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1.  A journey into a Mediterranean diet and type 2 diabetes: a systematic review with meta-analyses 
BMJ Open  2015;5(8):e008222.
To summarise the evidence about the efficacy of a Mediterranean diet on the management of type 2 diabetes and prediabetic states.
A systematic review of all meta-analyses and randomised controlled trials (RCTs) that compared the Mediterranean diet with a control diet on the treatment of type 2 diabetes and prediabetic states was conducted. Electronic searches were carried out up to January 2015. Trials were included for meta-analyses if they had a control group treated with another diet, if they were of sufficient duration (at least 6 months), and if they had at least 30 participants in each arm. A random-effect model was used to pool data.
Adults with or at risk for type 2 diabetes.
Dietary patterns that described themselves as using a ‘Mediterranean’ dietary pattern.
Outcome measures
The outcomes were glycaemic control, cardiovascular risk factors and remission from the metabolic syndrome.
From 2824 studies, 8 meta-analyses and 5 RCTs were eligible. A ‘de novo’ meta-analysis of 3 long-term (>6 months) RCTs of the Mediterranean diet and glycaemic control of diabetes favoured the Mediterranean diet as compared with lower fat diets. Another ‘de novo’ meta-analysis of two long-term RCTs showed a 49% increased probability of remission from the metabolic syndrome. 5 meta-analyses showed a favourable effect of the Mediterranean diet, as compared with other diets, on body weight, total cholesterol and high-density lipoprotein cholesterol. 2 meta-analyses demonstrated that higher adherence to the Mediterranean diet reduced the risk of future diabetes by 19–23%.
The Mediterranean diet was associated with better glycaemic control and cardiovascular risk factors than control diets, including a lower fat diet, suggesting that it is suitable for the overall management of type 2 diabetes.
PMCID: PMC4538272  PMID: 26260349
2.  A nomogram to estimate the HbA1c response to different DPP-4 inhibitors in type 2 diabetes: a systematic review and meta-analysis of 98 trials with 24 163 patients 
BMJ Open  2015;5(2):e005892.
To develop a nomogram for estimating the glycated haemoglobin (HbA1c) response to different dipeptidyl peptidase-4 (DPP-4) inhibitors in type 2 diabetes.
A systematic review and meta-analysis of randomised controlled trials (RCTs) of DPP-4 inhibitors (vildagliptin, sitagliptin, saxagliptin, linagliptin and alogliptin) on HbA1c were conducted. Electronic searches were carried out up to December 2013. Trials were included if they were carried out on participants with type 2 diabetes, lasted at least 12 weeks, included at least 30 participants and had a final assessment of HbA1c. A random effect model was used to pool data. A nomogram was used to represent results of the metaregression model.
Adults with type 2 diabetes.
Any DPP-4 inhibitor (vildagliptin, sitagliptin, saxagliptin, linagliptin or alogliptin).
Outcome measures
The HbA1c response to each DPP-4 inhibitor within 1 year of therapy.
We screened 928 citations and reviewed 98 articles reporting 98 RCTs with 100 arms in 24 163 participants. There were 26 arms with vildagliptin, 37 with sitagliptin, 13 with saxagliptin, 13 with linagliptin and 11 with alogliptin. For all 100 arms, the mean baseline HbA1c value was 8.05% (64 mmol/mol); the decrease of HbA1c from baseline was −0.77% (95% CI −0.82 to −0.72%), with high heterogeneity (I2=96%). Multivariable metaregression model that included baseline HbA1c, type of DPP-4 inhibitor and fasting glucose explained 58% of variance between studies, with no significant interaction between them. Other factors, including age, previous diabetes drugs and duration of treatment added low predictive power (<1%). The nomogram estimates the absolute HbA1c reduction from baseline using the type of DPP-4 inhibitor, baseline values of HbA1c and fasting glucose.
Baseline HbA1c level and fasting glucose explain most of the variance in HbA1c change in response to DPP-4 inhibitors: each increase of 1.0% units HbA1c provides a 0.4–0.5% units greater fall.
PMCID: PMC4336462  PMID: 25687897
6.  Glucagon-Like Peptide 1 Reduces Endothelial Dysfunction, Inflammation, and Oxidative Stress Induced by Both Hyperglycemia and Hypoglycemia in Type 1 Diabetes 
Diabetes Care  2013;36(8):2346-2350.
Hyperglycemia and hypoglycemia currently are considered risk factors for cardiovascular disease in type 1diabetes. Both acute hyperglycemia and hypoglycemia induce endothelial dysfunction and inflammation, raising the oxidative stress. Glucagon-like peptide 1 (GLP-1) has antioxidant properties, and evidence suggests that it protects endothelial function.
The effect of both acute hyperglycemia and acute hypoglycemia in type 1 diabetes, with or without the simultaneous infusion of GLP-1, on oxidative stress (plasma nitrotyrosine and plasma 8-iso prostaglandin F2alpha), inflammation (soluble intercellular adhesion molecule-1 and interleukin-6), and endothelial dysfunction has been evaluated.
Both hyperglycemia and hypoglycemia acutely induced oxidative stress, inflammation, and endothelial dysfunction. GLP-1 significantly counterbalanced these effects.
These results suggest a protective effect of GLP-1 during both hypoglycemia and hyperglycemia in type 1 diabetes.
PMCID: PMC3714509  PMID: 23564922
7.  Glycaemic durability with dipeptidyl peptidase-4 inhibitors in type 2 diabetes: a systematic review and meta-analysis of long-term randomised controlled trials 
BMJ Open  2014;4(6):e005442.
To evaluate glycaemic durability with dipeptidyl peptidase-4 (DPP-4) inhibitors in type 2 diabetes.
A systematic review and meta-analysis of long-term randomised trials of DPP-4 inhibitors on haemoglobin A1c (HbA1c) was conducted. Electronic searches were carried out on the following databases: MEDLINE, EMBASE, Scopus and Web of Knowledge to December 2013. Searches were supplemented by a review of trial registries and references from identified trials. Trials were included if they lasted at least 76 weeks, and had intermediate and final assessments of HbA1c. Citations and full-text articles were screened by two reviewers. A random effect model was used to pool data.
Adults with type 2 diabetes.
Any DPP-4 inhibitor (sitagliptin, vildagliptin, saxagliptin, linagliptin and alogliptin).
Outcome measures
The difference between final and intermediate HbA1c assessment was the primary outcome.
We screened 461 citations and reviewed 12 articles reporting 12 trials in 14 829 participants. All trials were of 76 weeks duration at least. The difference in HbA1c changes between final and intermediate points averaged 0.22% (95% CI 0.15% to 0.29%), with high heterogeneity (I2=91%, p<0.0001). Estimates of differences were not affected by the analysis of six extension trials (0.24%, 0.02 to 0.46), or five trials in which a DPP-4 inhibitor was added to metformin (0.24%, 0.16 to 0.32).
There is evidence that the effect of DPP-4 inhibitors on HbA1c in type 2 diabetes significantly declines during the second year of treatment. Future research should focus on the characteristics of patients that benefit most from DPP-4 inhibitors in terms of glycaemic durability.
PMCID: PMC4067816  PMID: 24916090
DIABETES & ENDOCRINOLOGY; DPP-4 inhibitors; Meta-analysis
8.  Cardiovascular guidelines: separate career may help attenuate controversy 
The release of recent guidelines for high cholesterol, hypertension and diabetes in the U.S. has been accompanied by great noise and concerns, both in the academic circuits and the lay press. For persons aged 40 to75 years, with LDL cholesterol levels between 70–189 mg/dL and 7.5% or higher estimated 10-year risk, the peril of a global “statinization” has been advocated, predicting a 70% increase of statin use in this otherwise healthy people. A minority of the Eight Joint National Committee panel disagreed with the recommendation to increase the target systolic blood pressure from 140 to 150 mmHg in persons aged 60 years or older without diabetes mellitus or chronic kidney disease. The 2013-American Association of Clinical Endocrinologists algorithm and consensus statement on diabetes has been criticized with particular concerns about transparency, conflicts of interest, group composition, and the abundant use of personal judgment and experience instead of rigorous methodology. Separate careers for experts who collect evidence from persons who write the actual guidelines seems a good opportunity in order to attenuate the noise associated with release of new guidelines, especially those that counter prior practice.
PMCID: PMC3973351  PMID: 24678917
9.  Basal Supplementation of Insulin Lispro Protamine Suspension Versus Insulin Glargine and Detemir for Type 2 Diabetes 
Diabetes Care  2012;35(12):2698-2705.
We compared the effect of insulin lispro protamine suspension (ILPS) with that of insulin glargine and insulin detemir, all given as basal supplementation, in the treatment of patients with type 2 diabetes.
We conducted an electronic search until February 2012, including online registries of ongoing trials and abstract books. All randomized controlled trials comparing ILPS with insulin glargine or detemir with a duration of ≥12 weeks were included.
We found four trials lasting 24–36 weeks involving 1,336 persons: three studies compared ILPS with glargine, and one trial compared ILPS with detemir. There was no significant difference in change in HbA1c level between ILPS and comparators, in the proportion of patients achieving the HbA1c goals of ≤6.5 or <7%, in weight change, or in daily insulin doses. There was no difference in overall hypoglycemia, but nocturnal hypoglycemia occurred significantly more with ILPS than with comparator insulins (mean difference 0.099 events/patient/30 days [95% CI 0.03–0.17]). In a prespecified sensitivity analysis comparing data obtained in patients who remained on their once-daily insulin regimen, not significantly different event rates for nocturnal hypoglycemia were observed between ILPS and comparator insulins (0.063 [−0.007 to 0.13]), and ILPS was associated with lower insulin dose (0.07 units/kg/day [0.05–0.09]).
There is no difference between ILPS and insulin glargine or detemir for targeting hyperglycemia, but nocturnal hypoglycemia occurred more frequently with ILPS than with comparator insulins. Nocturnal hypoglycemia was not significantly different in people who injected insulin once daily.
PMCID: PMC3507592  PMID: 23173139
10.  Metabolic Syndrome and Risk of Cancer 
Diabetes Care  2012;35(11):2402-2411.
Available evidence supports the emerging hypothesis that metabolic syndrome may be associated with the risk of some common cancers. We did a systematic review and meta-analysis to assess the association between metabolic syndrome and risk of cancer at different sites.
We conducted an electronic search for articles published through October 2011 without restrictions and by reviewing reference lists from retrieved articles. Every included study was to report risk estimates with 95% CIs for the association between metabolic syndrome and cancer.
We analyzed 116 datasets from 43 articles, including 38,940 cases of cancer. In cohort studies in men, the presence of metabolic syndrome was associated with liver (relative risk 1.43, P < 0.0001), colorectal (1.25, P < 0.001), and bladder cancer (1.10, P = 0.013). In cohort studies in women, the presence of metabolic syndrome was associated with endometrial (1.61, P = 0.001), pancreatic (1.58, P < 0.0001), breast postmenopausal (1.56, P = 0.017), rectal (1.52, P = 0.005), and colorectal (1.34, P = 0.006) cancers. Associations with metabolic syndrome were stronger in women than in men for pancreatic (P = 0.01) and rectal (P = 0.01) cancers. Associations were different between ethnic groups: we recorded stronger associations in Asia populations for liver cancer (P = 0.002), in European populations for colorectal cancer in women (P = 0.004), and in U.S. populations (whites) for prostate cancer (P = 0.001).
Metabolic syndrome is associated with increased risk of common cancers; for some cancers, the risk differs betweens sexes, populations, and definitions of metabolic syndrome.
PMCID: PMC3476894  PMID: 23093685
11.  Evidence That Hyperglycemia After Recovery From Hypoglycemia Worsens Endothelial Function and Increases Oxidative Stress and Inflammation in Healthy Control Subjects and Subjects With Type 1 Diabetes 
Diabetes  2012;61(11):2993-2997.
Currently there is debate on whether hypoglycemia is an independent risk factor for atherosclerosis, but little attention has been paid to the effects of recovery from hypoglycemia. In normal control individuals and in people with type 1 diabetes, recovery from a 2-h induced hypoglycemia was obtained by reaching normoglycemia or hyperglycemia for another 2 h and then maintaining normal glycemia for the following 6 h. Hyperglycemia after hypoglycemia was also repeated with the concomitant infusion of vitamin C. Recovery with normoglycemia is accompanied by a significant improvement in endothelial dysfunction, oxidative stress, and inflammation, which are affected by hypoglycemia; however, a period of hyperglycemia after hypoglycemia worsens all of these parameters, an effect that persists even after the additional 6 h of normoglycemia. This effect is partially counterbalanced when hyperglycemia after hypoglycemia is accompanied by the simultaneous infusion of vitamin C, suggesting that when hyperglycemia follows hypoglycemia, an ischemia–reperfusion-like effect is produced. This study shows that the way in which recovery from hypoglycemia takes place in people with type 1 diabetes could play an important role in favoring the appearance of endothelial dysfunction, oxidative stress, and inflammation, widely recognized cardiovascular risk factors.
PMCID: PMC3478543  PMID: 22891214
12.  Dipeptidyl peptidase-4 inhibitors in type 2 diabetes therapy – focus on alogliptin 
Type 2 diabetes mellitus is a complex and progressive disease that is showing an apparently unstoppable increase worldwide. Although there is general agreement on the first-line use of metformin in most patients with type 2 diabetes, the ideal drug sequence after metformin failure is an area of increasing uncertainty. New treatment strategies target pancreatic islet dysfunction, in particular gut-derived incretin hormones. Inhibition of the enzyme dipeptidyl peptidase-4 (DPP-4) slows degradation of endogenous glucagon-like peptide-1 (GLP-1) and thereby enhances and prolongs the action of the endogenous incretin hormones. The five available DPP-4 inhibitors, also known as ‘gliptins’ (sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin), are small molecules used orally with similar overall clinical efficacy and safety profiles in patients with type 2 diabetes. The main differences between the five gliptins on the market include: potency, target selectivity, oral bioavailability, long or short half-life, high or low binding to plasma proteins, metabolism, presence of active or inactive metabolites, excretion routes, dosage adjustment for renal and liver insufficiency, and potential drug–drug interactions. On average, treatment with gliptins is expected to produce a mean glycated hemoglobin (HbA1c) decrease of 0.5%–0.8%, with about 40% of diabetic subjects at target for the HbA1c goal <7%. There are very few studies comparing DPP-4 inhibitors. Alogliptin as monotherapy or added to metformin, pioglitazone, glibenclamide, voglibose, or insulin therapy significantly improves glycemic control compared with placebo in adult or elderly patients with inadequately controlled type 2 diabetes. In the EXAMINE trial, alogliptin is being compared with placebo on cardiovascular outcomes in approximately 5,400 patients with type 2 diabetes. In clinical studies, DPP-4 inhibitors were generally safe and well tolerated. However, there are limited data on their tolerability, due to their relatively recent marketing approval. Alogliptin will be used most when avoidance of hypoglycemic events is paramount, such as in patients with congestive heart failure, renal failure, and liver disease, and in the elderly.
PMCID: PMC3782406  PMID: 24068868
type 2 diabetes; DPP-4 inhibitors; alogliptin
14.  Efficacy and safety of insulin lispro protamine suspension as basal supplementation in patients with type 2 diabetes 
The three currently marketed long-acting insulin analogs, glargine, detemir and insulin lispro protamine suspension (ILPS), represent the most significant advances in basal insulin supplementation since the 1940s and 1950s and the introduction of the intermediate-acting NPH (neutral protamine Hagedorn) insulin. As injection of NPH insulin lacks chronic maintenance of a steady-state low-level basal insulin during fasting periods, which can also expose patients to unpredictable nocturnal hypoglycemia, long-acting insulin analogs have been developed to overcome this important limitation of NPH insulin. ILPS is a protamine-based, intermediate-acting insulin formulation of the short-acting analog insulin lispro: its pharmacokinetic and pharmacodynamic characteristics are quite similar to the other basal insulin analogs glargine and detemir. In recent head-to-head randomized controlled trials of insulin-naïve patients with type 2 diabetes, ILPS achieved similar glycemic control compared with glargine or detemir. ILPS administered once daily is an effective and safe way to maintain a steady-state low-level basal insulin during night time, not dissimilar from that currently obtained with a one-day glargine or detemir administration.
PMCID: PMC3474656  PMID: 23148201
detemir; glargine; ILPS (insulin lispro protamine suspension); long-acting insulin analogs
15.  The Possible Protective Role of Glucagon-Like Peptide 1 on Endothelium During the Meal and Evidence for an “Endothelial Resistance” to Glucagon-Like Peptide 1 in Diabetes 
Diabetes Care  2011;34(3):697-702.
Glucagon-like peptide 1 (GLP-1) stimulates insulin secretion. However, GLP-1 also improves endothelial function in diabetes.
Sixteen type 2 diabetic patients and 12 control subjects received a meal, an oral glucose tolerance test (OGTT), and two hyperglycemic clamps, with or without GLP-1. The clamps were repeated in diabetic patients after 2 months of strict glycemic control.
During the meal, glycemia, nitrotyrosine, and plasma 8-iso prostaglandin F2α (8-iso-PGF2a) remained unchanged in the control subjects, whereas they increased in diabetic patients. Flow-mediated vasodilation (FMD) decreased in diabetes, whereas GLP-1 increased in both groups. During the OGTT, an increase in glycemia, nitrotyrosine, and 8-iso-PGF2a and a decrease in FMD were observed at 1 h in the control subjects and at 1 and 2 h in the diabetic patients. In the same way, GLP-1 increased in both groups at the same levels of the meal. During the clamps, in both the control subjects and the diabetic patients, a significant increase in nitrotyrosine and 8-iso-PGF2a and a decrease in FMD were observed, effects that were significantly reduced by GLP-1. After improved glycemic control, hyperglycemia during the clamps was less effective in producing oxidative stress and endothelial dysfunction and the GLP-1 administration was most effective in reducing these effects.
Our data suggest that during the meal GLP-1 can simultaneously exert an incretin effect on insulin secretion and a protective effect on endothelial function, reasonably controlling oxidative stress generation. The ability of GLP-1 in protecting endothelial function seems to depend on the level of glycemia, a phenomenon already described for insulin secretion.
PMCID: PMC3041210  PMID: 21273492
16.  Efficacy of Insulin Analogs in Achieving the Hemoglobin A1c Target of <7% in Type 2 Diabetes 
Diabetes Care  2011;34(2):510-517.
Insulin analogs are increasingly used in patients with type 2 diabetes. We compared the effect of basal, biphasic, prandial, and basal-bolus insulin regimens with insulin analogs to reach the hemoglobin A1c (HbA1c) target of <7% in people with type 2 diabetes.
We conducted an electronic search for randomized controlled trials (RCTs) involving insulin analogs. RCTs were included if they lasted at least 12 weeks, reported the proportion of diabetic patients reaching the HbA1c target of <7% (primary outcome), and the number of patients in any arm was >30.
We found 16 RCTs, with 20 comparisons and 7,759 patients. A greater proportion of patients achieved the HbA1c goal of <7% with both biphasic (odds ratio 1.88 [95% CI 1.38–2.55]) and prandial (2.07 [1.16–3.69]) insulin compared with basal insulin; this was associated for biphasic insulin with greater hypoglycemia (event/patient/30 days, mean difference, 0.34 [range 0–0.69]) and weight gain in kg (1.0 kg [0.28–1.73]). Compared with biphasic insulin, the basal-bolus regimen was associated with a greater chance to reach the HbA1c goal (odds ratio 1.75 [95% CI 1.11–2.77]), with no greater hypoglycemia or weight gain. The effect of insulin analogs on long-term diabetes complications is still lacking.
A greater proportion of type 2 diabetic patients can achieve the HbA1c goal <7% with biphasic or prandial insulin compared with basal insulin; in absolute terms, the basal-bolus regimen was best for the attainment of the HbA1c goal.
PMCID: PMC3024378  PMID: 21216850
19.  Long-Term Effect of Mediterranean-Style Diet and Calorie Restriction on Biomarkers of Longevity and Oxidative Stress in Overweight Men 
We report the effects of a Mediterranean-style diet, with or without calorie restriction, on biomarkers of aging and oxidative stress in overweight men. 192 men were randomly assigned to either a Mediterranean-style diet or a conventional diet. The intervention program was based on implementation of a Mediterranean dietary pattern in the overweight group (MED diet group), associated with calorie restriction and increased physical activity in the obese group (lifestyle group). Both groups were compared with participants in two matched control groups (advice groups). After 2 years, there was a significant difference in weight loss between groups, which was −14 kg (95% CI −20 to −8) in lifestyle groups and −2.0 kg (−4.4 to 0) in the advice groups, with a difference of −11.9 kg (CI −19 to −4.7 kg, P < .001); moreover, there was a significant difference between groups at 2 years for insulin (P = .04), 8-iso-PGF2α (P = .037), glucose (P = .04), and adiponectin (P = .01). Prolonged adherence to a Mediterranean-style diet, with or without caloric restriction, in overweight or obese men is associated with significant amelioration of multiple risk factors, including a better cardiovascular risk profile, reduced oxidative stress, and improved insulin sensitivity.
PMCID: PMC3010676  PMID: 21197397
20.  Characterization of a Novel Polymorphism in PPARG Regulatory Region Associated with Type 2 Diabetes and Diabetic Retinopathy in Italy 
Peroxisome proliferator-activated receptor gamma polymorphisms have been widely associated with type 2 diabetes, although their role in the pathogenesis of vascular complications is not yet demonstrated. In this study, a cohort of 211 type 2 diabetes, 205 obese, and 254 control individuals was genotyped for Pro12Ala, C1431T, C-2821T polymorphisms, and for a newly identified polymorphism (A-2819G). The above-mentioned polymorphisms were analyzed by gene-specific PCR and direct sequencing of all samples. A significant difference was found for -2819G frequency when patients with type 2 diabetes—particularly diabetic women with the proliferative retinopathy—were compared with healthy control individuals. In conclusion, we identified a novel polymorphism, A-2819G, in PPARG gene, and we found it to be associated with type 2 diabetes and proliferative retinopathy in diabetic females. In the analyzed population, this variant represents a genetic risk factor for developing the diabetic retinopathy, whereas Pro12Ala and C1431T do not.
PMCID: PMC2610251  PMID: 19125195

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