Aims
Sodium glucose co‐transport‐2 (SGLT‐2) inhibitors, a new class of glucose‐lowering agents, reduce tubular glucose reabsorption, producing a reduction of blood glucose without stimulating insulin ...release. The aim of the present meta‐analysis is the assessment of the overall efficacy and safety profile of these drugs.
Methods
A meta‐analysis was performed including all trials with a duration of at least 12 weeks, comparing a SGLT‐2 inhibitor with a non‐SGLT‐2 inhibitor agent in type 2 diabetes. The principal outcome of this analysis was the effect of SGLT‐2 inhibitors on HbA1c at 12, 24 and 52 weeks. Hypoglycaemia, genital and urinary infections were retrieved and combined to calculate Mantel–Haenszel odds ratio (MH‐OR). Furthermore, data on body mass index (BMI), endpoint fasting plasma glucose, systolic and diastolic blood pressure, creatinine, hematocrit and lipid profile were collected.
Results
Among placebo‐controlled trials, HbA1c reduction at 12, 24 and 52 weeks was 0.5 0.4; 0.6, 0.6 0.6; 0.5 and 0.6 0.7; 0.5%. In placebo‐controlled studies, 24‐week reduction of HbA1c with SGLT‐2 inhibitors was greater in trials enrolling patients with a lower mean age and duration of diabetes, and a higher baseline BMI, HbA1c and fasting glucose. In placebo‐controlled trials, SGLT‐2 inhibitors determined a weight loss during the first 24 weeks, which was maintained up to 52 weeks.
Conclusions
SGLT‐2 inhibitors are effective in the treatment of type 2 diabetes, providing additional benefits, such as weight loss, reduction of blood pressure and increase in high‐density lipoprotein (HDL)‐cholesterol. Apart from genital and urinary infections, rather frequent but usually mild, SGLT‐2 inhibitors appear to be well tolerated.
Aims
Preliminary data from randomized trials with metabolic outcomes have shown that treatment with dipeptidyl peptidase‐4 inhibitors (DPP4i) could be associated with a reduced incidence of major ...cardiovascular events (MACE). The present meta‐analysis is aimed at verifying this protective effect, collecting all available data from randomized trials.
Methods
A comprehensive search for published and unpublished trials with a duration ≥24 weeks comparing DPP4i with placebo or other drugs was performed, retrieving all MACE reported as serious adverse events together with death from any cause. Mantel–Haenzel odds ratio (MH–OR) was calculated with random effect models for MACE, myocardial infarction, stroke and mortality. When available, effects on glycated haemoglobin, lipid profile and blood pressure were also assessed and used for the estimation of the modification of risk for myocardial infarction using the UKPDS risk engine.
Results
A total of 70 trials, enrolling 41 959 patients with a mean follow‐up of 44.1 weeks, was collected and included in the analysis. The MH–OR (95% Confidence Interval) was 0.710.59;0.86, 0.640.44;0.94, 0.770.48;1.24 and 0.600.41;0.88 for MACE, myocardial infarction, stroke and mortality, respectively.
Conclusions
Treatment with DPP4i reduces the risk of cardiovascular events (particularly myocardial infarction) and all‐cause mortality in patients with type 2 diabetes. The reduction in the incidence of myocardial infarction is greater than what predicted on the basis of conventional risk factors, suggesting a role for other mechanisms.
Aim
Cardiovascular safety of sulfonylurea has been questioned by some authors. This article aims at collecting all available data on this issue from randomized trials.
Methods
A meta‐analysis was ...performed including all trials with a duration of at least 6 months, comparing a sulfonylurea with a non‐sulfonylurea agent in type 2 diabetes. Major cardiovascular events (MACE) and mortality were retrieved and combined to calculate Mantel‐Haenzel odds ratio (MH‐OR).
Results
Of the 115 selected trials, 62 reported information on MACE, and 30 reported at least one event. MH‐OR for sulfonylurea was 1.08 0.86–1.36, p = 0.52 (1.85 1.20–2.87, p = 0.005, in the five trials vs. DPP4 inhibitors, no significant differences vs. other comparators). The MH‐OR for myocardial infarction and stroke was 0.88 0.75–1.04, p = 0.13 and 1.28 1.03–1.60, p = 0.026, respectively. Mortality was significantly increased with sulfonylureas (MH‐OR: 1.22 1.01–1.49, p = 0.047).
Conclusions
In type 2 diabetes, the use of sulfonylureas is associated with increased mortality and a higher risk of stroke, whereas the overall incidence of MACE appears to be unaffected. Significant differences in cardiovascular risk could be present in direct comparisons with specific classes of glucose‐lowering agents, such as DPP4 inhibitors, but this hypothesis needs to be confirmed in long‐term cardiovascular outcomes trials. The results of this meta‐analysis need to be interpreted with caution, mainly because of limitations in trial quality and under‐reporting of information on cardiovascular events and mortality. However, the cardiovascular safety of sulfonylureas cannot be considered established unless it is evaluated in long‐term cardiovascular outcomes trials.
Aim: Some studies suggested that metformin could reduce cardiovascular risk to a greater extent than that determined by glucose reduction. Aim of the present meta-analysis is to assess the effects of ...metformin on the incidence of cardiovascular events and mortality. Methods: An extensive search of Medline, EMBASE and the Cochrane Library (any date up to 31 October 2009) was performed for all trials containing the word ‘metformin'. Randomized trials with a duration ≥52 weeks were included. A meta-regression analysis was also performed to identify factors associated with cardiovascular morbidity and mortality in metformin-treated patients. Results: A total of 35 clinical trials were selected including 7171 and 11 301 participants treated with metformin and comparator, respectively, who had 451 and 775 cardiovascular (CV) events, respectively. Overall, metformin was not associated with significant harm or benefit on cardiovascular events (MH-OR 0.940.82-1.07, p = 0.34). A significant benefit was observed in trials versus placebo/no therapy (MH-OR 0.790.64-0.98, p = 0.031), but not in active-comparator trials (MH-OR 1.030.72-1.77, p = 0.89). Meta-regression showed a significant correlation of the effect of metformin on cardiovascular events with trial duration and with minimum and maximum age for inclusion, meaning that the drug appeared to be more beneficial in longer trials enrolling younger patients. It is likely that metformin monotherapy is associated with improved survival (MH-OR: 0.8010.625-1.024, p = 0.076). However, concomitant use with sulphonylureas was associated with reduced survival (MH-OR: 1.4321.068-1.918, p = 0.016). Conclusion: Available evidence seems to exclude any overall harmful effect of metformin on cardiovascular risk, suggesting a possible benefit versus placebo/no treatment. The observed detrimental effect of the combination with sulphonylureas deserves further investigation.
Aims Preliminary data from randomized trials with metabolic outcomes have shown that treatment with dipeptidyl peptidase-4 inhibitors (DPP4i) could be associated with a reduced incidence of major ...cardiovascular events (MACE). The present meta-analysis is aimed at verifying this protective effect, collecting all available data from randomized trials. Methods A comprehensive search for published and unpublished trials with a duration ≥24 weeks comparing DPP4i with placebo or other drugs was performed, retrieving all MACE reported as serious adverse events together with death from any cause. Mantel-Haenzel odds ratio (MH-OR) was calculated with random effect models for MACE, myocardial infarction, stroke and mortality. When available, effects on glycated haemoglobin, lipid profile and blood pressure were also assessed and used for the estimation of the modification of risk for myocardial infarction using the UKPDS risk engine. Results A total of 70 trials, enrolling 41959 patients with a mean follow-up of 44.1 weeks, was collected and included in the analysis. The MH-OR (95% Confidence Interval) was 0.710.59;0.86, 0.640.44;0.94, 0.770.48;1.24 and 0.600.41;0.88 for MACE, myocardial infarction, stroke and mortality, respectively. Conclusions Treatment with DPP4i reduces the risk of cardiovascular events (particularly myocardial infarction) and all-cause mortality in patients with type 2 diabetes. The reduction in the incidence of myocardial infarction is greater than what predicted on the basis of conventional risk factors, suggesting a role for other mechanisms. PUBLICATION ABSTRACT
Abstract Background & aims Recently, the SAVOR TIMI-53 (Saxagliptin Assessment of Vascular Outcomes Recorded in patients with diabetes mellitus – Thrombolysis in Myocardial Infarction-53) reported a ...significant increase in the risk of hospitalizations for heart failure in patients treated with saxagliptin in comparison with placebo. Aim of the present meta-analysis is the systematic collection and synthesis of information on treatment-emergent cases of acute heart failure described in randomized clinical trials with DPP4. Methods & results Data sources: An extensive Medline, Embase, and Cochrane Database search for “vildagliptin”, “sitagliptin”, “saxagliptin”, “alogliptin”, “linagliptin”, and “dutogliptin” was performed, collecting all randomized clinical trials on humans up to October 1st, 2013. Studies were included if they satisfied the following criteria: i) randomized trials, ii) duration ≥24 weeks; iii) on type 2 diabetes; iv) comparison of DPP4i with placebo or active drugs. The principal outcome was the effect of DPP4i on the incidence of acute heart failure. A total of 84 eligible trials was identified. The overall risk of acute heart failure was higher in patients treated with DPP4i in comparison with those treated with placebo/active comparators (MH–OR: 1.191.03; 1.37; p = 0.015). When trials with non-cardiovascular outcomes were analysed separately no signal of risk was detectable. Conclusion Available data from RCTs suggest that DPP4i could be associated with an increased risk of heart failure, without any clear evidence of differences among drugs of the class. Although it is plausible that the risk is greater in some sub-populations of patients, current evidence is not yet sufficient to identify susceptible patients.
Aim
Some observational studies reporting an increased risk of pancreatitis in association with Dipeptidyl Peptidase‐4 inhibitors (DPP4i) have raised concerns on the overall safety of this class. Aim ...of the present meta‐analysis is the systematic collection of information on pancreatitis in randomized clinical trials with DPP4i.
Methods
Data Sources: an extensive Medline, Embase and Cochrane Database search for ‘vildagliptin’, ‘sitagliptin’, ‘saxagliptin’, ‘alogliptin’, ‘linagliptin’ and ‘dutogliptin’ was performed up to 1 March 2013. Study Selection: studies were included if they satisfied the following criteria: (i) randomized trials, (ii) duration ≥12 weeks, (iii) on type 2 diabetes and (iv) comparison of DPP4i with placebo or active drugs. The identification and the selection of studies, and the subsequent data extraction were performed independently by two authors. Mantel‐Haenszel odds ratio with 95% Confidence Interval (MH‐OR) was calculated for all the adverse events defined below. The principal outcome was the effect of DPP4i on the incidence of pancreatitis.
Results
A total of 134 eligible trials were identified. The overall risk of pancreatitis and pancreatic cancer was not different between DPP4i and comparators (MH‐OR: 0.930.51–1.69; p = 0.82).
Conclusions
It should be recognized that the number of observed cases of incident pancreatitis is small and the confidence intervals of risk estimates are wide. However, the present meta‐analysis do not suggest any increase in the risk of pancreatitis with DPP4i.
Aims
Self-monitoring of blood glucose (SMBG) represented a major breakthrough in the treatment of type 1 diabetes. The aim of the present meta-analysis is to assess the effect of continues glucose ...monitoring (CGM) and flash glucose monitoring (FGM), on glycemic control in type 1 diabetes.
Materials and methods
The present analysis includes randomized clinical trials comparing CGM or FGM with SMBG, with a duration of at least 12 weeks, identified in Medline or clinicaltrials.gov. The principal endpoint was HbA1c at the end of the trial. A secondary endpoint was severe hypoglycemia. Mean and 95% confidence intervals for HbA1c and Mantel–Haenzel odds ratio MH-OR for severe hypoglycemia were calculated, using random effect models. A sensitivity analysis was performed using fixed effect models. In addition, the following secondary endpoints were explored, using the same methods: time in range, health-related quality of life, and treatment satisfaction. Separate analyses were performed for trials comparing CGM with SMBG, and those comparing CGM + CSII and SMBG + MDI and CGM-regulated insulin infusion system (CRIS) and CSII + SMBG.
Results
CGM was associated with a significantly lower HbA1c at endpoint in comparison with SMBG (− 0.24 − 0.34, − 0.13%); CGM was associated with a significantly lower risk of severe hypoglycemia than SMBG. Treatment satisfaction and quality of life were not measured, or not reported, in the majority of studies. FGM showed a significant reduction in the incidence of mild hypoglycemia and an increased treatment satisfaction, but no significant results are shown in HbA1c. CGM + CSII in comparison with SMBG + MDI was associated with a significant reduction in HbA1c. Only two trials with a duration of at least 12 weeks compared a CRIS with SMBG + CSII; HbA1c between the two treatment arms was not statistically significant (difference in means: − 0.23 − 0.91; 0.46%;
p
= 0.52).
Conclusion
GCM compared to SMBG has showed a reduction in HbA1c and severe hypoglycemia in patient with type 1 diabetes. The comparison between CGM + CSII and SMBG + MDI showed a large reduction in HbA1c; it is conceivable that the effects of CSII + CGM on glycemic control additives. The only comparison available between FGM and SMBG was conducted in patients in good control.
Aims
New drugs for type 2 diabetes need to demonstrate their cardiovascular safety, due regulatory requirements from the Food and Drug Administration. For this reason, glucagon‐like peptide‐1 ...receptor agonists (GLP‐1 RA) are currently undergoing large‐scale, long‐term randomized trials specifically designed for cardiovascular outcomes. Aim of the present meta‐analysis of randomized clinical trials is the assessment of the effects of GLP‐1 RA on major cardiovascular events (MACE), mortality and cardiovascular risk factors.
Methods
A meta‐analysis was performed including all trials with a duration of at least 6 months, comparing a GLP‐1 RA with a non‐GLP‐1 RA agent in type 2 diabetes. MACE and mortality were retrieved and combined to calculate Mantel–Haenzel odds ratio (MH‐OR). Furthermore, data on endpoint systolic and diastolic blood pressure, total and high‐density lipoprotein (HDL) cholesterol and triglyceride were collected.
Results
Of 37 selected trials, 33 reported information on MACE, and 25 reported at least one event. The difference in the incidence of MACE between GLP‐1 RA and comparators did not reach statistical significance MH‐OR 0.78 (0.54–1.13), p = 0.18. GLP‐1 RA were associated with a significant reduction in the incidence of MACE in comparisons with placebo and pioglitazone, with a non‐significant trend towards reduction in DPP4i‐controlled studies. No significant effect of GLP‐1 RA was observed on mortality, although a non‐significant favourable trend was observed in comparisons with placebo.
Conclusions
The present meta‐analysis confirms the cardiovascular safety of GLP‐1 RA, at least in the short term and in low‐risk individuals. GLP‐1 RA could have a beneficial effect on the incidence of MACE, at least in comparison with placebo.
