Dose-ranging effects of SGLT2 inhibitors in patients with type 2 diabetes: a systematic review and meta-analysis.

The lowest dosage of empagliflozin (10 mg) showed similar benefits on glycated hemoglobin (HbA1c) level, body weight, blood pressure, and total and cardiovascular mortality in comparison with the highest available dose (25 mg) in the EMPAREG trial. These findings have not been clearly demonstrated for canagliflozin and dapagliflozin. The objective was to compare the effect of different doses of SGLT2 inhibitors commercially available in Brazil on HbA1c and body weight of patients with type 2 diabetes. MEDLINE, Cochrane and Embase databases were searched from inception until 11th October 2021 for randomized controlled trials of SGLT2 inhibitors in type 2 diabetes patients, lasting at least 12 weeks. HbA1c and body weight variations were described using standard mean difference. We performed direct and indirect meta-analysis, as well as a meta-regression with medication doses as covariates. Eighteen studies were included, comprising 16,095 patients. In the direct meta-analysis, SGLT2 inhibitors reduced HbA1c by 0.62% (95% CI -0.66 to -0.59) and body weight by 0.60 kg (95% CI -0.64 to -0.55). In the indirect meta-analysis, canagliflozin 300 mg ranked the highest regarding reductions in HbA1c and body weight. The remaining medications and dosages were clinically similar, despite some statistically significant differences among them. Canagliflozin 300 mg seems to be more potent in reducing HbA1c and body weight in patients with type 2 diabetes. The remaining SGLT2 inhibitors at different doses lead to similar effects for both outcomes. Whether these glycemic and weight effects are reflected in lower mortality and cardiovascular events is still uncertain and may be a topic for further studies.

Dose-ranging effects of SGLT2 inhibitors in patients with type 2 diabetes: a systematic review and meta-analysis

ABSTRACT The lowest dosage of empagliflozin (10 mg) showed similar benefits on glycated hemoglobin (HbA1c) level, body weight, blood pressure, and total and cardiovascular mortality in comparison with the highest available dose (25 mg) in the EMPAREG trial. These findings have not been clearly demonstrated for canagliflozin and dapagliflozin. The objective was to compare the effect of different doses of SGLT2 inhibitors commercially available in Brazil on HbA1c and body weight of patients with type 2 diabetes. MEDLINE, Cochrane and Embase databases were searched from inception until 11th October 2021 for randomized controlled trials of SGLT2 inhibitors in type 2 diabetes patients, lasting at least 12 weeks. HbA1c and body weight variations were described using standard mean difference. We performed direct and indirect meta-analysis, as well as a meta-regression with medication doses as covariates. Eighteen studies were included, comprising 16,095 patients. In the direct meta-analysis, SGLT2 inhibitors reduced HbA1c by 0.62% (95% CI −0.66 to −0.59) and body weight by 0.60 kg (95% CI −0.64 to −0.55). In the indirect meta-analysis, canagliflozin 300 mg ranked the highest regarding reductions in HbA1c and body weight. The remaining medications and dosages were clinically similar, despite some statistically significant differences among them. Canagliflozin 300 mg seems to be more potent in reducing HbA1c and body weight in patients with type 2 diabetes. The remaining SGLT2 inhibitors at different doses lead to similar effects for both outcomes. Whether these glycemic and weight effects are reflected in lower mortality and cardiovascular events is still uncertain and may be a topic for further studies.

Glucagon-like peptide-1 receptor agonists and pancreatic cancer: a meta-analysis with trial sequential analysis.

We aimed to assess if GLP-1 agonists are associated with pancreatic cancer. Systematic review and meta-analysis of randomized trials with GLP-1 agonists as an intervention was performed. Trial sequential analysis (TSA) was performed to assess if the available information is sufficient to reject this association. Twelve trials met the study criteria, with a total of 36, 397 patients. GLP-1 analogues did not increase the risk for pancreatic cancer when compared to other treatments (OR 1.06; 95% CI 0.67 to 1.67; I2 14%). TSA confirmed that enough patients were randomized and again no association of the medications and pancreatic cancer was observed considering a NNH of 1000 and the short mean follow-up of the included trials (1.7 years). Larger studies with longer duration would be required to exclude a greater NNH and to aside concerns regarding possible influence of study duration and the outcome.

Dipeptidyl peptidase-4 inhibitors, pancreatic cancer and acute pancreatitis: A meta-analysis with trial sequential analysis.

The use of dipeptidyl peptidase-4 (DPP-4) inhibitors may be associated with pancreatic cancer and acute pancreatitis. Recent meta-analyses have reported conflicting findings. Therefore, we performed a meta-analysis to assess the risk of both pancreatic cancer and acute pancreatitis associated with the use of DPP-4 inhibitors. We also used trial sequential analysis to evaluate whether the number of patients included was enough to reach conclusions. We included randomised controlled trials lasting 24 weeks or more that compared DPP-4 inhibitors with placebo or other antihyperglycaemic agents. A total of 59,404 patients were included. There was no relationship between the use of DPP-4 inhibitors and pancreatic cancer (Peto odds ratio 0.65; 95% CI 0.35-1.21), and the optimal sample size was reached to determine a number needed to harm (NNH) of 1000 patients. DPP-4 inhibitors were associated with increased risk for acute pancreatitis (Peto odds ratio 1.72; 95% CI 1.18-2.53), with an NNH of 1066 patients, but the optimal sample size for this outcome was not reached. In conclusion, there is no association between DPP-4 inhibitors and pancreatic cancer, and a small risk for acute pancreatitis was observed with DPP-4 inhibitor use, although the latter finding is not definitive.

Screening for coronary artery disease in patients with type 2 diabetes: a meta-analysis and trial sequential analysis.

OBJECTIVE: To evaluate the efficacy of coronary artery disease screening in asymptomatic patients with type 2 diabetes and assess the statistical reliability of the findings. METHODS: Electronic databases (MEDLINE, EMBASE, Cochrane Library and clinicaltrials.org) were reviewed up to July 2016. Randomised controlled trials evaluating coronary artery disease screening in asymptomatic patients with type 2 diabetes and reporting cardiovascular events and/or mortality were included. Data were summarised with Mantel-Haenszel relative risk. Trial sequential analysis (TSA) was used to evaluate the optimal sample size to detect a 40% reduction in outcomes. Main outcomes were all-cause mortality and cardiac events (non-fatal myocardial infarction and cardiovascular death); secondary outcomes were non-fatal myocardial infarction, myocardial revascularisations and heart failure. RESULTS: One hundred thirty-five references were identified and 5 studies fulfilled the inclusion criteria and totalised 3315 patients, 117 all-cause deaths and 100 cardiac events. Screening for coronary artery disease was not associated with decrease in risk for all-cause deaths (RR 0.95(95% CI 0.66 to 1.35)) or cardiac events (RR 0.72(95% CI 0.49 to 1.06)). TSA shows that futility boundaries were reached for all-cause mortality and a relative risk reduction of 40% between treatments could be discarded. However, there is not enough information for firm conclusions for cardiac events. For secondary outcomes no benefit or harm was identified; optimal sample sizes were not reached. CONCLUSION: Current available data do not support screening for coronary artery disease in patients with type 2 diabetes for preventing fatal events. Further studies are needed to assess the effects on cardiac events. PROSPERO: CRD42015026627.

Metabolic syndrome as a risk indicator for periodontal disease and tooth loss.

OBJECTIVES: The aim of the present study was to evaluate the association of metabolic syndrome (MS) with periodontitis (PE) and tooth loss (TL). MATERIALS AND METHODS: A cross-sectional study was conducted with 363 individuals who underwent full-mouth periodontal examination, and the association between MS and PE was evaluated considering three outcomes: severe periodontitis, mean probing depth ≥2.4 mm, and mean clinical attachment loss ≥2.0 mm. The prevalence ratio (PR) between MS and PE was calculated using a model adjusted for gender, age, smoking, years of education, and socioeconomic status. RESULTS: The adjusted model showed a PR for severe periodontitis of 1.17 (95 % CI 0.83-1.65). There was no significant association between MS and PE defined as mean probing depth ≥2.4 mm. MS was significantly associated with PE defined as mean attachment loss ≥2 mm in individuals aged 41-60 years (PR 1.47, 95 % CI 1.05-2.06). In addition, MS was associated with TL (>6 teeth) (PR 1.23, 95 % CI 1.02-1.49) for all ages, both in crude and adjusted analyses. CONCLUSIONS: We concluded that there is a weak association of MS with both attachment loss and TL. CLINICAL RELEVANCE: Patients with MS seem to have a higher risk of attachment loss and tooth loss and should be screened for periodontal disease.

Insulin lispro low mixture twice daily vs basal insulin glargine once daily and prandial insulin lispro once daily as insulin intensification strategies in patients with type 2 diabetes: Latin American subpopulation analysis of a randomized trial.

BACKGROUND: This post hoc analysis examined the efficacy and safety of twice-daily insulin lispro low mixture (LM25) and once-daily basal insulin glargine plus once-daily prandial insulin lispro (IGL) in a Latin American subpopulation with type 2 diabetes mellitus (T2DM). METHODS: A phase 4, randomized, open-label, parallel-arm trial included participants aged 18-75 years with T2DM taking once-daily insulin glargine and stable doses of metformin and/or pioglitazone with glycated hemoglobin (HbA1c) 7.5-10.5 % and fasting plasma glucose ≤121 mg/dL. Participants were randomized 1:1 to receive their stable dose of metformin and/or pioglitazone plus twice-daily LM25 or IGL for 24 weeks. The primary efficacy outcome was change in HbA1c after 24 weeks of treatment. Results from participants in Argentina, Brazil, and Mexico are presented here. RESULTS: 162 participants (80 LM25; 82 IGL) with mean ± standard deviation (SD) age = 57.3 ± 9.0 years and body mass index = 31.3 ± 5.2 kg/m(2) were included. Mean ± SD change in HbA1c from baseline to week 24 was -1.5 ± 1.0 % (LM25) and -1.1 ± 1.2 % (IGL). At week 24, 35.1 % (LM25) and 31.6 % (IGL) of participants achieved HbA1c <7.0 %. Mean ± SD weight gain from baseline to week 24 was 2.4 ± 2.9 kg in the LM25 group and 1.0 ± 3.1 kg in the IGL group. The mean ± SD rates of total hypoglycemia per year were 18.9 ± 27.3 (LM25) and 21.6 ± 31.1 (IGL). Rates of treatment-emergent adverse events were 46 % (LM25) and 39 % (IGL). CONCLUSIONS: Our results suggest that both LM25 and IGL are viable treatment options for insulin intensification in Latin American patients with T2DM with suboptimal glycemic control on basal insulin glargine. The safety and tolerability profiles of LM25 and IGL are consistent between this Latin American population and the global trial-level population. Trial registration NCT01175824.

Classes of antihypertensive agents and mortality in hypertensive patients with type 2 diabetes-Network meta-analysis of randomized trials.

AIMS: The aim of this study was to evaluate the effects of antihypertensive drug classes in mortality in patients with type 2 diabetes. METHODS: MEDLINE, EMBASE, Clinical Trials and Cochrane Library were searched for randomized trials comparing thiazides, beta-blockers, calcium channel blockers (CCBs), angiotensin-converting inhibitors (ACEi) and angiotensin-receptor blockers (ARBs), alone or in combination for hypertension treatment in patients with type 2 diabetes. Outcomes were overall and cardiovascular mortality. Network meta-analysis was used to obtain pooled effect estimate. RESULTS: A total of 27 studies, comprising 49,418 participants, 5647 total and 1306 cardiovascular deaths were included. No differences in total or cardiovascular mortality were observed with isolated antihypertensive drug classes compared to each other or placebo. The ACEi and CCB combination showed evidence of reduction in cardiovascular mortality comparing to placebo [median HR, 95% credibility intervals: 0.16, 0.01-0.82], betablockers (0.20, 0.02-0.98), CCBs (0.21, 0.02-0.97) and ARBs (0.18, 0.02-0.91). In included trials, this combination was the treatment that most consistently achieved both lower systolic and diastolic end of study blood pressure. CONCLUSIONS: There is no benefit of a single antihypertensive class in reduction of mortality in hypertensive patients with type 2 diabetes. Reduction of cardiovascular mortality observed in patients treated with ACEi and CCB combination may be related to lower blood pressure levels.

A Multinational, Randomized, Open-label, Treat-to-Target Trial Comparing Insulin Degludec and Insulin Glargine in Insulin-Naïve Patients with Type 2 Diabetes Mellitus.

INTRODUCTION: To lower the barrier for initiating insulin treatment and obtain adequate glycemic control in type 2 diabetes mellitus (T2DM), new basal insulin preparations with improved pharmacological properties and consequently a lower risk of hypoglycemia are needed. The objective of this trial was to confirm the efficacy and compare the safety of insulin degludec (IDeg) with insulin glargine (IGlar) in a multinational setting with two thirds of subjects enrolled in China. METHODS: This was a 26-week, randomized, open-label, parallel-group, treat-to-target, non-inferiority trial in 833 subjects with T2DM (48 % were female, mean age 56 years, diabetes duration 8 years), inadequately controlled on oral antidiabetic drugs (OADs). Subjects were randomized 2:1 to once-daily IDeg (555 subjects) or IGlar (278 subjects), both with metformin. The primary endpoint was the change from baseline in glycosylated hemoglobin (HbA1c) after 26 weeks. RESULTS: The completion rate was high (IDeg 94.2 %; IGlar 91.4 %). Mean HbA1c decreased from 8.3 to 7.0 % in both groups. Estimated treatment difference (ETD) [95 % confidence interval (CI)] IDeg-IGlar in change from baseline was -0.05 % points [-0.18 to 0.08], confirming the non-inferiority of IDeg to IGlar. The proportion of subjects achieving HbA1c <7.0 % was 54.2 and 51.4 % with IDeg and IGlar, respectively (estimated odds ratio [95 % CI] IDeg/IGlar: 1.14 [0.84 to 1.54]). The mean decrease in fasting plasma glucose, self-measured plasma glucose profiles, and insulin dose were similar between groups. Numerically lower rates of overall (estimated rate ratio [95 % CI] IDeg/IGlar: 0.80 [0.59 to 1.10]) and nocturnal (0.77 [0.43 to 1.37]) confirmed hypoglycemia were observed with IDeg compared with IGlar. No treatment differences in other safety parameters were found. Subjects were more satisfied with the IDeg device compared with the IGlar device as reflected by the total Treatment Related Impact Measures-Diabetes Device score (ETD [95 % CI] IDeg-IGlar: 2.2 [0.2 to 4.3]). CONCLUSION: IDeg provided adequate glycemic control non-inferior to IGlar and a tendency for a lower hypoglycemia rate. IDeg is considered suitable for initiating insulin therapy in T2DM patients on OADs requiring intensified treatment. TRIAL REGISTRATION: Clinicaltrials.gov NCT01849289.

Efficacy and safety of a premixed versus a basal-plus insulin regimen as intensification for type 2 diabetes by timing of the main meal.

OBJECTIVE: To describe the efficacy and safety of premixed insulin lispro protamine suspension 75%/insulin lispro solution 25% (LM25) twice daily (bid) versus basal insulin glargine plus prandial insulin lispro (IGL), both once daily, according to main meal timing. METHODS: Data were obtained post hoc from a 24 week, randomized, open-label study comparing LM25 and IGL as insulin intensification in patients with type 2 diabetes inadequately controlled with once daily basal insulin glargine plus metformin and/or pioglitazone (ClinicalTrials.gov identifier: NCT01175824). Patients administered LM25 bid before breakfast and the evening meal, insulin glargine at bedtime and insulin lispro before the day's main meal (meal with the highest 2 hour postprandial glucose level during screening). Patients were grouped by main meal. Changes in glycosylated hemoglobin (HbA1c) and bodyweight were summarized using likelihood-based mixed models; hypoglycemia incidence was compared between treatments using Fisher's exact test. RESULTS: Overall, 476 patients (LM25, n = 236; IGL, n = 240) were randomized. In all main meal groups, with both insulin regimens, mean HbA1c significantly decreased from baseline to 24 weeks (p < 0.0001). Patients whose main meal was in the evening had a greater bodyweight increase with LM25 than with IGL (p = 0.015), and a smaller proportion of these patients experienced total (p = 0.027) and nocturnal (p = 0.006) hypoglycemia with LM25 compared with IGL. Patients whose main meal was lunch experienced more nocturnal hypoglycemia with LM25 than with IGL (p = 0.030). Study limitations include that this was a post hoc analysis and no assessments ensured that: SMBG results determined timing of the main meal, each patient's main meal remained unchanged throughout the study, or patients administered insulin lispro with that meal. CONCLUSIONS: Glycemic control improved in patients receiving either LM25 or IGL, irrespective of main meal timing. Both regimens can be used in patients with inadequate glycemic control who are in need of insulin intensification.

Endothelin-1 gene polymorphisms and diabetic kidney disease in patients with type 2 diabetes mellitus.

BACKGROUND AND AIMS: Diabetic kidney disease (DKD) is the leading cause of end stage renal disease worldwide and is associated with increased cardiovascular mortality. The endothelin system has been implicated in the pathogenesis of arterial hypertension and renal dysfunction. In the present study, the association of DKD with polymorphisms in ET-1 (EDN1) and ETRA (EDNRA) genes was analyzed in patients with type 2 diabetes mellitus (T2DM). METHODS: A case-control study was conducted in 548 white T2DM patients. Patients with proteinuria or on dialysis were considered cases and patients with normoalbuminuria were considered controls. Two polymorphisms in the EDN1 gene (rs1800541 and rs57072783) and five in EDNRA gene (rs6842241; rs4835083; rs4639051; rs5333 and rs5343) were genotyped and haplotype analyses were performed. RESULTS: The presence of rs57072783 T allele (TT/TG vs. GG) or rs1800541 G allele (GG/GT vs. TT) protected against DKD (OR = 0.69, 95 % CI 0.48-0.99, P = 0.049; and OR = 0.60, 95 % CI 0.41-0.88, P = 0.009, respectively). However in multivariate analyses, only the rs1800541 G allele remained independently associated with DKD (P = 0.046). CONCLUSIONS: The present study shows that ET-1 could be involved in the pathogenesis of DKD in patients with T2DM.

Inhaled Technosphere Insulin Compared With Injected Prandial Insulin in Type 1 Diabetes: A Randomized 24-Week Trial.

OBJECTIVE: To compare the efficacy and safety of Technosphere insulin (TI) and insulin aspart in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: This open-label noninferiority trial compared the change in HbA1c from baseline to week 24 of prandial TI (n = 174) with that of subcutaneous aspart (n = 171), both with basal insulin, in patients with type 1 diabetes and HbA1c 7.5-10.0% (56.8-86.0 mmol/mol). RESULTS: Mean change in HbA1c in TI patients (-0.21% [-2.3 mmol/mol]) from baseline (7.94% [63.3 mmol/mol]) was noninferior to that in aspart patients (-0.40% [-4.4 mmol/mol]) from baseline (7.92% [63.1 mmol/mol]). The between-group difference was 0.19% (2.1 mmol/mol) (95% CI 0.02-0.36), satisfying the noninferiority margin of 0.4%. However, more aspart patients achieved HbA1c <7.0% (53.0 mmol/mol) (30.7% vs. 18.3%). TI patients had a small weight loss (-0.4 kg) compared with a gain (+0.9 kg) for aspart patients (P = 0.0102). TI patients had a lower hypoglycemia event rate than aspart patients (9.8 vs. 14.0 events/patient-month, P < 0.0001). Cough (generally mild) was the most frequent adverse event (31.6% with TI, 2.3% with aspart), leading to discontinuation in 5.7% of patients. Treatment group difference for mean change from baseline in forced expiratory volume in 1 s was small (40 mL) and disappeared upon TI discontinuation. CONCLUSIONS: In patients with type 1 diabetes receiving basal insulin, HbA1c reduction with TI was noninferior to that of aspart, with less hypoglycemia and less weight gain but increased incidence of cough.

Effects of the DASH Diet and Walking on Blood Pressure in Patients With Type 2 Diabetes and Uncontrolled Hypertension: A Randomized Controlled Trial.

Data on the potential beneficial effects of combining diet and exercise on blood pressure (BP) are still scarce. A 4-week randomized controlled clinical trial was undertaken in 40 hypertensive patients with type 2 diabetes with uncontrolled blood pressure (BP) in office and daytime ambulatory BP monitoring (ABPM). Patients were assigned to follow a Dietary Approaches to Stop Hypertension (DASH) diet associated with advice to increase walking using a pedometer (intervention group) or a diet based on the American Diabetes Association recommendations (control group). The lifestyle intervention caused a greater ABPM (mm Hg) reduction in systolic 24-hour, diastolic 24-hour, nighttime systolic, daytime systolic, and daytime diastolic measurements than observed in the control group. In the intervention group there was a decrease in urinary sodium and an increase in urinary potassium, plasma aldosterone, and the number of steps per day (P<.05). The DASH diet and increased walking were associated with clinically significant reductions in ABPM values in hypertensive patients with type 2 diabetes.

Human pancreatic islet transplantation: an update and description of the establishment of a pancreatic islet isolation laboratory.

Type 1 diabetes mellitus (T1DM) is associated with chronic complications that lead to high morbidity and mortality rates in young adults of productive age. Intensive insulin therapy has been able to reduce the likelihood of the development of chronic diabetes complications. However, this treatment is still associated with an increased incidence of hypoglycemia. In patients with "brittle T1DM", who have severe hypoglycemia without adrenergic symptoms (hypoglycemia unawareness), islet transplantation may be a therapeutic option to restore both insulin secretion and hypoglycemic perception. The Edmonton group demonstrated that most patients who received islet infusions from more than one donor and were treated with steroid-free immunosuppressive drugs displayed a considerable decline in the initial insulin independence rates at eight years following the transplantation, but showed permanent C-peptide secretion, which facilitated glycemic control and protected patients against hypoglycemic episodes. Recently, data published by the Collaborative Islet Transplant Registry (CITR) has revealed that approximately 50% of the patients who undergo islet transplantation are insulin independent after a 3-year follow-up. Therefore, islet transplantation is able to successfully decrease plasma glucose and HbA1c levels, the occurrence of severe hypoglycemia, and improve patient quality of life. The goal of this paper was to review the human islet isolation and transplantation processes, and to describe the establishment of a human islet isolation laboratory at the Endocrine Division of the Hospital de Clínicas de Porto Alegre - Rio Grande do Sul, Brazil.

Human pancreatic islet transplantation: an update and description of the establishment of a pancreatic islet isolation laboratory

Type 1 diabetes mellitus (T1DM) is associated with chronic complications that lead to high morbidity and mortality rates in young adults of productive age. Intensive insulin therapy has been able to reduce the likelihood of the development of chronic diabetes complications. However, this treatment is still associated with an increased incidence of hypoglycemia. In patients with “brittle T1DM”, who have severe hypoglycemia without adrenergic symptoms (hypoglycemia unawareness), islet transplantation may be a therapeutic option to restore both insulin secretion and hypoglycemic perception. The Edmonton group demonstrated that most patients who received islet infusions from more than one donor and were treated with steroid-free immunosuppressive drugs displayed a considerable decline in the initial insulin independence rates at eight years following the transplantation, but showed permanent C-peptide secretion, which facilitated glycemic control and protected patients against hypoglycemic episodes. Recently, data published by the Collaborative Islet Transplant Registry (CITR) has revealed that approximately 50% of the patients who undergo islet transplantation are insulin independent after a 3-year follow-up. Therefore, islet transplantation is able to successfully decrease plasma glucose and HbA1c levels, the occurrence of severe hypoglycemia, and improve patient quality of life. The goal of this paper was to review the human islet isolation and transplantation processes, and to describe the establishment of a human islet isolation laboratory at the Endocrine Division of the Hospital de Clínicas de Porto Alegre – Rio Grande do Sul, Brazil.

Increased protein intake is associated with uncontrolled blood pressure by 24-hour ambulatory blood pressure monitoring in patients with type 2 diabetes.

OBJECTIVE: To analyze possible associations of dietary components, especially protein intake, with blood pressure (BP) during ambulatory BP monitoring (ABPM) in patients with type 2 diabetes. METHODS: In this cross-sectional study, BP of outpatients with type 2 diabetes was evaluated by 24-hour ABPM (Spacelabs 90207) and usual diet by 3-day weighed diet records. Patients were divided into 2 groups according to their daytime ABPM: uncontrolled BP (systolic BP ≥ 135 mmHg or diastolic BP ≥ 85 mmHg) and controlled BP (systolic BP < 135 mmHg and diastolic BP < 85 mmHg). Logistic regression models unadjusted and adjusted for possible confounders (covariates) were used to analyze the association of protein and uncontrolled BP. RESULTS: A total of 121 patients with type 2 diabetes aged 62.3 years, 54.5% of whom were women, were studied. The uncontrolled BP group had higher glycated hemoglobin (HbA1C) values (8.4 ± 2.0 vs 7.6 ± 1.3%; p = 0.04) and consumed more protein (20.0 ± 3.8 vs 18.2 ± 3.6% of energy; p = 0.01) and meat, (2.6 [1.45, 2.95] vs 2.0 [1.49, 2.90] g/kg weight; p = 0.04) than the controlled BP group. In a multivariate analysis, protein intake (% of energy) increased the chance for uncontrolled BP (odds ratio [OR] = 1.16; 95% confidence interval [CI], 1.02, 1.30; p = 0.02), adjusted for body mass index (BMI), HbA1C, low-density lipoprotein (LDL) cholesterol, number of antihypertensive medications, and ethnicity. Meat consumption higher than 3.08 g/kg weight/day more than doubled the chance for uncontrolled BP (OR = 2.53; 95% CI, 1.01, 7.60; p = 0.03). CONCLUSION: High protein intake and meat consumption were associated with high daytime ABPM values in patients with type 2 diabetes. Reducing meat intake might represent an additional dietary intervention in hypertensive patients with type 2 diabetes.

The -308G>a polymorphism of the TNF gene is associated with proliferative diabetic retinopathy in Caucasian Brazilians with type 2 diabetes.

PURPOSE: We tested the hypothesis that tumor necrosis factor (TNF) gene polymorphisms are associated with diabetic retinopathy (DR) in Caucasians with type 2 diabetes mellitus. METHODS: In a case-control study, the -238G>A (rs361525), -308G>A (rs1800629), and -857C>T (rs1799724) polymorphisms of the TNF gene were genotyped in 745 outpatients with type 2 diabetes, including 331 subjects without DR, 246 with nonproliferative DR (NPDR), and 168 with proliferative DR (PDR). RESULTS: Genotype and allele frequencies of the -238G>A, -308G>A, and -857C>T polymorphisms in subjects with NPDR were not significantly different from those of subjects without DR (P > 0.05 for all comparisons). However, the A allele of the -308G>A polymorphism was more frequent in subjects with PDR than in those with no DR (18.1% vs. 11.5%, corrected P = 0.035). Multivariate logistic regression analysis showed that the -308A allele was independently associated with an increased risk of PDR, under a dominant model (adjusted odds ratio [aOR], 1.82; 95% confidence interval [CI], 1.11-2.98). The combined analysis of the three polymorphisms also showed that haplotypes containing the -308A allele were associated with an increased risk of PDR (aOR, 2.36; 95% CI, 1.29-4.32). CONCLUSIONS: This study detected, for the first time to our knowledge, an independent association of the -308G>A polymorphism in the TNF gene with PDR in Caucasian Brazilians with type 2 diabetes. This finding suggests that TNF is a potential susceptibility gene for PDR.

Fiber intake and inflammation in type 1 diabetes.

BACKGROUND: Higher intake of dietary fiber is associated with lower risk of coronary heart disease, the leading cause of mortality among people with type 1 diabetes. The protective effect includes the anti-inflammatory properties of some foods. Population-based studies have shown an inverse association between some nutritional habits and high sensitive -C-reactive protein (hs-CRP). This study aimed to ascertain the association between fiber intake and hs-CPR levels in patients with type 1 diabetes. METHODS: This cross-sectional study was conducted with 106 outpatients with type 1 diabetes; age 40 ± 11 years; diabetes duration of 18 ± 8.8 years. Dietary intake was evaluated by 3-day weighed-diet records. Patients were categorized in 2 groups, according to fiber intake (>20 g/day and <20 g/day). RESULTS: The group with fiber intake > 20 g/day had lower hs-CRP levels [median (25(th-)75(th)) 0.7 mg/dl (0.4-2.4) vs. 1.9 mg/dl (1.0-4.4); P = 0.002], than the other group. Controlled for HbA1c and energy intake, an inverse relation was observed between hs-CRP levels and total fiber [ß = - 0.030 (SE: 0.0120), P = 0.02], soluble fiber [ß = - 0.078 (SE: 0.0421), P = 0.06] and insoluble fiber [ß = - 0.039 (SE: 0.01761), P = 0.026]. Even, after additional adjustment fibers remained associated with lower hs-CRP levels. Total fibers were stratified in 4 groups: < 10 g/day, from 10 to < 20 g/day, from 20 to 30 g/day and > 30 g/day. Compared to the group who ingested < 10 g/day of total fiber (referent group), the group who consumed > 30 g/d had significantly lower hs-CRP levels [-2.45 mg/L, P = 0.012] independent of the HbA1c values. CONCLUSIONS: The present study suggests that an increased consumption of dietary fiber > 30 g/day may play a role in reducing inflammation in individuals with type 1 diabetes.

Advancing basal insulin replacement in type 2 diabetes inadequately controlled with insulin glargine plus oral agents: a comparison of adding albiglutide, a weekly GLP-1 receptor agonist, versus thrice-daily prandial insulin lispro.

OBJECTIVE: GLP-1 receptor agonists may provide an alternative to prandial insulin for advancing basal insulin therapy. Harmony 6 was a randomized, open-label, active-controlled trial testing once-weekly albiglutide vs. thrice-daily prandial insulin lispro as an add-on to titrated once-daily insulin glargine. RESEARCH DESIGN AND METHODS: Patients taking basal insulin (with or without oral agents) with HbA1c 7-10.5% (53-91 mmol/mol) entered a glargine standardization period, followed by randomization to albiglutide, 30 mg weekly (n = 282), subsequently uptitrated to 50 mg, if necessary, or thrice-daily prandial lispro (n = 281) while continuing metformin and/or pioglitazone. Glargine was titrated to fasting plasma glucose of <5.6 mmol/L, and lispro was adjusted based on glucose monitoring. The primary end point was the difference in the HbA1c change from baseline at week 26. RESULTS: At week 26, HbA1c decreased from baseline by -0.82 ± SE 0.06% (9.0 mmol/mol) with albiglutide and -0.66 ± 0.06% (7.2 mmol/mol) with lispro; treatment difference, -0.16% (95% CI -0.32 to 0.00; 1.8 mmol/mol; P < 0.0001), meeting the noninferiority end point (margin, 0.4%). Weight decreased with albiglutide but increased with lispro (-0.73 ± 0.19 kg vs. +0.81 ± 0.19 kg). The mean glargine dose increased from 47 to 53 IU (albiglutide) and from 44 to 51 IU (lispro). Adverse events for albiglutide versus lispro included severe hypoglycemia (0 vs. 2 events), documented symptomatic hypoglycemia (15.8% vs. 29.9%), nausea (11.2% vs. 1.4%), vomiting (6.7% vs. 1.4%), and injection site reactions (9.5% vs. 5.3%). CONCLUSIONS: Weekly albiglutide is a simpler therapeutic option than thrice-daily lispro for advancing basal insulin glargine therapy, resulting in comparable HbA1c reduction with weight loss and lower hypoglycemia risk.

Brain death-induced inflammatory activity in human pancreatic tissue: a case-control study.

BACKGROUND: Long-term insulin independence after islet transplantation depends on engraftment of a large number of islets. However, the yield of pancreatic islets from brain-dead donors is negatively affected by the up-regulation of inflammatory mediators. Brain death is also believed to increase tissue factor (TF) expression, contributing to a low rate of engraftment. METHODS: We conducted a case-control study to assess brain death-induced inflammatory effects in human pancreas. Seventeen brain-dead patients and 20 control patients undergoing pancreatectomy were studied. Serum tumor necrosis factor (TNF), interleukin (IL) 6, IL-1ß, interferon (IFN) γ, and TF were measured using enzyme-linked immunosorbent assay kits. Gene expressions of these cytokines and TF were evaluated by reverse transcriptase quantitative polymerase chain reaction. Protein quantification was performed by immunohistochemistry in paraffin-embedded pancreas sections. RESULTS: Brain-dead patients had higher serum concentrations of TNF and IL-6 and increased TNF protein levels compared to controls. The groups had similar TNF, IL-6, IL-1ß, and IFN-γ messenger RNA levels in pancreatic tissue. Reverse transcriptase quantitative polymerase chain reaction revealed TF messenger RNA up-regulation in controls. Immunohistochemical analyses showed that brain-dead patients had increased TNF protein levels compared to controls. CONCLUSIONS: Brain death induces inflammation evidenced by the up-regulation of TNF in serum and pancreatic tissue. Blocking the expression of key inflammatory mediators in brain-dead donors should be evaluated as a new approach to improve the outcomes of islet transplantation.