Dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: systematic review and meta-analysis.

OBJECTIVE: To assess the efficacy and safety of dipeptidyl peptidase-4 (DPP-4) inhibitors compared with metformin as monotherapy, or with other commonly used hypoglycaemic drugs combined with metformin, in adults with type 2 diabetes mellitus. DESIGN: Systematic review and meta-analysis of randomised controlled trials. DATA SOURCES: Medline, Embase, the Cochrane Library, conference proceedings, trial registers, and drug manufacturers' websites. ELIGIBILITY CRITERIA: Randomised controlled trials of adults with type 2 diabetes mellitus that compared a DPP-4 with metformin as monotherapy or with a sulfonylurea, pioglitazone, a glucagon-like peptide-1 (GLP-1) agonist, or basal insulin combined with metformin on the change from baseline in glycated haemoglobin (HbA(1c)). DATA EXTRACTION: The primary outcome was the change in HbA(1c). Secondary outcomes included the proportion of patients achieving the goal of HbA(1c) <7%, the change in body weight, discontinuation rate because of any adverse event, occurrence of any serious adverse event, all cause mortality, and incidence of hypoglycaemia, nasopharyngitis, urinary tract infection, upper respiratory infection, nausea, vomiting, and diarrhoea. RESULTS: 27 reports of 19 studies including 7136 patients randomised to a DPP-4 inhibitor and 6745 patients randomised to another hypoglycaemic drug were eligible for the systematic review and meta-analysis. Overall risk of bias for the primary outcome was low in three reports, unclear in nine, and high in 14. Compared with metformin as monotherapy, DPP-4 inhibitors were associated with a smaller decline in HbA(1c) (weighted mean difference 0.20, 95% confidence interval 0.08 to 0.32) and in body weight (1.5, 0.9 to 2.11). As a second line treatment, DPP-4 inhibitors were inferior to GLP-1 agonists (0.49, 0.31 to 0.67) and similar to pioglitazone (0.09, -0.07 to 0.24) in reducing HbA(1c) and had no advantage over sulfonylureas in the attainment of the HbA(1c) goal (risk ratio in favour of sulfonylureas 1.06, 0.98 to 1.14). DPP-4 inhibitors had a favourable weight profile compared with sulfonylureas (weighted mean difference -1.92, -2.34 to -1.49) or pioglitazone (-2.96, -4.13 to -1.78), but not compared with GLP-1 agonists (1.56, 0.94 to 2.18). Only a minimal number of hypoglycaemias were observed in any treatment arm in trials comparing a DPP-4 inhibitor with metformin as monotherapy or with pioglitazone or a GLP-1 agonist as second line treatment. In most trials comparing a DPP-4 inhibitor with sulfonylureas combined with metformin, the risk for hypoglycaemia was higher in the group treated with a sulfonylurea. Incidence of any serious adverse event was lower with DPP-4 inhibitors than with pioglitazone. Incidence of nausea, diarrhoea, and vomiting was higher in patients receiving metformin or a GLP-1 agonist than in those receiving a DPP-4 inhibitor. Risk for nasopharyngitis, upper respiratory tract infection, or urinary tract infection did not differ between DPP-4 inhibitors and any of the active comparators. CONCLUSION: In patients with type 2 diabetes who do not achieve the glycaemic targets with metformin alone, DPP-4 inhibitors can lower HbA(1c), in a similar way to sulfonylureas or pioglitazone, with neutral effects on body weight. Increased unit cost, which largely exceeds that of the older drugs, and uncertainty about their long term safety, however, should also be considered

Dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: systematic review and meta-analysis.

OBJECTIVE: To assess the efficacy and safety of dipeptidyl peptidase-4 (DPP-4) inhibitors compared with metformin as monotherapy, or with other commonly used hypoglycaemic drugs combined with metformin, in adults with type 2 diabetes mellitus. DESIGN: Systematic review and meta-analysis of randomised controlled trials. DATA SOURCES: Medline, Embase, the Cochrane Library, conference proceedings, trial registers, and drug manufacturers' websites. ELIGIBILITY CRITERIA: Randomised controlled trials of adults with type 2 diabetes mellitus that compared a DPP-4 with metformin as monotherapy or with a sulfonylurea, pioglitazone, a glucagon-like peptide-1 (GLP-1) agonist, or basal insulin combined with metformin on the change from baseline in glycated haemoglobin (HbA(1c)). DATA EXTRACTION: The primary outcome was the change in HbA(1c). Secondary outcomes included the proportion of patients achieving the goal of HbA(1c) <7%, the change in body weight, discontinuation rate because of any adverse event, occurrence of any serious adverse event, all cause mortality, and incidence of hypoglycaemia, nasopharyngitis, urinary tract infection, upper respiratory infection, nausea, vomiting, and diarrhoea. RESULTS: 27 reports of 19 studies including 7136 patients randomised to a DPP-4 inhibitor and 6745 patients randomised to another hypoglycaemic drug were eligible for the systematic review and meta-analysis. Overall risk of bias for the primary outcome was low in three reports, unclear in nine, and high in 14. Compared with metformin as monotherapy, DPP-4 inhibitors were associated with a smaller decline in HbA(1c) (weighted mean difference 0.20, 95% confidence interval 0.08 to 0.32) and in body weight (1.5, 0.9 to 2.11). As a second line treatment, DPP-4 inhibitors were inferior to GLP-1 agonists (0.49, 0.31 to 0.67) and similar to pioglitazone (0.09, -0.07 to 0.24) in reducing HbA(1c) and had no advantage over sulfonylureas in the attainment of the HbA(1c) goal (risk ratio in favour of sulfonylureas 1.06, 0.98 to 1.14). DPP-4 inhibitors had a favourable weight profile compared with sulfonylureas (weighted mean difference -1.92, -2.34 to -1.49) or pioglitazone (-2.96, -4.13 to -1.78), but not compared with GLP-1 agonists (1.56, 0.94 to 2.18). Only a minimal number of hypoglycaemias were observed in any treatment arm in trials comparing a DPP-4 inhibitor with metformin as monotherapy or with pioglitazone or a GLP-1 agonist as second line treatment. In most trials comparing a DPP-4 inhibitor with sulfonylureas combined with metformin, the risk for hypoglycaemia was higher in the group treated with a sulfonylurea. Incidence of any serious adverse event was lower with DPP-4 inhibitors than with pioglitazone. Incidence of nausea, diarrhoea, and vomiting was higher in patients receiving metformin or a GLP-1 agonist than in those receiving a DPP-4 inhibitor. Risk for nasopharyngitis, upper respiratory tract infection, or urinary tract infection did not differ between DPP-4 inhibitors and any of the active comparators. CONCLUSION: In patients with type 2 diabetes who do not achieve the glycaemic targets with metformin alone, DPP-4 inhibitors can lower HbA(1c), in a similar way to sulfonylureas or pioglitazone, with neutral effects on body weight. Increased unit cost, which largely exceeds that of the older drugs, and uncertainty about their long term safety, however, should also be considered

Assessing the treatment effect in metabolic syndrome without perceptible diabetes (ATTEMPT): A prospective-randomized study in middle aged men and women

Aim: To assess the reduction in estimated cardiovascular disease (e-CVD) risk after multifactorial treatment for 6 months and follow this change during the next 3-years. Patients-Methods: This prospective, randomized, target driven study included 1,123 subjects (512/611 men/women, aged 45-65 years) with metabolic syndrome (MetS) without diabetes or CVD referred to specialist outpatient clinics. Patients were randomized to two treatment groups: group A with low density lipoprotein cholesterol (LDL-C) target of &lt;100 mg/dl and group B with a target of &lt;130 mg/dl. Atorvastatin was used in both groups on top of optimal multifactorial treatment, (quinapril, amlodipine, hydrochlorothiazide for hypertension, metformin for impaired fasting glucose, and orlistat for obesity). The e-CVD risk was calculated using the Framingham, the PROCAM and Reynold&apos;s equations. Results: Reductions in e-CVD risk at 6 months were &gt;50% in all patients, but were superior in group A and in women. Reductions were even greater during the next 3-years and were mainly attributed to changes in lipid profile. Actual CVD events were 1 in group A and 13 in group B; p=0.0012. Conclusions: Attaining the treatment target of LDL-C&lt;100 mg/dl within multifactorial treatment of MetS by expert clinics, is achievable and beneficial even in patients without diabetes or known CVD. This induces a considerable e-CVD risk reduction in MetS patients. Actual CVD events were negligible, suggesting that e-CVD risk overestimates actual CVD risk in MetS, at least in patients achieving LDL-C&lt;100 mg/dl [ClinicalTrials.gov ID: NCT00416741]. © 2011 Bentham Science Publishers