Continuous glucose monitoring in adults with type 2 diabetes: a systematic review and meta-analysis.

AIMS/HYPOTHESIS: Continuous glucose monitoring (CGM) is increasingly used in the treatment of type 2 diabetes, but the effects on glycaemic control are unclear. The aim of this systematic review and meta-analysis is to provide a comprehensive overview of the effect of CGM on glycaemic control in adults with type 2 diabetes. METHODS: We performed a systematic review using Embase, MEDLINE, Web of Science, Scopus and ClinicalTrials.gov from inception until 2 May 2023. We included RCTs investigating real-time CGM (rtCGM) or intermittently scanned CGM (isCGM) compared with self-monitoring of blood glucose (SMBG) in adults with type 2 diabetes. Studies with an intervention duration <6 weeks or investigating professional CGM, a combination of CGM and additional glucose-lowering treatment strategies or GlucoWatch were not eligible. Change in HbA1c and the CGM metrics time in range (TIR), time below range (TBR), time above range (TAR) and glycaemic variability were extracted. We evaluated the risk of bias using the Cochrane risk-of-bias tool version 2. Data were synthesised by performing a meta-analysis. We also explored the effects of CGM on severe hypoglycaemia and micro- and macrovascular complications. RESULTS: We found 12 RCTs comprising 1248 participants, with eight investigating rtCGM and four isCGM. Compared with SMBG, CGM use (rtCGM or isCGM) led to a mean difference (MD) in HbA1c of -3.43 mmol/mol (-0.31%; 95% CI -4.75, -2.11, p<0.00001, I2=15%; moderate certainty). This effect was comparable in studies that included individuals using insulin with or without oral agents (MD -3.27 mmol/mol [-0.30%]; 95% CI -6.22, -0.31, p=0.03, I2=55%), and individuals using oral agents only (MD -3.22 mmol/mol [-0.29%]; 95% CI -5.39, -1.05, p=0.004, I2=0%). Use of rtCGM showed a trend towards a larger effect (MD -3.95 mmol/mol [-0.36%]; 95% CI -5.46 to -2.44, p<0.00001, I2=0%) than use of isCGM (MD -1.79 mmol/mol [-0.16%]; 95% CI -5.28, 1.69, p=0.31, I2=64%). CGM was also associated with an increase in TIR (+6.36%; 95% CI +2.48, +10.24, p=0.001, I2=9%) and a decrease in TBR (-0.66%; 95% CI -1.21, -0.12, p=0.02, I2=45%), TAR (-5.86%; 95% CI -10.88, -0.84, p=0.02, I2=37%) and glycaemic variability (-1.47%; 95% CI -2.94, -0.01, p=0.05, I2=0%). Three studies reported one or more events of severe hypoglycaemia and macrovascular complications. In comparison with SMBG, CGM use led to a non-statistically significant difference in the incidence of severe hypoglycaemia (RR 0.66, 95% CI 0.15, 3.00, p=0.57, I2=0%) and macrovascular complications (RR 1.54, 95% CI 0.42, 5.72, p=0.52, I2=29%). No trials reported data on microvascular complications. CONCLUSIONS/INTERPRETATION: CGM use compared with SMBG is associated with improvements in glycaemic control in adults with type 2 diabetes. However, all studies were open label. In addition, outcome data on incident severe hypoglycaemia and incident microvascular and macrovascular complications were scarce. REGISTRATION: This systematic review was registered on PROSPERO (ID CRD42023418005).

Continuous glucose monitoring metrics and pregnancy outcomes in insulin-treated diabetes: A post-hoc analysis of the GlucoMOMS trial.

AIM: To investigate the association between continuous glucose monitoring (CGM) metrics and perinatal outcomes in insulin-treated diabetes mellitus in pregnancy. MATERIALS AND METHODS: In a post-hoc analysis of the GlucoMOMS randomized controlled trial, we investigated the association between the metrics of an offline, intermittent CGM, glycated haemoglobin (HbA1c) and perinatal outcomes per trimester in different types of diabetes (type 1, 2 or insulin-treated gestational diabetes mellitus [GDM]). Data were analysed using multivariable binary logistic regression. Outcomes of interest were neonatal hypoglycaemia, pre-eclampsia, preterm birth, large for gestational age (LGA) and Neonatal Intensive Care Unit (NICU) admission. The glucose target range was defined as 3.5-7.8 mmol/L (63-140 mg/dL). RESULTS: Of the 147 participants (N = 50 type 1 diabetes, N = 94 type 2 diabetes/insulin-treated GDM) randomized to the CGM group of the GlucoMOMS trial, 115 participants had CGM metrics available and were included in the current study. We found that, in pregnancies with type 1 diabetes, a higher second trimester mean glucose was associated with LGA (odds ratio 2.6 [95% confidence interval 1.1-6.2]). In type 2 and insulin-treated gestational diabetes, an increased area under the curve above limit was associated with LGA (odds ratio 10.0 [95% confidence interval 1.4-72.8]). None of the CGM metrics were associated with neonatal hypoglycaemia, pre-eclampsia, shoulder dystocia, preterm birth and NICU admission rates for pregnancies complicated by any type of diabetes. CONCLUSION: In this study, in type 2 diabetes or insulin-treated GDM, the glucose increased area under the curve above limit was associated with increased LGA. In type 1 diabetes, the mean glucose was the major determinant of LGA. Our study found no evidence that other CGM metrics determined adverse pregnancy outcomes.

Comparison of Postoperative Neurocognitive Function in Older Adult Patients with and without Diabetes Mellitus.

INTRODUCTION: Delayed neurocognitive recovery (DNR; neurocognitive disorder up to 30 days postoperative) and postoperative neurocognitive disorders (POCD; neurocognitive disorder 1-12 months postoperative) occur frequently after surgery, with diabetes mellitus (DM) suggested to contribute to this. This was a single-center prospective cohort study. The main aim of this study was to investigate the role of DM and preoperative hemoglobin A1c (HbA1c) in the development of POCDs after noncardiac surgery. METHODS: Older adult patients ≥65 years of age scheduled for elective surgery were recruited. The Modified Telephone Interview for Cognitive Status questionnaire (TICS-M), a test of global cognitive functioning, was administered to determine cognition. Preoperative, 30-day postoperative, and 6-month postoperative cognition were compared for patients with and without DM. Cognitive decline was subdivided into mild (1 to 2 standard deviations below controls) and major (≥2 standard deviations below controls) DNR or POCD. Preoperative HbA1c levels were correlated with TICS-M scores. RESULTS: We analyzed 102 patients [median (IQR [range]) age 72.0 (5 [68-74])]), who were divided into patients with DM (80 patients [78%]) and patients without DM (22 patients [22%]). Baseline cognitive function was similar for both groups. Repeated measures ANOVA showed that mean DM patient TICS-M scores decreased 30 days postoperative (F(2, 200) = 4.0, p = 0.02), with subsequent recovery 6-month postoperative, compared to stable TICS-M scores in non-DM patients. There were significantly more DM patients with DNR than non-DM patients (n = 11 [50%] vs. n = 14 [17.5%]; p = 0.031). There were no between-group differences in mild or major POCD. Higher preoperative HbA1c levels were significantly correlated with decreased 30-day Δcognition scores (F(1, 54) = 9.4, p = 0.003) with an R2 of 0.149 (ß -0.45, 95% confidence interval: -0.735 to -0.154). CONCLUSIONS: Older adult patients with DM undergoing surgery have an increased risk of DNR compared to older adult non-DM patients, but no increased risk of POCD. In DM patients, higher preoperative HbA1c levels were associated with an increased risk of DNR.

The management of type 1 diabetes in adults. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).

The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) convened a writing group to develop a consensus statement on the management of type 1 diabetes in adults. The writing group has considered the rapid development of new treatments and technologies and addressed the following topics: diagnosis, aims of management, schedule of care, diabetes self-management education and support, glucose monitoring, insulin therapy, hypoglycaemia, behavioural considerations, psychosocial care, diabetic ketoacidosis, pancreas and islet transplantation, adjunctive therapies, special populations, inpatient management and future perspectives. Although we discuss the schedule for follow-up examinations and testing, we have not included the evaluation and treatment of the chronic microvascular and macrovascular complications of diabetes as these are well-reviewed and discussed elsewhere. The writing group was aware of both national and international guidance on type 1 diabetes and did not seek to replicate this but rather aimed to highlight the major areas that healthcare professionals should consider when managing adults with type 1 diabetes. Though evidence-based where possible, the recommendations in the report represent the consensus opinion of the authors. Graphical abstract.

Glucagon-like peptide-1, a matter of taste?

Understanding of gustatory coding helps to predict, and perhaps even modulate the ingestive decision circuitry, especially when eating behaviour becomes dysfunctional. Preclinical research demonstrated that glucagon like peptide 1 (GLP-1) is locally synthesized in taste bud cells in the tongue and that GLP-1 receptor exists on the gustatory nerves in close proximity to GLP-1 containing taste bud cells. In humans, the tongue has not yet been addressed as clinically relevant target for GLP-1 based therapies. The primary aim of the current review was to elaborate on the role of GLP- 1 in mammalian gustatory system, in particular in the perception of sweet. Secondly, we aimed to explore what modulates gustatory coding and whether the GLP-1 based therapies might be involved in regulation of taste perception. We performed a series of PubMed, Medline and Embase databases systemic searches. The Population-Intervention-Comparison-Outcome (PICO) framework was used to identify interventional studies. Based on the available data, GLP-1 is specifically involved in the perception of sweet. Aging, diabetes and obesity are characterized by diminished taste and sweet perception. Calorie restriction and bariatric surgery are associated with a diminished appreciation of sweet food. GLP-1 receptor agonists (RAs) modulate food preference, yet its modulatory potential in gustatory coding is currently unknown. Future studies should explore whether GLP-1 RAs modulate taste perception to the extent that changes of food preference and consumption ensue.

ADO09, a co-formulation of the amylin analogue pramlintide and the insulin analogue A21G, lowers postprandial blood glucose versus insulin lispro in type 1 diabetes.

AIM: To compare the safety, pharmacokinetics and pharmacodynamics of ADO09 with insulin lispro (Lispro) and separate subcutaneous injections of human insulin and pramlintide (Ins&Pram) in 24 subjects with type 1 diabetes. METHODS: At three dosing visits, participants received single doses of ADO09, Ins&Pram or Lispro immediately before eating a standardized mixed meal together with 1 g of acetaminophen, which was used as a surrogate marker to evaluate the kinetics of gastric emptying. Premeal blood glucose was adjusted to 126 mg/dL ± 10% by means of insulin and glucose infusions. The insulin dose was 7.5 U and the pramlintide dose was 45 µg. Blood glucose, glucagon and acetaminophen concentrations were assessed as pharmacodynamic endpoints; insulin and pramlintide concentrations were analysed as pharmacokinetic endpoints, and safety and tolerability were assessed. RESULTS: Compared with Lispro, ADO09 reduced postprandial blood glucose (ppBG) excursions by more than 95% in the first hour postmeal (mean ± SD ∆AUC BG 0-1 h: 1.4 ± 9.9 mg*h/dL vs. 43.5 ± 15.3 mg*h/dL; p < .0001). Maximum ppBG was significantly improved with ADO09 (∆BGmax 87.0 ± 35.5 mg/dL) versus both Lispro (109.2 ± 31.1 mg/dL; p = .0133) and Ins&Pram (109.4 ± 44.3 mg/dL; p = .0357). Gastric emptying with ADO09 was similar to Ins&Pram and significantly slower than with Lispro. All treatments were well tolerated and both adverse events and hypoglycaemic events were rare during the meal test procedure. CONCLUSION: ADO09 was well tolerated and markedly reduced ppBG compared with Lispro. ADO09 formulation was generally similar to the separate administration of insulin and pramlintide, except for a better BG level in the 4-8 h interval postmeal. These positive results warrant further investigations with ADO09.

Long-term quality of life and exocrine and endocrine insufficiency after pancreatic surgery: a multicenter, cross-sectional study.

BACKGROUND: Data regarding long-term quality of life and exocrine and endocrine insufficiency after pancreatic surgery for premalignant and benign (non-pancreatitis) disease are lacking. METHODS: This cross-sectional study included patients ≥3 years after pancreatoduodenectomy or left pancreatectomy in six Dutch centers (2006-2016). Outcomes were measured with the EQ-5D-5L, the EORTC QLQ-C30, an exocrine and endocrine pancreatic insufficiency questionnaire, and PAID20. RESULTS: Questionnaires were completed by 153/183 patients (response rate 84%, median follow-up 6.3 years). Surgery related complaints were reported by 72/153 patients (47%) and 13 patients (8.4%) would not undergo this procedure again. The VAS (EQ-5D-5L) was 76 ± 17 versus 82 ± 0.4 in the general population (p < 0.001). The mean global health status (QLQ-C30) was 78 ± 17 versus 78 ± 17, p = 1.000. Fatigue, insomnia, and diarrhea were clinically relevantly worse in patients. Exocrine pancreatic insufficiency was reported by 62 patients (41%) with relieve of symptoms by enzyme supplementation in 48%. New-onset diabetes mellitus was present in 22 patients (14%). The median PAID20 score was 6.9/20 (IQR 2.5-17.8). CONCLUSION: Although generic quality of life after pancreatic resection for pre-malignant and benign disease was similar to the general population and diabetes-related distress was low, almost half suffered from a range of symptoms highlighting the need for long-term counseling.

Liraglutide for perioperative management of hyperglycaemia in cardiac surgery patients: a multicentre randomized superiority trial.

AIMS: Most cardiac surgery patients, with or without diabetes, develop perioperative hyperglycaemia, for which intravenous insulin is the only therapeutic option. This is labour-intensive and carries a risk of hypoglycaemia. We hypothesized that preoperative administration of the glucagon-like peptide-1 receptor agonist liraglutide reduces the number of patients requiring insulin for glycaemic control during cardiac surgery. MATERIALS AND METHODS: In this randomized, blinded, placebo-controlled, parallel-group, balanced (1:1), multicentre randomized, superiority trial, adult patients undergoing cardiac surgery in four Dutch tertiary hospitals were randomized to receive 0.6 mg subcutaneous liraglutide on the evening before surgery and 1.2 mg after induction of anaesthesia or matching placebo. Blood glucose was measured hourly and controlled using an insulin-bolus algorithm. The primary outcome was insulin administration for blood glucose >8.0 mmol/L in the operating theatre. Research pharmacists used centralized, stratified, variable-block, randomization software. Patients, care providers and study personnel were blinded to treatment allocation. RESULTS: Between June 2017 and August 2018, 278 patients were randomized to liraglutide (139) or placebo (139). All patients receiving at least one study drug injection were included in the intention-to-treat analyses (129 in the liraglutide group, 132 in the placebo group). In the liraglutide group, 55 (43%) patients required additional insulin compared with 80 (61%) in the placebo group and absolute difference 18% (95% confidence interval 5.9-30.0, P = 0.003). Dose and number of insulin injections and mean blood glucose were all significantly lower in the liraglutide group. We observed no difference in the incidence of hypoglycaemia, nausea and vomiting, mortality or postoperative complications. CONCLUSIONS: Preoperative liraglutide, compared with placebo, reduces insulin requirements while improving perioperative glycaemic control during cardiac surgery.

Lower rates of hypoglycaemia in older individuals with type 2 diabetes using insulin degludec versus insulin glargine U100: Results from SWITCH 2.

AIM: This study aimed to investigate the safety of insulin degludec (degludec) in relation to age and risk of hypoglycaemia post hoc in individuals with type 2 diabetes (T2D) (SWITCH 2 trial). METHODS: In this crossover study, individuals with T2D who were at risk of hypoglycaemia were randomized to double-blind treatment with degludec or insulin glargine 100 units/mL (glargine U100) ± oral antidiabetic drugs. After 32 weeks, patients crossed over to the other treatment. Primary endpoint was number of overall severe (positively adjudicated) or glucose-confirmed (plasma glucose <56 mg/dL; 3.1 mmol/L) symptomatic hypoglycaemia events during the two 16-week maintenance periods. RESULTS: For individuals ≤65 (n = 450) and >65 (n = 270) years, baseline median (range) duration of diabetes was 12 (1-40) vs 15 (1-54) years, mean HbA1c was 7.7% vs 7.4% and mean estimated glomerular filtration rate was 87.0 vs 63.7 mL/min/1.73 m2 , respectively. No significant differences in HbA1c reduction were seen in individuals ≤65 or >65 years. During both maintenance periods, treatment with degludec lowered rates of hypoglycaemia (overall/nocturnal symptomatic) vs those with glargine U100 in individuals ≤65 (31% vs 43%) and >65 (30% vs 41%) years. With degludec and glargine U100, respectively, six vs nine severe hypoglycaemic events occurred in individuals ≤65 years and four vs eight events occurred in those >65 years. Adverse event rates were 3.2 and 3.3 events/patient-year for individuals ≤65 years and were 3.5 and 4.1 events/patient-year for individuals >65 years with degludec and glargine U100, respectively. CONCLUSION: Treatment with degludec was safe and effective, with a frequency of hypoglycaemia lower than that with glargine U100 in both younger and older individuals (>65 years) with T2D.

Better glycaemic control with BioChaperone glargine lispro co-formulation than with insulin lispro Mix25 or separate glargine and lispro administrations after a test meal in people with type 2 diabetes.

Because of its physico-chemical properties, insulin glargine is usually not mixable with rapid insulins. BioChaperone BC147 is a polyanionic amphiphilic polymer, solubilizing insulin glargine at neutral pH, and thus enabling stable glargine formulation with fast-acting insulin lispro (BioChaperone glargine lispro co-formulation [BC Combo]). We investigated pharmacokinetic (PK) endpoints and postprandial glucose (PPG) control after administration of BC Combo (75% insulin glargine, 25% insulin lispro), insulin lispro Mix25 (LMix) and separate injections of insulins glargine (75% total dose) and lispro (25% total dose [G + L]) immediately before ingestion of a mixed meal in people with type 2 diabetes mellitus (T2DM), using a randomized, double-blind, double-dummy crossover study design. Participants received individualized bolus doses (mean 0.62 U/kg) of BC Combo, LMix or G + L, together with a solid mixed meal (610 kcal, 50% carbohydrate, 30% fat, 20% protein). Insulin dosages were kept constant for each study day. Thirty-nine participants with T2DM (mean ± SD age and glycated haemoglobin 60.8 ± 7.5 years and 64 ± 6 mmol/mol, respectively) were randomized. BC Combo improved the predefined primary endpoint, early PPG control, compared to LMix (incremental area under the blood glucose concentration-time curve from 0 to 2 hours after the meal [ΔAUCBG,0-2h ] reduction of 18%; P = 0.0009) and G + L (ΔAUCBG,0-2h reduction of 10%; P = 0.0450). The number of mealtime hypoglycaemic episodes per participant was lower with BC Combo (22 episodes in 14 participants) compared to LMix (43 episodes in 20 participants; P = 0.0028), but not significantly different from G + L (28 episodes in 19 participants; P = 0.2523). BC Combo demonstrated superior early PPG control with fewer hypoglycaemic episodes compared to LMix and superior early PPG control compared to separate G + L administrations.

Day-to-day fasting self-monitored blood glucose variability is associated with risk of hypoglycaemia in insulin-treated patients with type 1 and type 2 diabetes: A post hoc analysis of the SWITCH Trials.

AIMS: To investigate the association between day-to-day fasting self-monitored blood glucose (SMBG) variability and risk of hypoglycaemia in type 1 (T1D) and type 2 diabetes (T2D), and to compare day-to-day fasting SMBG variability between treatments with insulin degludec (degludec) and insulin glargine 100 units/mL (glargine U100). MATERIALS AND METHODS: Data were retrieved from two double-blind, randomized, treat-to-target, two-period (32 weeks each) crossover trials of degludec vs glargine U100 in T1D (SWITCH 1, n = 501) and T2D (SWITCH 2, n = 720). Available fasting SMBGs were used to determine the standard deviation (SD) of day-to-day fasting SMBG variability for each patient and the treatment combination. The association between day-to-day fasting SMBG variability and overall symptomatic, nocturnal symptomatic and severe hypoglycaemia was analysed for the pooled population using linear regression, with fasting SMBG variability included as a three-level factor defined by population tertiles. Finally, day-to-day fasting SMBG variability was compared between treatments. RESULTS: Linear regression showed that day-to-day fasting SMBG variability was significantly associated with overall symptomatic, nocturnal symptomatic and severe hypoglycaemia risk in T1D and T2D (P < 0.05). Day-to-day fasting SMBG variability was significantly associated (P < 0.01) with all categories of hypoglycaemia risk, with the exception of severe hypoglycaemia in T2D when analysed within tertiles. Degludec was associated with 4% lower day-to-day fasting SMBG variability than glargine U100 in T1D (P = 0.0082) and with 10% lower day-to-day fasting SMBG variability in T2D (P < 0.0001). CONCLUSIONS: Higher day-to-day fasting SMBG variability is associated with an increased risk of overall symptomatic, nocturnal symptomatic and severe hypoglycaemia. Degludec has significantly lower day-to-day fasting SMBG variability vs glargine U100.

A randomized, multicentre trial evaluating the efficacy and safety of fast-acting insulin aspart in continuous subcutaneous insulin infusion in adults with type 1 diabetes (onset 5).

AIM: To evaluate the efficacy and safety of fast-acting insulin aspart (faster aspart) vs insulin aspart (IAsp) used in continuous subcutaneous insulin infusion (CSII) in participants with type 1 diabetes (T1D). MATERIALS AND METHODS: This was a double-blind, treat-to-target, randomized, 16-week trial investigating CSII treatment with faster aspart (n = 236) or IAsp (n = 236). All available information, regardless of treatment discontinuation, was used for the evaluation of effect. RESULTS: Faster aspart was non-inferior to IAsp regarding the change from baseline in glycated haemoglobin (HbA1c; primary endpoint). The mean HbA1c changed from 58.4 mmol/mol (7.5%) at baseline to 57.8 mmol/mol (7.4%) with faster aspart and to 56.8 mmol/mol (7.4%) with IAsp after 16 weeks' treatment, with an estimated treatment difference (ETD) of 1.0 mmol/mol (95% confidence interval [CI] 0.14; 1.87) or 0.09% (95% CI 0.01; 0.17; P < 0.001) for non-inferiority (0.4% margin; P < 0.02 for statistical significance in favour of IAsp). Faster aspart was superior to IAsp in change from baseline in 1-hour postprandial glucose (PPG) increment after a meal test (ETD -0.91 mmol/L [95% CI -1.43; -0.39] or -16.4 mg/dL [95% CI -25.7; -7.0]; P = 0.001), with statistically significant reductions also at 30 minutes and 2 hours. The improvement in PPG was reflected in the change from baseline in 1-hour interstitial glucose increment after all meals (ETD -0.21 mmol/L [95% CI -0.31; -0.11] or -3.77 mg/dL [95% CI -5.53; -2.01]). There was no statistically significant difference in the overall rate of severe or blood glucose-confirmed hypoglycaemia (estimated rate ratio 1.00 [95% CI 0.85; 1.16]). A numerical imbalance in severe hypoglycaemic episodes between faster aspart and IAsp was seen in the treatment (21 vs 7) and 4-week run-in periods (4 vs 0). CONCLUSIONS: Faster aspart provides an effective and safe option for CSII treatment in T1D.

BioChaperone Lispro versus faster aspart and insulin aspart in patients with type 1 diabetes using continuous subcutaneous insulin infusion: A randomized euglycemic clamp study.

We investigated the pharmacodynamics (PD) and pharmacokinetics (PK) of BioChaperone insulin Lispro (BCLIS), faster insulin aspart (FIA) and insulin aspart (ASP) in patients with type 1 diabetes using an insulin pump. In this randomized, double-blind, three-way crossover glucose clamp study, 43 patients received a bolus dose of each insulin (0.15 U/kg) in addition to a basal rate (0.01 U/kg/h), delivered via an insulin pump. With BCLIS, the AUC-GIR,0-60 minutes (primary endpoint) was improved compared to ASP (least square means ratio, 1.63; 95% CI, 1.44-1.88; P < 0.0001) and was similar compared to FIA (least square means ratio, 1.06; 95% CI, 0.94-1.18; P = 0.4609). BCLIS showed faster-on PD (tearly0.5GIRmax ) than ASP and faster-off PD (tlate0.5GIRmax ) than both FIA and ASP. BCLIS also demonstrated significantly higher early exposure (AUCins, 0-60 minutes) and lower late exposure (AUCins,120-600 minutes) than both other insulins. In patients with type 1 diabetes using an insulin pump, BCLIS better mimics prandial insulin secretion and action than ASP and shows a faster off-PD than FIA.

Use of fast-acting insulin aspart in insulin pump therapy in clinical practice.

Fast-acting insulin aspart (faster aspart) is a novel formulation of insulin aspart (IAsp) containing the additional excipients niacinamide and L-arginine. The improved pharmacological profile and greater early glucose-lowering action of faster aspart compared with IAsp suggests that faster aspart may be advantageous for people with diabetes using continuous subcutaneous insulin infusion (CSII). The recent onset 5 trial was the first to evaluate the efficacy and safety of an ultra-fast-acting insulin in CSII therapy in a large number of participants with type 1 diabetes (T1D). Non-inferiority of faster aspart to IAsp in terms of change from baseline in HbA1c was confirmed, with an estimated treatment difference (ETD) of 0.09% (95% CI, 0.01; 0.17; P < 0.001 for non-inferiority [0.4% margin]). Faster aspart was superior to IAsp in terms of change from baseline in 1-hour post-prandial glucose (PPG) increment after a meal test (ETD [95% CI], -0.91 mmol/L [-1.43; -0.39]; P = 0.001), with statistically significant improvements also at 30 minutes and 2 hours. The overall rate of severe or blood glucose-confirmed hypoglycaemia was not statistically significantly different between treatments, with an estimated rate ratio of 1.00 (95% CI, 0.85; 1.16). A numerical imbalance in severe hypoglycaemic episodes between faster aspart and IAsp was seen in the treatment (21 vs 7) and the 4-week run-in periods (4 vs 0). Experience from clinical practice indicates that all pump settings should be reviewed when initiating faster aspart with CSII, and that the use of continuous glucose monitoring or flash glucose monitoring, along with a good understanding of meal content and bolus type, may also facilitate optimal use. This review summarizes the available clinical evidence for faster aspart administered via CSII and highlights practical considerations based on clinical experience that may help healthcare providers and individuals with T1D successfully initiate and adjust faster aspart with CSII.

Comparison of perioperative glucose regulation in patients with type 1 vs type 2 diabetes mellitus: A retrospective cross-sectional study.

BACKGROUND: Most perioperative diabetes mellitus (DM) guidelines do not distinguish between patients with type 1 (DM1) and type 2 (DM2). We hypothesised that similar treatment of DM1 and DM2 patients leads to differences in their perioperative glucose control. METHODS: We performed a retrospective cross-sectional study, of all DM patients undergoing surgery between May 2013 and November 2015 in a Dutch university hospital. We compared DM1 with DM2 patients, treated according to the same perioperative glucose protocol. Our primary outcome was the incidence of hyperglycaemia (glucose ≥10 mmol/L). Secondary outcomes were short-term glycaemic control (glucose before surgery and peak glucose perioperatively), long-term glycaemic control (HbA1c in 90 days before and after surgery) and the incidence of hypoglycaemia (glucose <4 mmol/L). RESULTS: We included 2259 patients with DM, 216 (10%) of which had DM1. The calculated incidences in our population were 7 out of 1000 patients with DM1 and 69 out of 1000 patients with DM2. Compared to those with DM2, patients with DM1 were younger, had a lower BMI, a higher glucose concentration before surgery, and a higher perioperative peak glucose concentration (11.0 [8.2-14.7] vs 9.4 [7.7-11.7], P < 0.001). The incidence of the primary endpoint, perioperative hyperglycaemia, was significantly higher in DM1 compared to DM2 patients (63% vs 43%, P < 0.001). Hypoglycaemia occurred more often in the DM1 population (7.1% vs 1.3%, P < 0.001). CONCLUSION: Providing similar perioperative treatment to patients with DM1 and DM2 is associated with poorer short-term and long-term glycaemic control in DM1 throughout the perioperative period as well as an increased risk of hypoglycaemia.

Retinal neurodegeneration may precede microvascular changes characteristic of diabetic retinopathy in diabetes mellitus.

Diabetic retinopathy (DR) has long been recognized as a microvasculopathy, but retinal diabetic neuropathy (RDN), characterized by inner retinal neurodegeneration, also occurs in people with diabetes mellitus (DM). We report that in 45 people with DM and no to minimal DR there was significant, progressive loss of the nerve fiber layer (NFL) (0.25 µm/y) and the ganglion cell (GC)/inner plexiform layer (0.29 µm/y) on optical coherence tomography analysis (OCT) over a 4-y period, independent of glycated hemoglobin, age, and sex. The NFL was significantly thinner (17.3 µm) in the eyes of six donors with DM than in the eyes of six similarly aged control donors (30.4 µm), although retinal capillary density did not differ in the two groups. We confirmed significant, progressive inner retinal thinning in streptozotocin-induced "type 1" and B6.BKS(D)-Lepr(db)/J "type 2" diabetic mouse models on OCT; immunohistochemistry in type 1 mice showed GC loss but no difference in pericyte density or acellular capillaries. The results suggest that RDN may precede the established clinical and morphometric vascular changes caused by DM and represent a paradigm shift in our understanding of ocular diabetic complications.

Haemoglobin glycation index and risk for diabetes-related complications in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial.

AIMS/HYPOTHESIS: Previous studies have suggested that the haemoglobin glycation index (HGI) can be used as a predictor of diabetes-related complications in individuals with type 1 and type 2 diabetes. We investigated whether HGI was a predictor of adverse outcomes of intensive glucose lowering and of diabetes-related complications in general, using data from the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. METHODS: We studied participants in the ADVANCE trial with data available for baseline HbA1c and fasting plasma glucose (FPG) (n = 11,083). HGI is the difference between observed HbA1c and HbA1c predicted from a simple linear regression of HbA1c on FPG. Using Cox regression, we investigated the association between HGI, both categorised and continuous, and adverse outcomes, considering treatment allocation (intensive or standard glucose control) and compared prediction of HGI and HbA1c. RESULTS: Intensive glucose control lowered mortality risk in individuals with high HGI only (HR 0.74 [95% CI 0.61, 0.91]; p = 0.003), while there was no difference in the effect of intensive treatment on mortality in those with high HbA1c. Irrespective of treatment allocation, every SD increase in HGI was associated with a significant risk increase of 14-17% for macrovascular and microvascular disease and mortality. However, when adjusted for identical covariates, HbA1c was a stronger predictor of these outcomes than HGI. CONCLUSIONS/INTERPRETATION: HGI predicts risk for complications in ADVANCE participants, irrespective of treatment allocation, but no better than HbA1c. Individuals with high HGI have a lower risk for mortality when on intensive treatment. Given the discordant results and uncertain relevance beyond HbA1c, clinical use of HGI in type 2 diabetes cannot currently be recommended.

Achieving glycaemic control without weight gain, hypoglycaemia, or gastrointestinal adverse events in type 2 diabetes in the SUSTAIN clinical trial programme.

AIM: To evaluate the potential for semaglutide to help people with type 2 diabetes (T2D) achieve glycated haemoglobin (HbA1c) targets while avoiding unwanted outcomes, such as weight gain, hypoglycaemia and gastrointestinal (GI) side effects. MATERIALS AND METHODS: Data from the phase IIIa SUSTAIN 1 to 5 clinical trials were analysed. Participants had inadequately controlled T2D and were drug-naïve (SUSTAIN 1) or on a range of background treatments (SUSTAIN 2 to 5). The main protocol-specified composite endpoint was the proportion of participants achieving HbA1c <53 mmol/mol (7.0%) at end of treatment (30 or 56 weeks) without weight gain and with no severe or blood glucose (BG)-confirmed symptomatic hypoglycaemia. A post hoc composite endpoint was the proportion of participants achieving the primary composite endpoint without moderate or severe GI adverse events (AEs). RESULTS: Across the SUSTAIN trials 1 to 5, 3918 participants with T2D were randomized to once-weekly subcutaneous semaglutide 0.5 mg, 1.0 mg, or comparators (placebo, sitagliptin 100 mg, exenatide extended release 2.0 mg or insulin glargine). The proportion of participants achieving HbA1c <53 mmol/mol (7.0%) with no weight gain and no severe/BG-confirmed symptomatic hypoglycaemia was 47% to 66% (semaglutide 0.5 mg) and 57% to 74% (semaglutide 1.0 mg) vs 7% to 19% (placebo) and 16% to 29% (active comparators; all P < .0001). More participants achieved the primary composite endpoint with no moderate or severe GI AEs with semaglutide vs comparators (all P < .0001). CONCLUSION: Semaglutide helped more people with T2D achieve HbA1c targets than did comparators in the SUSTAIN 1 to 5 trials, while avoiding unwanted outcomes such as weight gain, hypoglycaemia and GI side effects.