Microvascular complications (MC) affect CV risk and mortality in T2D. We explored the association of cumulative burden of retinopathy, nephropathy and peripheral neuropathy with mortality, CV events ...and ESRD in a single-centre, observational study involving 986 T2D over a 12.9±2.7 yrs follow-up. Vital status and rates of outcomes were censored on December 2017. The cohort included 491 (49.8%), 318 (32.3%), 135 (13.7%) and 42 (4.3%) people with no, 1, 2 or 3 MC. All-cause mortality (23.3%) increased from no-MC (15.3%) to 1 MC (23.3%, HR 1.60; 95%CI 1.16-2.20), 2 MC (41.5%, 3.19; 2.25-4.51) and 3 MC (59.5%, 5.32; 3.38-8.36; p<0.0001). After adjustments, HRs were: 1 MC, 1.21 (0.87-1.69); 2 MC, 1.72 (1.15-2.56) and 3 MC, 3.17 (1.89-5.33, p<0.0001). Irrespective of number of baseline CV risk factors not at target (HbA1c ≥7%, LDL ≥100 mg/dl, BP ≥140/90 mmHg), age and sex adjusted HRs raised with MC (p<0.0001). CV events occurred in 276 T2D (28.4%). Incidence raised with MC: no-MC, 20.8%; 1 MC, 31.3% (HR 1.65; 1-25-2.18); 2 MC, 42.7% (2.77; 2.00-3.85); 3 MC, 50.0% (3.78; 2.36-6.05, p<0.0001). After adjustments, HRs for CV events were: 1 MC, 1.37 (1.03-1.82); 2 MC, 1.61 (1.12-2.30) and 3 MC, 2.42 (1.48-3.99, p<0.0001). Rate of heart failure hospitalization (hHF) was 3.3% in no-MC, 11.5% in 1 MC (HR 3.19; 1.83-5.56), 17.6% in 2 MC (5.68; 3.09-10.45) and 14.3% (5.00; 2.00-12.54) in 3 MC (p<0.0001). After adjustments, rate of hHF raised in 1 MC (2.28; 1.30-4.01), 2 MC (3.38; 1.79-6.40) and 3 MC (3.02; 1.19-7.65). Also ESRD raised with MC: no-MC, 4.9%; 1 MC, 6.7% (HR 1.44; 0.80-2.59); 2 MC, 11.5% (2.76; 1.45-5.27); 3 MC, 26.2% (7.67; 3.75-15.70; p<0.0001). After adjustments, ESRD raised with 2 MC (HR 2.34; 1.21-4.53) and 3 MC (6.41; 3.19-13.16, p<0.0001). Incidence of CV events, hHF, and ESRD raised with number of MC after stratification for risk factors not at target (p<0.0001). In T2D, the cumulative burden of MC predicts mortality, CV events, hHF and ESRD, offering an accessible tool for improving risk prediction.
Disclosure
M. Garofolo: None. E. Gualdani: None. R. Giannarelli: None. D. Lucchesi: None. R. Miccoli: None. P. Francesconi: None. S. Del Prato: Advisory Panel; Self; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Takeda Pharmaceutical Company Limited. G. Penno: None.
Context:
In subjects with normal glucose tolerance (NGT) 1-hour postload plasma glucose (1-h oral glucose tolerance test OGTT) of >155 mg/dL predicts type 2 diabetes (T2DM) and is associated with ...subclinical atherosclerosis.
Objective:
The purpose of this study was to evaluate β-cell function, insulin resistance, and cardiovascular risk profile in subjects with NGT with a 1-h OGTT glucose of >155 mg/dL.
Patients and Methods:
The GENFIEV (Genetics, PHYsiopathology, and Evolution of Type 2 diabetes) study is a multicenter study recruiting individuals at high risk of T2DM. A total of 926 subjects underwent a 75-g OGTT for assessment of plasma glucose and C-peptide for mathematical modeling of β-cell function (derivative and proportional control). Fasting insulin, lipid profile, and clinical parameters were determined as well.
Results:
A 1-hour OGTT glucose of >155 mg/dL was found in 39% of subjects with NGT, 76% with impaired fasting glucose (IFG), 90% with impaired glucose tolerance (IGT), and 99% and 98% with IFG + IGT or newly diagnosed T2DM, respectively. Among subjects with NGT (n = 474), those with 1-hour OGTT glucose of >155 mg/dL were more insulin-resistant and had worse β-cell function than those with 1-hour OGTT glucose of ≤155 mg/dL. Moreover, glycosylated hemoglobin, blood pressure, low-density lipoprotein cholesterol, and triglycerides were higher in subjects with NGT with 1-hour OGTT glucose of >155 mg/dL, whereas high-density lipoprotein cholesterol was lower compared with that in subjects with NGT with 1-hour OGTT glucose of ≤155 mg/dL. Compared with subjects with IGT, those with NGT with 1-hour OGTT glucose of >155 mg/dL had comparable cardiovascular risk profile and insulin resistance but slightly better β-cell function.
Conclusions:
Among subjects with NGT, those with 1-hour OGTT glucose of >155 mg/dL showed lower insulin sensitivity, impaired β-cell function, and worse cardiovascular risk profile and therefore are at greater risk of developing T2DM and cardiovascular disease.
Abstract
Context
Hypoglycemic drugs with proven cardiovascular (CV) benefits are recommended for patients with type 2 diabetes and CV disease. Whether the beneficial effects extend to those at lower ...risk remains unclear.
Aim
We investigated the long-term CV effects of pioglitazone or sulfonylureas (SUs) across the spectrum of pretreatment CV risk.
Methods
Among 2820 participants of the TOSCA.IT trial, four subgroups with different risk of outcome—a composite of all-cause death, nonfatal myocardial infarction, nonfatal stroke, urgent coronary revascularization—were identified by the RECursive Partitioning and AMalgamation (RECPAM) method. Within each group, the effect of SUs or pioglitazone on the outcome was evaluated.
Results
Sex was the first splitting variable, followed by urinary albumin-to-creatinine ratio (UACR) (>9 mg/g or ≤9 mg/g) and body mass index (BMI) (>28.7 or ≤28.7 kg/m2). Female patients had the lowest risk (reference); male patients with UACR >9 mg/g and BMI >28.7 kg/m2 had the highest risk hazard ratio (HR), 5.58; 95% CI, 3.32 to 9.69. Patients in this group present a cluster of conditions suggestive of marked insulin resistance (higher BMI, waist circumference, triglycerides, blood pressure, and UACR and lower high-density lipoprotein cholesterol) than the other groups. Treatment with pioglitazone in this group was associated with a significantly lower occurrence of the outcome than SUs (HR, 0.48; 95% CI, 0.25 to 0.76). No significant difference between study treatments was observed in the other RECPAM classes.
Conclusions
It is possible to identify patients with type 2 diabetes early in the stage of their disease and who are largely free from evident CV disease in whom add-on pioglitazone to metformin confers CV protection as compared with SUs.
A parsimonious set of clinical variables identifies patients with diabetes in whom add-on pioglitazone to metformin confers cardiovascular protection, thus supporting more personalized diabetes care.
In the primary care setting providers have more tools available than ever before to impact positively obesity, diabetes, and their complications, such as renal and cardiac diseases. It is important ...to recognise what is available for treatment taking into account diabetes heterogeneity. For those who develop type 2 diabetes (T2DM), effective treatments are available that for the first time have shown a benefit in reducing mortality and macrovascular complications, in addition to the well‐established benefits of glucose control in reducing microvascular complications. Some of the newer medications for treating hyperglycaemia have also a positive impact in reducing heart failure (HF). Technological advances have also contributed to improving the quality of care in patients with diabetes. The use of technology, such as continuous glucose monitoring systems (CGM), has improved significantly glucose and glycated haemoglobin A1c (HbA1c) values, while limiting the frequency of hypoglycaemia. Other technological support derives from the use of predictive algorithms that need to be refined to help predict those subjects who are at great risk of developing the disease and/or its complications, or who may require care by other specialists. In this review we also provide recommendations for the optimal use of the new medications; sodium‐glucose co‐transporter‐2 inhibitors (SGLT2i) and Glucagon‐like peptide‐receptor agonists 1 (GLP1RA) in the primary care setting considering the relevance of these drugs for the management of T2DM also in its early stage.
Summary
Obesity is a chronic, multifactorial, relapsing disease. Despite multicomponent lifestyle interventions, including pharmacotherapy, maintaining bodyweight loss is challenging for many people. ...The pathophysiology of obesity is complex, and currently approved pharmacotherapies only target a few of the many pathways involved; thus, single‐targeting agents have limited efficacy. Proglucagon‐derived peptides, glucagon, and the incretin hormones glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP), represent attractive targets for managing obesity and metabolic disorders because they may have direct roles in multiple mechanisms including satiety, energy homeostasis, and lipolytic activity. Unimolecular dual and triple agonists targeting glucagon and incretin hormone receptors have been shown to promote bodyweight loss, lower glucose levels, and reduce food intake in animal models of obesity. Multiple dual receptor agonists are in clinical development for the treatment of obesity, including GLP‐1/GIP and GLP‐1/glucagon receptor agonists. The extent to which glucagon contributes to treatment effects remains to be understood, but it may promote bodyweight loss by reducing food intake, while concomitant GLP‐1 receptor agonism ensures normal glucose control. Further research is required to fully understand the molecular mechanisms of action and metabolic effects of both dual and triple receptor agonists.
With increasing population aging and prevalence of type 2 diabetes (T2D) worldwide, prevention of diabetic complications remains a major unmet need. While cardiovascular outcomes of diabetes are ...improving over time, diabetic kidney disease (DKD) still leads to an exceedingly high rate of end‐stage kidney disease (ESKD). A game‐changing opportunity is offered by treatment with sodium‐glucose cotransporter‐2 (SGLT2) inhibitors. Randomized controlled trials (RCTs) have indisputably shown that SGLT2 inhibitors reduce the rate of DKD progression, the decline in estimated glomerular filtration rate (eGFR), and the development of ESKD. In parallel, SGLT2 inhibitors improve cardiovascular outcomes, especially the risk of hospitalization for heart failure. Real‐world studies (RWSs) have largely confirmed the findings of RCTs in broader populations of subjects with T2D followed under routine care. In the present paper, we review RWSs exploring the renal effects of SGLT2 inhibitors and highlight the most critical challenges that can be encountered in designing and conducting such studies. Channelling bias (confounding by indication), time‐lag bias, conditioning on the future, database heterogeneity, linearity of eGFR change over time, and duration of observation are critical issues that may undermine the robustness of RWS findings. We then elaborate on the new opportunities to overcome such limitations by describing the design and objectives of the DARWIN (DApagliflozin Real‐World evIdeNce)‐Renal study, a new RWS promoted by the Italian Diabetes Society. Fine‐tuning of methods for comparative observational research will improve evidence derived from RWSs on the renal effects of SGLT2 inhibitors, aiding the evolving discussion regarding the place of SGLT2 inhibitors in T2D treatment algorithms in different stages of DKD.
T2DM is a complex disease underlined by multiple pathogenic defects responsible for the development and progression of hyperglycaemia. Each of these factors can now be tackled in a more targeted ...manner thanks to glucose‐lowering drugs that have been made available in the past 2 to 3 decades. Recognition of the multiplicity of the mechanisms underlying hyperglycaemia calls for treatments that address more than 1 of these mechanisms, with more emphasis placed on the earlier use of combination therapies. Although chronic hyperglycaemia contributes to and amplifies cardiovascular risk, several trials have failed to show a marked effect from intensive glycaemic control. During the past 10 years, the effect of specific glucose‐lowering agents on cardiovascular risk has been explored with dedicated trials. Overall, the cardiovascular safety of the new glucose‐lowering agents has been proven with some of the trials summarized in this review, showing significant reduction of cardiovascular risk. Against this background, pioglitazone, in addition to exerting a sustained glucose‐lowering effect, also has ancillary metabolic actions of potential interest in addressing the cardiovascular risk of T2DM, such as preservation of beta‐cell mass and function. As such, it seems a logical agent to combine with other oral anti‐hyperglycaemic agents, including dipeptidyl peptidase‐4 inhibitors (DPP4i). DPP4i, which may also have a potential to preserve beta‐cell function, is available as a fixed‐dose combination with pioglitazone, and could, potentially, attenuate some of the side effects of pioglitazone, particularly if a lower dose of the thiazolidinedione is used. This review critically discusses the potential for early combination of pioglitazone and DPP4i.
Obesity leads to changes in synaptic plasticity. We aimed at investigating the impact of bariatric surgery (RYGB) on visual neural plasticity (NP) and its relationship with the main gut peptides, ...leptin, and brain-derived neurotrophic factor (BDNF).
NP was assessed testing binocular rivalry before and after 2 h of monocular deprivation (index of visual brain plasticity) in 15 subjects with obesity (age 42.3 ± 9.8 years; BMI 46.1 ± 4.9 kg/m
) before and after RYGB. Gut peptides, leptin, and BDNF were obtained at baseline and 6 months after surgery in 13 subjects.
A significant reduction in BMI (p < 0.001 vs. baseline) and a significant increase of disposition index (DI, p = 0.02 vs baseline) were observed after RYGB. Total and active GLP-1 release in response to glucose ingestion significantly increased after RYGB, while no changes occurred in VIP, GIP, and BDNF levels. Fasting leptin concentration was lower after RYGB (p = 0.001 vs. baseline). Following RYGB, NP was progressively restored (p < 0.002). NP was correlated with DI and fasting glucose at baseline (r = 0.75, p = 0.01; r = -0.7, p = 0.02; respectively), but not with BMI. A positive correlation between post-pre-RYGB changes in AUC
and NP was observed (r = 0.70, p < 0.01). Leptin was inversely correlated with NP 6 months after surgery (r = -0.63, p = 0.02). No correlation was observed between GIP, VIP, BDNF, and NP.
Visual plasticity is altered in subjects with obesity, and it can be restored after RYGB. The improvement may be mediated by amelioration of insulin sensitivity, increased GLP-1 levels, and reduced leptin levels.
Background: The use of flash glucose monitoring (FGM) has expanded widely among diabetic patients. Large randomized controlled trials demonstrated that use of FGM resulted in significant reductions ...in hypoglycemia, increased time in target range, reduced glycemic variability, and greater patient satisfaction compared with finger stick but no significant effects on glycemic control. Nonetheless, there is sparse guidance for what actions individuals should take based on the trend arrow data.
Aim of the Study: To verify the impact of published recommendation (Bianchi C., Aragona M. J Diabetes Complications. 2018 Oct 24) on glycemic control in type 1 diabetic subjects (T1DM). Patients and Methods: Since January 2018, 145 T1DM patients initiated FGM, after a period of education on the system and how to adjust insulin doses based on trend arrow (Trained Group - TG) and compared to a matched group of 204 patients who started FMG before recommendations were elaborated and therefore not being trained (Not Trained Group - NTG). The two groups showed no significant difference in terms of age, sex, duration of disease, type of treatment, BMI and insulin requirements.
Results: In TG HbA1c at baseline was 59±14 mmol/mol to decline 55±12 mmol/mol at month 6 (p<0.00001). In NTG HbA1c at baseline was 58±14 mmol/mol with minimal though statistically significant reduction after 6 months (56±12 mmol/mol; p<0.04). In both groups there was no change in BMI and Insulin Requirements.
Conclusions and Comments: In our clinical practice, FGM implementation was associated with a small but significant reduction in HbA1c, particularly in trained patients. Prospective and larger studies are needed to validate international guidelines for the education of diabetic patients adopting these new technologies.
Disclosure
C. Rodia: None. C. Bianchi: None. A. Bertolotto: Speaker's Bureau; Self; Abbott, Lilly Diabetes. R. Giannarelli: None. F. Campi: None. S. Gennai: None. S. Del Prato: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, GlaxoSmithKline plc., Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Sanofi, Servier, Takeda Pharmaceutical Company Limited. Board Member; Self; AstraZeneca. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Pharmaceutical Company Limited. M. Aragona: None.
Aims/hypothesis
The glucosuria induced by sodium–glucose cotransporter 2 (SGLT2) inhibition stimulates endogenous (hepatic) glucose production (EGP), blunting the decline in HbA
1c
. We hypothesised ...that, in response to glucosuria, a renal signal is generated and stimulates EGP. To examine the effect of acute administration of SGLT2 inhibitors on EGP, we studied non-diabetic individuals who had undergone renal transplant with and without removal of native kidneys.
Methods
This was a parallel, randomised, double-blind, placebo-controlled, single-centre study, designed to evaluate the effect of a single dose of dapagliflozin or placebo on EGP determined by stable-tracer technique. We recruited non-diabetic individuals who were 30–65 years old, with a BMI of 25–35 kg/m
2
and stable body weight (±2 kg) over the preceding 3 months, and HbA
1c
<42 mmol/mol (6.0%). Participants had undergone renal transplant with and without removal of native kidneys and were on a stable dose of immunosuppressive medications. Participants received a single dose of dapagliflozin 10 mg or placebo on two separate days, at a 5- to 14-day interval, according to randomisation performed by our hospital pharmacy, which provided dapagliflozin and matching placebo, packaged in bulk bottles that were sequentially numbered. Both participants and investigators were blinded to group assignment.
Results
Twenty non-diabetic renal transplant patients (ten with residual native kidneys, ten with bilateral nephrectomy) participated in the study. Dapagliflozin induced greater glucosuria in individuals with residual native kidneys vs nephrectomised individuals (8.6 ± 1.1 vs 5.5 ± 0.5 g/6 h;
p
= 0.02; data not shown). During the 6 h study period, plasma glucose decreased only slightly and similarly in both groups, with no difference compared with placebo (data not shown). Following administration of placebo, there was a progressive time-related decline in EGP that was similar in both nephrectomised individuals and individuals with residual native kidneys. Following dapagliflozin administration, EGP declined in both groups, but the differences between the decrement in EGP with dapagliflozin and placebo in the group with bilateral nephrectomy (Δ = 1.11 ± 0.72 μmol min
−1
kg
−1
) was significantly lower (
p
= 0.03) than in the residual native kidney group (Δ = 2.56 ± 0.33 μmol min
−1
kg
−1
). In the population treated with dapagliflozin, urinary glucose excretion was correlated with EGP (
r
= 0.34,
p
< 0.05). Plasma insulin, C-peptide, glucagon, prehepatic insulin:glucagon ratio, lactate, alanine and pyruvate concentrations were similar following placebo and dapagliflozin treatment. β-Hydroxybutyrate increased with dapagliflozin treatment in the residual native kidney group, while a small increase was observed only at 360 min in the nephrectomy group. Plasma adrenaline (epinephrine) did not change after dapagliflozin and placebo treatment in either group. Following dapagliflozin administration, plasma noradrenaline (norepinephrine) increased slightly in the residual native kidney group and decreased in the nephrectomy group.
Conclusions/interpretation
In nephrectomised individuals, the hepatic compensatory response to acute SGLT2 inhibitor-induced glucosuria was attenuated, as compared with individuals with residual native kidneys, suggesting that SGLT2 inhibitor-mediated stimulation of hepatic glucose production via efferent renal nerves occurs in an attempt to compensate for the urinary glucose loss (i.e. a renal–hepatic axis).
Trial registration
ClinicalTrials.gov
NCT03168295
Funding
This protocol was supported by Qatar National Research Fund (QNRF) Award No. NPRP 8-311-3-062 and NIH grant DK024092-38.
Graphical abstract
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