROUND: Diabetes has long been recognised as a strong, independent risk factor for cardiovascular disease, a problem which accounts for approximately 70% of all mortality in people with diabetes. Prospective studies show that compared to their non-diabetic counterparts, the relative risk of cardiovascular mortality for men with diabetes is two to three and for women with diabetes is three to four. The two biggest trials in type 2 diabetes, the United Kingdom Prospective Diabetes Study (UKPDS) and the University Group Diabetes Program (UGDP) study did not reveal a reduction of cardiovascular endpoints through improved metabolic control. Theoretical benefits of the peroxisome proliferator activated receptor gamma (PPAR-gamma) activator rosiglitazone on endothelial function and cardiovascular risk factors might result in fewer macrovascular disease events in people with type 2 diabetes mellitus. OBJECTIVES: To assess the effects of rosiglitazone in the treatment of type 2 diabetes. SEARCH STRATEGY: Studies were obtained from computerised searches of MEDLINE, EMBASE and The Cochrane Library. SELECTION CRITERIA: Studies were included if they were randomised controlled trials in adult people with type 2 diabetes mellitus and had a trial duration of at least 24 weeks. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. Pooling of studies by means of fixed-effects meta-analysis could be performed for adverse events only. MAIN RESULTS: Eighteen trials which randomised 3888 people to rosiglitazone treatment were identified. Longest duration of therapy was four years with a median of 26 weeks. Published studies of at least 24 weeks rosiglitazone treatment in people with type 2 diabetes mellitus did not provide evidence that patient-oriented outcomes like mortality, morbidity, adverse effects, costs and health-related quality of life are positively influenced by this compound. Metabolic control measured by glycosylated haemoglobin A1c (HbA1c) as a surrogate endpoint did not demonstrate clinically relevant differences to other oral antidiabetic drugs. Occurrence of oedema was significantly raised (OR 2.27, 95% confidence interval (CI) 1.83 to 2.81). The single large RCT (ADOPT - A Diabetes Outcomes Progression Trial) indicated increased cardiovascular risk. New data on raised fracture rates in women reveal extensive action of rosiglitazone in various body tissues. AUTHORS' CONCLUSIONS: New studies should focus on patient-oriented outcomes to clarify the benefit-risk ratio of rosiglitazone therapy. Safety data and adverse events of all investigations (published and unpublished) should be made available to the public.

Pioglitazone for type 2 diabetes mellitus.

BACKGROUND: Diabetes has long been recognised as a strong, independent risk factor for cardiovascular disease, a problem which accounts for approximately 70% of all mortality in people with diabetes. Prospective studies show that compared to their non-diabetic counterparts, the relative risk of cardiovascular mortality for men with diabetes is two to three and for women with diabetes is three to four. The two biggest trials in type 2 diabetes, the United Kingdom Prospective Diabetes Study (UKPDS) and the University Group Diabetes Program (UGDP) study did not reveal a reduction of cardiovascular endpoints through improved metabolic control. Theoretical benefits of the newer peroxisome proliferator activated receptor gamma (PPAR-gamma) activators like pioglitazone on endothelial function and cardiovascular risk factors might result in fewer macrovascular disease events in people with type 2 diabetes mellitus. OBJECTIVES: To assess the effects of pioglitazone in the treatment of type 2 diabetes. SEARCH STRATEGY: Studies were obtained from computerised searches of MEDLINE, EMBASE and The Cochrane Library. The last search was conducted in August 2006. SELECTION CRITERIA: Studies were included if they were randomised controlled trials in adult people with type 2 diabetes mellitus and had a trial duration of at least 24 weeks. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. Pooling of studies by means of random-effects meta-analysis could be performed for adverse events only. MAIN RESULTS: Twenty-two trials which randomised approximately 6200 people to pioglitazone treatment were identified. Longest duration of therapy was 34.5 months. Published studies of at least 24 weeks pioglitazone treatment in people with type 2 diabetes mellitus did not provide convincing evidence that patient-oriented outcomes like mortality, morbidity, adverse effects, costs and health-related quality of life are positively influenced by this compound. Metabolic control measured by glycosylated haemoglobin A1c (HbA1c) as a surrogate endpoint did not demonstrate clinically relevant differences to other oral antidiabetic drugs. Occurrence of oedema was significantly raised. The results of the single trial with relevant clinical endpoints (Prospective Pioglitazone Clinical Trial In Macrovascular Events--PROactive study) have to be regarded as hypothesis-generating and need confirmation. AUTHORS' CONCLUSIONS: Until new evidence becomes available, the benefit-risk ratio of pioglitazone remains unclear. Different therapeutic indications for pioglitazone of the two big U.S. and European drug agencies should be clarified to reduce uncertainties amongst patients and physicians.