Insulin Treatment May Increase Adverse Outcomes in Patients With COVID-19 and Diabetes: A Systematic Review and Meta-Analysis

Yang, Y.,  Zixin, C. & Zhang, J. | 2021| Insulin Treatment May Increase Adverse Outcomes in Patients With COVID-19 and Diabetes: A Systematic Review and Meta-Analysis | Frontiers in Endocrinology | https://doi.org/10.3389/fendo.2021.696087

The reviewers invovlved in this analysis, conducted a systematic review and meta-analysis to determine the association between insulin injection and the outcomes of COVID-19 to provide certain clinical information for patients with Covid-19 and diabetes. They recognise that while their findings may provide evidence of the adverse effect of insulin treatment among patients with COVID-19 and diabetes, especially among those with type 2 diabetes (T2DM), as the subjects in most included studies suffered from T2DM. However, considering the limited number of studies concerning type 1 diabetes (T1DM) in our meta-analysis, the association between insulin treatment and adverse outcomes in patients with COVID-19 and T1DM are needed to be investigated in more large-scale clinical studies (Source: Yang, Zixin & Zhang, 2021).

Background and Objective: 

Recently, insulin treatment has been found to be associated with increased mortality and other adverse outcomes in patients with coronavirus disease 2019 (COVID-19) and diabetes, but the results remain unclear and controversial, therefore, we conducted this meta-analysis.

Methods: 

Four databases, namely, PubMed, Web of Science, EMBASE and the Cochrane Library, were used to identify all studies concerning insulin treatment and the adverse effects of COVID-19, including mortality, incidence of severe/critical complications, in-hospital admission and hospitalization time. To assess publication bias, funnel plots, Begg’s tests and Egger’s tests were used. The odds ratios (ORs) with 95% confidence intervals (CIs) were used to access the effect of insulin therapy on mortality, severe/critical complications and in-hospital admission. The association between insulin treatment and hospitalization time was calculated by the standardized mean difference (SMD) with 95% CIs.

Results: 

Eighteen articles, involving a total of 12277 patients with COVID-19 and diabetes were included. Insulin treatment was significantly associated with an increased risk of mortality (OR=2.10; 95% CI, 1.51-2.93) and incidence of severe/critical COVID-19 complications (OR=2.56; 95% CI, 1.18-5.55). Moreover, insulin therapy may increase in-hospital admission in patients with COVID-19 and diabetes (OR=1.31; 95% CI, 1.06-1.61). However, there was no significant difference in the hospitalization time according to insulin treatment (SMD=0.21 95% CI, -0.02-0.45).

Conclusions: 

Insulin treatment may increase mortality and severe/critical complications in patients with COVID-19 and diabetes, but more large-scale studies are needed to confirm and explore the exact mechanism.

Insulin Treatment May Increase Adverse Outcomes in Patients With COVID-19 and Diabetes: A Systematic Review and Meta-Analysis [primary paper]

Continuous subcutaneous insulin infusion therapy is associated with reduced retinopathy progression compared with multiple daily injections of insulin

Reid, L.J., et al | 2021|  Continuous subcutaneous insulin infusion therapy is associated with reduced retinopathy progression compared with multiple daily injections of insulin| Diabetologia | https://doi.org/10.1007/s00125-021-05456-w

The authors of this study set out to address the research question: Is the introduction of continuous subcutaneous insulin infusion (CSII) therapy associated with early diabetic retinopathy worsening or long term benefits in diabetic retinopathy progression vs continued MDI therapy in adults with type 1 diabetes?

The researchers used the Scottish Care Information Diabetes database for retinal screening outcomes and HbA1c changes in 204 adults commenced on CSII therapy between 2013 and 2016, and 211 adults eligible for CSII during the same period but who continued on MDI therapy.  Their results show that no evidence of early diabetic retinopathy worsening following the introduction of CSII therapy in those with no or mild baseline diabetic retinopathy.

Image source: Reid et al, 2021 Image description: graphical abstract outlining the study design, its outcomes, results and providing a summary of the research.

Abstract

Aims/hypothesis

We aimed to compare diabetic retinopathy outcomes in people with type 1 diabetes following introduction of continuous subcutaneous insulin infusion (CSII) therapy with outcomes in people receiving continuing therapy with multiple daily insulin injections (MDI).

Methods

This is a retrospective cohort study using the Scottish Care Information – Diabetes database for retinal screening outcomes and HbA1c changes in 204 adults commenced on CSII therapy between 2013 and 2016, and 211 adults eligible for CSII during the same period but who continued on MDI therapy. Diabetic retinopathy progression (time to minimum one-grade worsening in diabetic retinopathy from baseline grading) was plotted for CSII and MDI cohorts using Kaplan–Meier curves, and outcomes were compared using multivariate Cox regression analysis adjusting for age, sex, baseline HbA1c, blood pressure, cholesterol, smoking status and socioeconomic quintile. Impact of baseline HbA1c and change in HbA1c on diabetic retinopathy progression was assessed within CSII and MDI cohorts.

Results

CSII participants were significantly younger, were from less socially deprived areas, and had lower HbA1c and higher diastolic BP at baseline. There was a larger reduction in HbA1c at 1 year in those on CSII vs MDI (−6 mmol/mol [−0.6%] vs −2 mmol/mol [−0.2%], p < 0.01). Diabetic retinopathy progression occurred in a smaller proportion of adults following commencement of CSII vs continued MDI therapy over mean 2.3 year follow-up (26.5% vs 18.6%, p = 0.0097). High baseline HbA1c (75 mmol/mol [9%]) was associated with diabetic retinopathy progression in the MDI group (p = 0.0049) but not the CSII group (p = 0.93). Change in HbA1c at follow-up, irrespective of baseline glycaemic status, did not significantly affect diabetic retinopathy progression in either group.

Conclusions/interpretation

CSII was associated with reduced diabetic retinopathy progression compared with continued MDI therapy, and may be protective against diabetic retinopathy progression for those with high baseline HbA1c. Progression of diabetic retinopathy over 3 years was not associated with a change in HbA1c.

Continuous subcutaneous insulin infusion therapy is associated with reduced retinopathy progression compared with multiple daily injections of insulin

NICE Medtech innovation briefing [MIB227 t:slim X2 insulin pump for managing blood glucose levels in type 1 diabetes

NICE | 22 September 2020 | Medtech innovation briefing [MIB227 t:slim X2 insulin pump for managing blood glucose levels in type 1 diabetes

NICE has developed a medtech innovation briefing (MIB) on t:slim X2 insulin pump for managing blood glucose levels in type 1 diabetes.

Full details from NICE

Insulin Safety Week: National campaign promotes insulin safety

Diabetes Times | May 2019 | National campaign promotes insulin safety

This week to mark Insulin Safety Week (20-26 May 2019) over 500 diabetes teams predominantly in hospitals from the UK and Ireland  will promote the message of insulin safety. 

According to the results from the latest National Diabetes Inpatient Audit, extrapolated by the Diabetes Times, two in five people with diabetes on insulin (40 per cent) experience an error related to the administration of the drug while in hospital.

In response, the seven-day awareness campaign in an attempt to reduce incidents of insulin errors as part of Insulin Safety Week.

A total of 343 sites, mainly hospitals and GP surgeries, took part in the first-ever national Insulin Safety Week in May 2019, building on interest generated by successful local campaigns across the country in 2017, including in Leicester, Hastings, Eastbourne and Southampton.

Full, unabridged story from Diabetes Times

Improving insulin administration in a community setting

NHS England | March 2019 | Improving insulin administration in a community setting

Specialist Diabetes nurses have led on the development and implementation of a new, modular training programme for both community nurses and non-registered practitioners in diabetes care. 

Diabetes specialist nurses found variation in diabetes care in both the community and in residential care homes, with increased demand for district nurses to administer insulin.

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They identified an opportunity to  implement insulin delegation- the process by which a registered nurse allocates the task of insulin administration to a named, competent, non-registered practitioner, such as a healthcare assistant. An insulin delegation programme involves:

  • Developing an insulin delegation policy, and updating other relevant policies and procedures;
  • Assessing the diabetes knowledge and skills of everyone involved in diabetes care, including registered nursing staff;
  • Theoretical and practical training for all staff who require it, and additional training for staff administering insulin;
  • Competency assessment, mentoring and support for those administering insulin.

Specialist diabetes nurses carried out a detailed audit to establish the level of diabetes knowledge amongst community nurses and identify areas where delegation could be considered.  An audit was undertaken by registered community nurses, this underlined opportunities for upskilling colleagues in relation to insulin therapy, illness management, nutritional management and footcare.

The training programme that was developed comprises three modules:

  • Diabetes awareness
  • Expansion of diabetes knowledge
  • Insulin administration for non-registered practitioners

Some of the community staff became diabetes mentors for the programme, the mentors also participated in the same training course as the non- registered practitioners.

This programme led to better use of resources:

The insulin delegation programme offers a way of supporting complex care by providing skill and competency development, supported by robust governance infrastructure. Non-registered practitioners can administer diabetes care, including insulin, while still under the supervision of a community nurse, ensuring patient safety and quality of care. Community nurses can be released to support other patient groups. There is now improved diabetes care planning with the use of non-registered practitioners to support their own clients in residential care home settings, reducing the need for, and frequency and number of, district nurse visits, especially in rural locations ( Source: NHS England).

Improving insulin administration in a community setting

Self-monitoring of blood glucose provides no important benefit for most people with type 2 diabetes

NIHR | October 2018 | Self-monitoring of blood glucose provides no important benefit for most people with type 2 diabetes

Patients with type 2 diabetes who monitor their blood glucose themselves may see small, short-term improvements in blood sugar control. This is not enough to be clinically important or outweigh the costs and personal inconvenience of long-term self-testing, reports an NIHR Signal. 

The signal highlights a systematic review (SR) that identified 24 recent randomised controlled trials involving more than  5000 people with type 2 diabetes to compare self- monitoring with control strategies where people were not taking insulin.

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Self-monitoring gave a 0.3 percentage point reduction in glycated haemoglobin (HbA1c) at six months. This is just below the 0.4% threshold for a meaningful clinical difference in this measure of average 3-month sugar control. People who had poorer blood glucose control at the start saw a greater benefit. However, there was no difference between the self-monitoring and control groups by 12 months.

The review supports current guideline recommendations that self-monitoring is not routinely used for people with type 2 diabetes controlled on diet or tablets (Source: NIHR).

Read the signal in full from NIHR 

Machry, R. V., Rados, D. V., de Gregório, G. R., & Rodrigues, T. C. |2018|  Self-Monitoring Blood Glucose improves glycemic control in Type 2 Diabetes without intensive treatment: a systematic review and meta-analysis|  Diabetes research and clinical practice| 

Abstract

AIMS: Systematic review and meta-analysis to evaluate the effect of Self-Monitoring of Blood Glucose (SMBG) on glycemic control in patients with type 2 Diabetes (T2D).

METHODS: We searched the Medline, Embase, Cochrane Central, and ClinicalTrials.gov databases up to 20 July 2017. We also performed a manual search of abstracts from recent meetings of the American Diabetes Association and the European Association for the Study of Diabetes.

STUDY SELECTION: randomized controlled trials (RCTs) conducted in patients with T2D comparing any kind of SMBG to a control group. Two independent reviewers assessed the eligibility of references. Influence of SMBG in glycated hemoglobin (HbA1c) was aggregated as weighted mean difference accessed by direct random effect meta-analyses at 12, 24 weeks and 1 year. Sub-analyses were made to assess the effects of previous glycemic control and number of tests performed.

RESULTS: SMBG was associated with a reduction of HbA1c at 12 weeks and 24 weeks, but no difference was found for 1 year. Subgroup analysis including studies with baseline HbA1c greater than 8% showed a higher reduction of HbA1c: -0.83% at 12 weeks, and -0.48%  at 24 weeks, with no difference for 1 year nor for the stratification for number the tests.

CONCLUSION: SMBG seems to lead to a slightly better glycemic control in the short term in patients with T2D. Patients decompensated at baseline appear to have the greatest benefit. PROSPERO register: CRD42016033558.

 

Insulin pumps offer little value over multiple injections for children at the onset of diabetes

NIHR | November 2018 | Insulin pumps offer little value over multiple injections for children at the onset of diabetes 

Young people newly diagnosed with type 1 diabetes achieve similar blood glucose control by 12 months if they are treated with multiple daily insulin injections or continuously via an insulin pump, according to the findings of a randomised controlled trial (RCT) that looked at 93 children  up to 15 years of age  in 15 centres in England all  newly diagnosed with type 1 diabetes. The control group  received multiple daily injections (4 or more injections daily including both short- and long-acting insulin) and the intervention group received continuous subcutaneous infusion of short-acting insulin via a pump.

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The RCT found that parent-reported quality of life was higher in the artificial pancreas group than the in the group with daily injections.  Currently, both regimens are used in the management of type 1 diabetes, with the number of children using insulin pumps is increasing. This NIHR-funded trial indicates that at an additional cost of £1,863 per patient annually with equivalent outcomes, the high costs of insulin pumps seem unjustified at this stage of the condition (Source: NIHR Signal).

Full reference: Blair,  J. | 2018 | Continuous subcutaneous insulin infusion versus multiple daily injections in children and young people at diagnosis of type 1 diabetes: the SCIPI RCT| Published on 15 August 2018 | Health Technology Assessment | Vol. 22| Issue 42 | 10.3310/signal-000680

Abstract

Background The risk of developing long-term complications of type 1 diabetes (T1D) is related to glycaemic control and is reduced by the use of intensive insulin treatment regimens: multiple daily injections (MDI) (more than or equal to 4) and continuous subcutaneous insulin infusion (CSII). Despite a lack of evidence that the more expensive treatment with CSII is superior to MDI, both treatments are used widely within the NHS.
Objectives (1) To compare glycaemic control during treatment with CSII and MDI and (2) to determine safety and cost-effectiveness of the treatment, and quality of life (QoL) of the patients.
Design A pragmatic, open-label randomised controlled trial with an internal pilot and 12-month follow-up with 1 : 1 web-based block randomisation stratified by age and centre.
Setting Fifteen diabetes clinics in hospitals in England and Wales.
Participants Patients aged 7 months to 15 years. Interventions Continuous subsutaneous insulin infusion or MDI initiated within 14 days of diagnosis of T1D.
Data sources Data were collected at baseline and at 3, 6, 9 and 12 months using paper forms and were entered centrally. Data from glucometers and CSII were downloaded. The Health Utilities Index Mark 2 was completed at each visit and the Pediatric Quality of Life Inventory (PedsQL, diabetes module) was completed at 6 and 12 months. Costs were estimated from hospital patient administration system data.
Outcomes The primary outcome was glycosylated haemoglobin (HbA1c) concentration at 12 months. The secondary outcomes were (1) HbA1c concentrations of less than  48 mmol/mol, (2) severe hypoglycaemia, (3) diabetic ketoacidosis (DKA), (4) T1D- or treatment-related adverse events (AEs), (5) change in body mass index and height standard deviation score, (6) insulin requirements, (7) QoL and (8) partial remission rate. The economic outcome was the incremental cost per quality-adjusted life-year (QALY) gained.
Results A total of 293 participants, with a median age of 9.8 years (minimum 0.7 years, maximum 16 years), were randomised  between May 2011 and January 2015. Primary outcome data were available for 97% of participants. At 12 months, age-adjusted least mean squares HbA1c concentrations were comparable between groups: CSII, 60.9 mmol/mol; MDI, 58.5 mmol/mol; and the difference of CSII – MDI, 2.4 mmol/mol. For HbA1c concentrations of less than 48 mmol/mol (CSII, 22/143 participants; MDI, 29/142 participants), the relative risk was 0.75 (95% CI 0.46 to 1.25), and for partial remission rates (the relative risk was 0.74 . The incidences of severe hypoglycaemia (CSII, 6/144; MDI, 2/149 participants) and DKA ( were low. In total, 68 AEs (14 serious) were reported during CSII treatment and 25 AEs (eight serious) were reported during MDI treatment. Growth outcomes did not differ. The reported insulin use was higher with CSII . QoL was slightly higher for those randomised to CSII. From a NHS perspective, CSII was more expensive than MDI mean total cost (£1863, 95% CI £1620 to £2137) with no additional QALY gains.
Limitations
Generalisability beyond 12 months is uncertain.
Conclusions No clinical benefit of CSII over MDI was identified. CSII is not a cost-effective treatment in patients representative of the study population. Future work Longer-term follow-up is required to determine if clinical outcomes diverge after 1 year. A qualitative exploration of patient and professional experiences of MDI and CSII should be considered.

 

Closed loop insulin pump improves glucose control in hospital for people with type 2

NIHR | November 2018 | ‘Artificial pancreas’ improves glucose control in hospital patients with type 2 diabetes

A closed loop insulin pump, also referred to as an ‘artificial pancreas’   which continuously monitor blood glucose and administer insulin accordingly, can improve blood glucose control among patients with type 2 diabetes admitted to hospital for non-critical care. Those using the system spent about six hours longer in the target range, and this could hasten their recovery and reduce staff workload.

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The randomised controlled trial (RCT) involved  over 100 adults with type 2 diabetes admitted to general wards at two hospitals in the UK and Switzerland, all with raised blood sugar who needed insulin. Two-thirds of patients were already having insulin as part of their usual treatment.  Patients either continued with their usual insulin and glucose lowering treatments, which clinicians adjusted according to  conventional glucose measurements or they were assigned to the intervention and used the closed loop system to deliver insulin.  All patients wore an implanted continuous glucose monitor to record their glucose levels and were followed up after two weeks or until hospital discharge.  The study found that closed loop insulin delivery increased the percentage of time that blood glucose was in the target range of 100-180 mg per decilitre  by about 6 hours per day: 65.8% of the time in range (±16.8%) compared with 41.5% (±16.9%) in the control group, 

Read the signal in full at NIHR 

“The burden of diabetes is increasing, as is the proportion of hospital in-patients with diabetes. This study evaluates an alternative technology an automated closed-loop (also known as Artificial Pancreas) for improving the glucose control among hospital in-patients with diabetes.

The target glucose range was 5.6 to 10.0 mmol/L, with the standard care patients spending 12 hours/day hyperglycaemic (mean glucose 10.4 mmol/L). The closed-loop group spent about six hours more within range and six hours less with glucose levels 10.0 mmol/L or more.

The study highlights the inadequacy of current in-patient diabetes care and suggests that new technologies may allow for in-patient care that is safer and more effective than current clinical approaches.”

Dr HR Murphy, Professor of Medicine (Diabetes and Antenatal Care), Norwich Medical School

Source: NIHR

Abstract 

Background In patients with diabetes, hospitalization can complicate the achievement of recommended glycemic targets. There is increasing evidence that a closed-loop delivery system (artificial pancreas) can improve glucose control in patients with type 1 diabetes. We wanted to investigate whether a closed-loop system could also improve glycemic control in patients with type 2 diabetes who were receiving noncritical care.

Methods In this randomized, open-label trial conducted on general wards in two tertiary hospitals located in the United Kingdom and Switzerland, we assigned 136 adults with type 2 diabetes who required subcutaneous insulin therapy to receive either closed-loop insulin delivery (70 patients) or conventional subcutaneous insulin therapy, according to local clinical practice (66 patients). The primary end point was the percentage of time that the sensor glucose measurement was within the target range of 100 to 180 mg per deciliter (5.6 to 10.0 mmol per liter) for up to 15 days or until hospital discharge.

Results The mean (+/-SD) percentage of time that the sensor glucose measurement was in the target range was 65.8+/-16.8% in the closed-loop group and 41.5+/-16.9% in the control group, a difference of 24.3+/-2.9 percentage points; values above the target range were found in 23.6+/-16.6% and 49.5+/-22.8% of the patients, respectively, a difference of 25.9+/-3.4 percentage points. The mean glucose level was 154 mg per deciliter (8.5 mmol per liter) in the closed-loop group and 188 mg per deciliter (10.4 mmol per liter) in the control group (P less than0.001). There was no significant between-group difference in the duration of hypoglycemia or in the amount of insulin that was delivered (median dose, 44.4 U and 40.2 U, respectively; P=0.50). No episode of severe hypoglycemia or clinically significant hyperglycemia with ketonemia occurred in either trial group.

Conclusions Among inpatients with type 2 diabetes receiving noncritical care, the use of an automated, closed-loop insulin-delivery system resulted in significantly better glycemic control than conventional subcutaneous insulin therapy, without a higher risk of hypoglycemia. (Funded by Diabetes UK and others; ClinicalTrials.gov number, NCT01774565 .).

 

 

 

 

 

Full reference: Bally L, Thabit H, Hartnell S et al. | 2018 |  Closed-loop insulin delivery for glycemic control in noncritical care|  New England Journal of  Medicine | 379| 6| P. 547-56.

Delivering insulin in a pill

Researchers have developed an oral delivery method that could dramatically transform the way in which diabetics keep their blood sugar levels in check | Proceedings of the National Academy of Sciences | via ScienceDaily

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Insulin therapy, by injection just under the skin or delivered by an insulin pump, generally keeps the glucose levels of most diabetics in check. However, many people fail to adhere to that regimen due to pain, phobia of needles, and the interference with normal activities. The resulting poor glycemic control can lead to serious health complications.

Finding a way to deliver insulin orally has been elusive; the protein does not fare well when it encounters the stomach’s acidic environment and it is poorly absorbed out of the intestine. The key to the new approach is to carry insulin in an ionic liquid comprised of choline and geranic acid that is then put inside a capsule with an acid-resistant enteric coating. The formulation is biocompatible, easy to manufacture, and can be stored for up to two months at room temperature without degrading, which is longer than some injectable insulin products currently on the market.

Full story at ScienceDaily

Full reference: Banerjee, A et al. | Ionic liquids for oral insulin delivery | Proceedings of the National Academy of Sciences | published online June 25th 2018

National Diabetes Insulin Pump Audit 2016-2017

Health Quality Improvement Partnership | June 2018| National Diabetes Insulin Pump Audit 2016-2017

The Insulin pump audit collects information on the number and characteristics of people with diabetes using an insulin pump, the reasons for going on an insulin pump and the outcomes achieved since starting the pump. The data included in the attached report was collected between 2016-2017 from Trusts based within England and Wales. 

National Diabetes Insulin Pump Audit, 2016-2017
Image source: hqip.org.uk

Key findings include:
Improved participation and data quality means that the report this year is more comprehensive and clinically useful

  • The rate at which people with Type 1 diabetes are starting pump treatment has stabilised
  • The proportion of people with Type 1 diabetes attending specialist services that are treated with pumps varies from more than 40% to less than 5%
  • Between two thirds and three quarters of pump users are recorded as achieving their pump treatment goals
  • Nine out of ten people reached their target goal for hypoglycaemia
  • Seven out of ten people reached their target goal for glucose control
  • Despite being a younger cohort, Type 1 diabetes pump users more often achieve all their treatment targets, and on average have a lower HbA1c, than their non-pump using peers.

The full audit is available to download as PowerPoint slides from NHS Digital via HQIP