Glucose Control and Vascular Outcomes in Type 2 Diabetes: Is the Picture Clear?

Giorgino, Francesco; Home, Philip; Tuomilehto, Jaakko

doi:10.2337/dcs15-3023

Cited by 47 publications

(32 citation statements)

References 71 publications

(28 reference statements)

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“…When patients with recent-onset type 1 diabetes were followed under near-normoglycemia for 24 years, the (3), the impact of longterm normalized HbA 1c levels on improving neuropathy outcomes in type 2 diabetes had never been reported. Tight GC needs to be maintained for .3-5 years to yield benefit (20). The current study followed patients with poorly controlled type 2 diabetes for .4 years on average, and mean HbA 1c levels in patients with EHC over the whole follow-up period and last 2 years were 6.1% (43.2 mmol/mol) and 5.8% (39.9 mmol/mol), respectively.…”

Section: Discussionmentioning

confidence: 90%

Improvement in Neuropathy Outcomes With Normalizing HbA1c in Patients With Type 2 Diabetes

et al. 2018

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OBJECTIVETo investigate the impact of normalizing HbA 1c by extensive HbA 1c control (EHC) on neuropathy outcome measures (NOMs), nephropathy, and retinopathy in type 2 diabetes. RESEARCH DESIGN AND METHODSDetailed clinical and neurological examinations were performed in two cohorts of 38 patients with uncontrolled type 2 diabetes (HbA 1c 9.6% [81.4 mmol/mol]) at baseline and after glycemic control (GC) with or without EHC by diet restriction and hypoglycemic agents over 4 years along with 48 control subjects with normal glucose tolerance (NGT) and 34 subjects with impaired glucose tolerance (IGT) only at baseline. EHC patients, control subjects, and subjects with IGT underwent oral glucose tolerance tests. Glycemic variability (GV) was evaluated by SD and coefficient of variation of monthly measured HbA 1c levels and casual plasma glucose. RESULTSIn the EHC cohort, HbA 1c levels over 4.3 years and the last 2 years improved to 6.1% (43.2 mmol/mol) and 5.8% (39.9 mmol/mol) with 7.3 kg body wt reduction, and 50% and 28.9% of patients returned to IGT and NGT, respectively, at end point. Baseline neurophysiological and corneal nerve fiber (CNF) measures were impaired in patients. Normalized HbA 1c with EHC improved neurophysiological and CNF measures to be similar for those for IGT, while GC without EHC (mean HbA 1c level 7.0% [53.5 mmol/mol]) improved only vibration perception. The mean normalized HbA 1c levels by EHC determined NOM improvements. The high GV and baseline HbA 1c levels compromised NOMs. Albumin excretion rate significantly decreased, while retinopathy severity and frequency insignificantly worsened on EHC. CONCLUSIONSNormalizing HbA 1c in type 2 diabetes of short duration improves microvascular complications including neuropathy and nephropathy more effectively than standard GC but not retinopathy.Intensive glycemic control (GC) has shown an equivocal efficacy regarding diabetic peripheral neuropathy (DPN) in type 2 diabetes (1), mainly due to nonoptimized HbA 1c levels. Randomized trials (2,3) have not been able to establish the optimum GC level for improving neuropathy outcomes in type 2 diabetes. In type 1

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Section: Discussionmentioning

confidence: 90%

Improvement in Neuropathy Outcomes With Normalizing HbA1c in Patients With Type 2 Diabetes

et al. 2018

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“…Unlike the UKPDS and the DCCT study, which were designed to achieve glycemic differences, the EMPA-REG OUTCOME trial was designed as a glycemic equipoise trial, and only a modest difference in HbA 1c between the empagliflozin and placebo groups was found. Furthermore, unlike the UKPDS with a cumulative follow-up of .10 years (30), trials of shorter duration did not convincingly demonstrate CV benefits from this degree of glucose lowering (31). The smaller mediation effect of glycemia relative to hematological variables, therefore, may reflect these factors.…”

Section: Discussionmentioning

confidence: 91%

How Does Empagliflozin Reduce Cardiovascular Mortality? Insights From a Mediation Analysis of the EMPA-REG OUTCOME Trial

et al. 2017

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OBJECTIVEIn the BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) trial involving 7,020 patients with type 2 diabetes and established cardiovascular (CV) disease, empagliflozin given in addition to standard of care reduced the risk of CV death by 38% versus placebo (hazard ratio [HR] 0.62 [95% CI 0.49, 0.77]). This exploratory mediation analysis assesses the extent to which treatment group differences in covariates during the trial contributed to CV death risk reduction with empagliflozin. RESEARCH DESIGN AND METHODSEffects of potential mediators, identified post hoc, on the HR for CV death with empagliflozin versus placebo were analyzed by Cox regression models, with treatment group adjusted for the baseline value of the variable and its change from baseline or updated mean (i.e., considering all prior values), each as a time-dependent covariate. HRs were compared with a model without adjustment for covariates. Multivariable analyses also were performed. RESULTSChanges in hematocrit and hemoglobin mediated 51.8% and 48.9%, respectively, of the effect of empagliflozin versus placebo on the risk of CV death on the basis of changes from baseline, with similar results in analyses on the basis of updated means. Smaller mediation effects (maximum 29.3%) were observed for uric acid, fasting plasma glucose, and HbA 1c . In multivariable models, which incorporated effects of empagliflozin on hematocrit, fasting glucose, uric acid, and urine albumin:creatinine ratio, the combined changes from baseline provided 85.2% mediation, whereas updated mean analyses provided 94.6% mediation of the effect of empagliflozin on CV death. CONCLUSIONSIn this exploratory analysis from the EMPA-REG OUTCOME trial, changes in markers of plasma volume were the most important mediators of the reduction in risk of CV death with empagliflozin versus placebo.Empagliflozin, a highly selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, was the first glucose-lowering agent to demonstrate a reduction in cardiovascular (CV) death in patients with type 2 diabetes and high CV risk (1). In the BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) trial, over a median observation time of 3.1 years, treatment

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“…Diabetes is a major cause of blindness, kidney failure, heart attack, stroke, and lower limb amputations, leading to a major economic impact on people with diabetes, their families, and the health‐care system . A timely type 2 diabetes treatment aiming at blood glucose concentrations close to the normal range reduces the incidence and progression of complications, microvascular, and possibly macrovascular . Management based on lifestyle modifications, medications, and regular screening and treatment of complications and comorbidities is thus strongly advised…”

Section: Introductionmentioning

confidence: 99%

“…1 A timely type 2 diabetes treatment aiming at blood glucose concentrations close to the normal range reduces the incidence and progression of complications, microvascular, and possibly macrovascular. 2 Management based on lifestyle modifications, medications, and regular screening and treatment of complications and comorbidities is thus strongly advised. 3 If glycaemic targets are not achieved, current guidelines recommend a dual-agent therapy, followed by a triple-agent therapy with two drugs added to metformin.…”

Section: Introductionmentioning

confidence: 99%

GLP‐1 receptor agonist added to insulin versus basal‐plus or basal‐bolus insulin therapy in type 2 diabetes: A systematic review and meta‐analysis

Castellana

Cignarelli

Brescia

et al. 2018

Diabetes Metabolism Res

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Background Current guidelines recommend that antihyperglycaemic treatment in patients with type 2 diabetes not achieving the HbA1c target on basal insulin should be intensified with a glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) or basal‐plus/basal‐bolus (BP/BB) insulin regimen. We conducted a systematic review and meta‐analysis to compare the effects of GLP‐1RA/insulin combinations versus BP/BB. Methods The review was registered on PROSPERO (CRD42017079547). PubMed, Scopus, CENTRAL, and http://ClinicalTrials.gov were searched until July 2018. All randomized controlled trials (RCTs) reporting HbA1c, body weight, daily insulin dose, hypoglycaemic events, and discontinuation due to lack of efficacy were included. A subgroup analysis on different combinations of GLP‐1RA and insulin was performed. Results Out of 1885 retrieved papers, 13 RCTs were included in the review. Compared with BP/BB, GLP‐1RA/insulin combinations were associated with a similar HbA1c reduction (Δ = −0.06%; 95% confidence interval [CI], −0.14 to 0.02; P = 0.13; I2 = 52%), greater weight loss (Δ = −3.72 kg; 95% CI, −4.49 to −2.95; P < 0.001; I2 = 89%), and lower incidence of hypoglycaemic events (relative risk [RR] = 0.46; 95% CI, 0.38‐0.55; P < 0.001; I2 = 99%). The daily insulin dosage among GLP‐1RA/insulin users was 30.3 IU/day (95% CI, −41.2 to −19.3; P < 0.001; I2 = 94%), lower than with BP/BB. No difference was found for discontinuation due to lack of efficacy. Conclusions The present review supports treatment intensification with GLP‐1RA added to insulin versus BP/BB in uncontrolled type 2 diabetes. This could provide similar antihyperglycaemic efficacy while leading to weight loss and sparing of hypoglycaemia and insulin dose. As a consequence, a considerable number of patients with type 2 diabetes could be potentially shifted from BP/BB to GLP‐1RA/insulin combinations.

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Glucose Control and Vascular Outcomes in Type 2 Diabetes: Is the Picture Clear?

Cited by 47 publications

References 71 publications

Improvement in Neuropathy Outcomes With Normalizing HbA1c in Patients With Type 2 Diabetes

Improvement in Neuropathy Outcomes With Normalizing HbA1c in Patients With Type 2 Diabetes

How Does Empagliflozin Reduce Cardiovascular Mortality? Insights From a Mediation Analysis of the EMPA-REG OUTCOME Trial

GLP‐1 receptor agonist added to insulin versus basal‐plus or basal‐bolus insulin therapy in type 2 diabetes: A systematic review and meta‐analysis

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