Ilaria Dicembrini

Safety of dipeptidyl peptidase-4 inhibitors: A meta-analysis of randomized clinical trials

Abstract Objective: Dipeptidyl peptidase-4 inhibitors (DPP4i) have been recently associated with increased risk of pancreatitis and cancer. The aim of the present meta-analysis of randomized clinical trials is the assessment of the effect of DPP4i on the incidence of major cardiovascular events (MACE), cancer, and pancreatitis. Research design and methods: An extensive Medline and Embase search for ‘vildagliptin’, ‘sitagliptin’, ‘saxagliptin’, ‘alogliptin’, ‘linagliptin’, and ‘dutogliptin’ was performed, collecting all randomized clinical trials on humans up to March 1, 2011. The present meta-analysis was therefore performed including all randomized clinical trials with a duration of at least 24 weeks, enrolling patients with type 2 diabetes, comparing DPP4i with either placebo or active drugs. Completed but still unpublished trials were identified through a search of www.clinicaltrials.gov, Food and Drug Administration, and European Medicines Agency website. Results: Fifty-three trials enrolling 20,312 and 13,569 patients for DPP4i and comparators, respectively, were included, reporting 176 malignancies, 257 MACE, and 22 pancreatitis. DPP4i, compared with placebo or other treatment, were associated with a similar risk of cancer (MH-OR 1.020 [0.742–1.402]; p = 0.90) and pancreatitis (0.786 [0.357–1.734], p = 0.55), and with a reduced risk of MACE (MH-OR 0.689 [0.528–0.899], p = 0.006). Conclusions: The present meta-analysis seems to exclude any relevant short term effect of DPP4i on the incidence of cancer and suggest a possible protection from cardiovascular events. This result should be interpreted with caution, as those events were not the principal endpoint, the trial duration was short, and the characteristics of patients included could be different from routine clinical practice.

Dipeptidyl Peptidase-4 Inhibitors and Bone Fractures A meta-analysis of randomized clinical trials

OBJECTIVE Thiazolidinediones and insulin are associated with a higher risk of fractures in type 2 diabetic patients. Incretin hormones increase bone density in experimental models, but the effect of dipeptidyl peptidase-4 (DPP-4) inhibitors on bone fractures has not been reported so far. RESEARCH DESIGN AND METHODS A meta-analysis was performed including all randomized clinical trials with a duration of at least 24 weeks, enrolling patients with type 2 diabetes, comparing DPP-4 inhibitors with placebo or active drugs. RESULTS Twenty-eight trials enrolling 11,880 and 9,175 patients for DPP-4 inhibitors and comparators, respectively, were included, reporting 63 fractures. DPP-4 inhibitors, compared with placebo or other treatments, were associated with a reduced risk of fractures (Mantel–Haenszel odds ratio [MH-OR] 0.60, 95% CI 0.37–0.99, P = 0.045), even after the exclusion of comparisons with thiazolidinediones or sulfonylureas (MH-OR 0.56, 0.33–0.93, P = 0.026). CONCLUSIONS The present meta-analysis suggests that treatment with DPP-4 inhibitors could be associated with a reduced risk of bone fractures.

Effects of glucagon-like peptide-1 receptor agonists on cardiovascular risk: a meta-analysis of randomized clinical trials.

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.

METFORMIN AND CANCER OCCURRENCE IN INSULIN-TREATED TYPE 2 DIABETIC PATIENTS.

OBJECTIVE Metformin is associated with reduced cancer-related morbidity and mortality. The aim of this study was to assess the effect of metformin on cancer incidence in a consecutive series of insulin-treated patients. RESEARCH DESIGN AND METHODS A nested case-control study was performed in a cohort of 1,340 patients by sampling, for each case subject, age-, sex-, and BMI-matched control subjects from the same cohort. RESULTS During a median follow-up of 75.9 months, 112 case patients who developed incident cancer and were compared with 370 control subjects. A significantly lower proportion of case subjects were exposed to metformin and sulfonylureas. After adjustment for comorbidity, glargine, and total insulin doses, exposure to metformin, but not to sulfonylureas, was associated with reduced incidence of cancer (odds ratio 0.46 [95% CI 0.25–0.85], P = 0.014 and 0.75 [0.39–1.45], P = 0.40, respectively). CONCLUSIONS The reduction of cancer risk could be a further relevant reason for maintaining use of metformin in insulin-treated patients.

Dipeptidyl peptidase-4 inhibitors and pancreatitis risk: a meta-analysis of randomized clinical trials.

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.

Is Glucose Control Important for Prevention of Cardiovascular Disease in Diabetes

Patients affected by diabetes show an increased risk of cardiovascular disease (CVD) and mortality that reduces their life expectancy by 5–15 years (depending on the age at diagnosis). An 18-year follow-up study from Finland demonstrated a similar impact of type 1 and type 2 diabetes on cardiovascular mortality, with an increased risk of 5.2 and 4.9 times for type 1 and type 2 diabetes, respectively (1). In type 1 diabetes, follow-up results from a large randomized clinical trial suggest that the improvement of metabolic control, obtained through intensive insulin treatment, can prevent CVD in the long term. On the other hand, despite some encouraging results (2,3), the results of trials assessing the long-term cardiovascular effects of improving metabolic control in type 2 diabetes are controversial. Here, we will present the main points supporting and will illustrate the main counterpoints challenging the importance of glucose control for prevention of CVD in diabetic patients. ### Pros #### Pathophysiological effects of hyperglycemia on cardiovascular system. There is convincing evidence from epidemiological and pathophysiological studies that hyperglycemia has a detrimental effect on cardiovascular risk profile in its own right. It is well known that among patients with type 2 diabetes, those with higher levels of blood glucose and HbA1c are at greater risk for CVD. Glycemic fluctuations and chronic hyperglycemia are triggers for inflammatory responses via increased endoplasmic reticulum stress and mitochondrial superoxide production. The molecular pathways underlying hyperglycemia, low-grade inflammation, and oxidative stress have been widely recognized in the pathogenesis of endothelial dysfunction, which represents the first step of atherogenesis. Through this pathway, hyperglycemia-induced early atherogenesis may lead to an increased probability of cardiovascular events later in life. Direct effects of glucose toxicity, oxidative stress, and low-grade inflammation act in a vicious cycle that determines impaired insulin sensitivity, β-cell loss, and endothelial dysfunction, thus leading to micro- and macrovascular complications …

Effects of glucagon-like peptide-1 receptor agonists on body weight: a meta-analysis.

Glucagon-Like Peptide-1 receptor agonists (GLP-1RAs), approved as glucose-lowering drugs for the treatment of type 2 diabetes, have also been shown to reduce body weight. An extensive Medline, Cochrane database, and Embase search for “exenatide,” “liraglutide,” “albiglutide,” “semaglutide,” and “lixisenatide” was performed, collecting all randomized clinical trials on humans up to December 15, 2011, with a duration of at least 24 weeks, comparing GLP-1 receptor agonists with either placebo or active drugs. Twenty two (7,859 patients) and 7 (2,416 patients) trials with available results on body weight at 6 and 12 months, respectively, were included. When compared with placebo, GLP-1RAs determine a reduction of BMI at 6 months of −1.0 [−1.3; −0.6] kg/m2. Considering the average BMI at baseline (32.4 kg/m2) these data means a weight reduction of about 3% at 6 months. This result could seem modest from a clinical standpoint; however, it could be affected by many factors contributing to an underestimation of the effect of GLP-1RA on body weight, such as non adequate doses, inclusion criteria, efficacy of GLP-1RA on reducing glycosuria, and association to non-pharmacological interventions not specifically aimed to weight reduction.

National Cholesterol Education Program and International Diabetes Federation definitions of metabolic syndrome in the prediction of diabetes. Results from the FIrenze-Bagno A Ripoli study

Background:  The International Diabetes Federation (IDF) proposed to modify the diagnostic criteria for metabolic syndrome (MS) previously issued by the National Cholesterol Education Program (NCEP). Aim of the present investigation is to compare the predictive value for diabetes of NCEP and IDF definitions of MS in a large sample of predominantly Caucasian subjects.

3‐Iodothyronamine: a modulator of the hypothalamus‐pancreas‐thyroid axes in mice

BACKGROUND AND PURPOSE Preclinical pharmacology of 3‐iodothyronamine (T1AM), an endogenous derivative of thyroid hormones, indicates that it is a rapid modulator of rodent metabolism and behaviour. Since T1AM undergoes rapid enzymatic degradation, particularly by MAO, we hypothesized that the effects of T1AM might be altered by inhibition of MAO.

Inflammation Markers and Metabolic Characteristics of Subjects With 1-h Plasma Glucose Levels

OBJECTIVE To assess the association of 1-h plasma glucose (1hPG) and inflammation with normal glucose tolerance (NGT) and pre-diabetes. RESEARCH DESIGN AND METHODS A cohort of 1,062 subjects was enrolled. After oral glucose load (oral glucose tolerance test), we compared subjects with NGT and pre-diabetes above and below the 1hPG cut point (155 mg/dl). Fibrinogen and leukocytes count (white blood cells [WBCs]) for subclinical inflammation, lipid ratios, insulin sensitivity (Matsuda index) were determined. RESULTS Patients with NGT and pre-diabetes (1hPG >155 mg/dl) showed a significant increase of inflammatory markers and lipid ratios (for all, P < 0.05). In age-, sex-, and BMI-adjusted analysis, 1hPG was associated with a significantly higher WBC count and fibrinogen (P < 0.05). Patients with elevated 1hPG showed a highly significant lower insulin sensitivity than subjects <1hPG (P < 0.01). CONCLUSIONS Elevated 1hPG in subjects with NGT and pre-diabetes is associated with subclinical inflammation, high lipid ratios, and insulin resistance. Therefore, 1hPG >155 mg/dl could be considered a new “marker” for cardiovascular risk.