Background
Diabetes is a condition that causes a person's blood sugar (glucose) level to become too high. Insulin is a hormone that is released by the pancreas (a small organ behind the stomach) which controls the blood levels of glucose. In people with type 1 diabetes mellitus (T1DM) the pancreas does not produce any insulin, so the person has to inject insulin to control the glucose levels and keep well. The goal of insulin therapy is to provide insulin that mimics physiologic insulin secretion. Insulin is given by an injection under the skin (subcutaneous) by means of insulin syringes, insulin pens or insulin pumps. In order to control blood glucose levels in periods of fasting, basal or background insulin is needed. Basal insulin can be given by means of daily or twice-daily injections of an intermediate-acting or (ultra-)long-acting insulin. Basal insulin can be given as intermediate-acting human neutral protamine Hagedorn (NPH) insulin or as (ultra-)long-acting analogue insulin (synthetic insulin). Bolus insulin is taken at mealtime (prandial insulin) to control blood glucose levels following a meal and is given by means of short-acting or rapid-acting insulin. The aim for most people with T1DM is to achieve near-normal blood glucose levels to avoid long-term complications such as kidney and eye disease and to allow flexibility regarding time, type and amount of food intake. The major unwanted effect of insulin therapy is hypoglycaemia (low blood glucose) which can be severe.
We wanted to find out whether one type of (ultra-)long-acting insulin compared with NPH insulin or another type of (ultra-)long-acting insulin is better for people with T1DM. The outcomes we were specifically interested in were death, health-related quality of life, severe (night-time) hypoglycaemia, serious unwanted events, non-fatal complications of diabetes (heart attacks, strokes) and levels of glycosylated haemoglobin A1c (HbA1c) which is an indicator of long-term glucose control.
What did we look for?
We searched medical databases and contacted pharmaceutical manufacturers and drug regulatory agencies for studies that:
— were randomised controlled trials (medical studies where participants are put randomly into one of the treatment groups);
— included people with T1DM;
— compared one (ultra-)long-acting insulin with another (ultra-)long-acting insulin or NPH insulin;
— lasted at least 24 weeks.
What did we find?
We found 26 studies including a total of 8780 participants (21% were children). The studies lasted between 24 weeks and two years. They compared:
— NPH insulin with insulin detemir (nine studies);
— NPH insulin with insulin glargine (nine studies);
— Insulin detemir with insulin glargine (two studies);
— Insulin degludec with insulin detemir (two studies);
— Insulin degludec with insulin glargine (four studies).
No study compared NPH insulin with insulin degludec.
Key results
There were no clear differences for all main outcomes comparing (ultra-)long-acting insulin analogues with each other.
Severe hypoglycaemic episodes were reduced with insulin detemir: among 1000 participants using NPH insulin, 115 would experience severe hypoglycaemia; using insulin detemir there would be 36 participants fewer (9 to 55 participants fewer) experiencing severe hypoglycaemia. However, the results were inconsistent, meaning if another study was performed there may not be a clear difference between insulin detemir and NPH insulin. There was no clear difference regarding the risk of severe night-time hypoglycaemia. There were no clear differences for health-related quality of life, serious unwanted effects or HbA1c levels. Very few people experienced a heart attack or died, and stroke was not reported.
There were no clear differences comparing insulin glargine with NPH insulin for all main outcomes. Very few people experienced a heart attack, stroke or died.
There were also no clear differences for all comparisons between children and adults.
Certainty of the evidence
In the comparison of the insulin analogues detemir and glargine with NPH insulin, we are moderately confident about the results for death, severe (night-time) hypoglycaemia, serious unwanted effects and HbA1c levels. We are uncertain about the effects on heart attacks, stroke and health-related quality of life, mainly because there were only a few studies which did not last long enough to reliably investigate these outcomes.
How up to date is this review?
This evidence is up-to-date as of 24 August 2020.
Comparing insulin detemir with NPH insulin for T1DM showed lower risk of severe hypoglycaemia in favour of insulin detemir (moderate-certainty evidence). However, the 95% prediction interval indicated inconsistency in this finding. Both insulin detemir and insulin glargine compared with NPH insulin did not show benefits or harms for severe nocturnal hypoglycaemia. For all other main outcomes with overall low risk of bias and comparing insulin analogues with each other, there was no true beneficial or harmful effect for any intervention. Data on patient-important outcomes such as QoL, macrovascular and microvascular diabetic complications were sparse or missing. No clinically relevant differences were found between children and adults.
People with type 1 diabetes mellitus (T1DM) need treatment with insulin for survival. Whether any particular type of (ultra-)long-acting insulin provides benefit especially regarding risk of diabetes complications and hypoglycaemia is unknown.
To compare the effects of long-term treatment with (ultra-)long-acting insulin analogues to NPH insulin (neutral protamine Hagedorn) or another (ultra-)long-acting insulin analogue in people with type 1 diabetes mellitus.
We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Scopus, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform and the reference lists of systematic reviews, articles and health technology assessment reports. We explored the US Food and Drug Administration (FDA) and European Medical Agency (EMA) web pages. We asked pharmaceutical companies, EMA and investigators for additional data and clinical study reports (CSRs). The date of the last search of all databases was 24 August 2020.
We included randomised controlled trials (RCTs) with a duration of 24 weeks or more comparing one (ultra-)long-acting insulin to NPH insulin or another (ultra-)long-acting insulin in people with T1DM.
Two review authors assessed risk of bias using the new Cochrane 'Risk of bias' 2 (RoB 2) tool and extracted data. Our main outcomes were all-cause mortality, health-related quality of life (QoL), severe hypoglycaemia, non-fatal myocardial infarction/stroke (NFMI/NFS), severe nocturnal hypoglycaemia, serious adverse events (SAEs) and glycosylated haemoglobin A1c (HbA1c). We used a random-effects model to perform meta-analyses and calculated risk ratios (RRs) and odds ratios (ORs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) and 95% prediction intervals for effect estimates. We evaluated the certainty of the evidence applying the GRADE instrument.
We included 26 RCTs. Two studies were unpublished. We obtained CSRs, clinical study synopses or both as well as medical reviews from regulatory agencies on 23 studies which contributed to better analysis of risk of bias and improved data extraction. A total of 8784 participants were randomised: 2428 participants were allocated to NPH insulin, 2889 participants to insulin detemir, 2095 participants to insulin glargine and 1372 participants to insulin degludec. Eight studies contributing 21% of all participants comprised children. The duration of the intervention varied from 24 weeks to 104 weeks.
Insulin degludec versus NPH insulin: we identified no studies comparing insulin degludec with NPH insulin.
Insulin detemir versus NPH insulin (9 RCTs): five deaths reported in two studies including adults occurred in the insulin detemir group (Peto OR 4.97, 95% CI 0.79 to 31.38; 9 studies, 3334 participants; moderate-certainty evidence). Three studies with 870 participants reported QoL showing no true beneficial or harmful effect for either intervention (low-certainty evidence). There was a reduction in severe hypoglycaemia in favour of insulin detemir: 171/2019 participants (8.5%) in the insulin detemir group compared with 138/1200 participants (11.5%) in the NPH insulin group experienced severe hypoglycaemia (RR 0.69, 95% CI 0.52 to 0.92; 8 studies, 3219 participants; moderate-certainty evidence). The 95% prediction interval ranged between 0.34 and 1.39. Only 1/331 participants in the insulin detemir group compared with 0/164 participants in the NPH insulin group experienced a NFMI (1 study, 495 participants; low-certainty evidence). No study reported NFS. A total of 165/2094 participants (7.9%) in the insulin detemir group compared with 102/1238 participants (8.2%) in the NPH insulin group experienced SAEs (RR 0.95, 95% CI 0.75 to 1.21; 9 studies, 3332 participants; moderate-certainty evidence). Severe nocturnal hypoglycaemia was observed in 70/1823 participants (3.8%) in the insulin detemir group compared with 60/1102 participants (5.4%) in the NPH insulin group (RR 0.67, 95% CI 0.39 to 1.17; 7 studies, 2925 participants; moderate-certainty evidence). The MD in HbA1c comparing insulin detemir with NPH insulin was 0.01%, 95% CI -0.1 to 0.1; 8 studies, 3122 participants; moderate-certainty evidence.
Insulin glargine versus NPH insulin (9 RCTs): one adult died in the NPH insulin group (Peto OR 0.14, 95% CI 0.00 to 6.98; 8 studies, 2175 participants; moderate-certainty evidence). Four studies with 1013 participants reported QoL showing no true beneficial effect or harmful effect for either intervention (low-certainty evidence). Severe hypoglycaemia was observed in 122/1191 participants (10.2%) in the insulin glargine group compared with 145/1159 participants (12.5%) in the NPH insulin group (RR 0.84, 95% CI 0.67 to 1.04; 9 studies, 2350 participants; moderate-certainty evidence). No participant experienced a NFMI and one participant in the NPH insulin group experienced a NFS in the single study reporting this outcome (585 participants; low-certainty evidence). A total of 109/1131 participants (9.6%) in the insulin glargine group compared with 110/1098 participants (10.0%) in the NPH insulin group experienced SAEs (RR 1.08, 95% CI 0.63 to 1.84; 8 studies, 2229 participants; moderate-certainty evidence). Severe nocturnal hypoglycaemia was observed in 69/938 participants (7.4%) in the insulin glargine group compared with 83/955 participants (8.7%) in the NPH insulin group (RR 0.83, 95% CI 0.62 to 1.12; 6 studies, 1893 participants; moderate-certainty evidence). The MD in HbA1c comparing insulin glargine with NPH insulin was 0.02%, 95% CI -0.1 to 0.1; 9 studies, 2285 participants; moderate-certainty evidence.
Insulin detemir versus insulin glargine (2 RCTs), insulin degludec versus insulin detemir (2 RCTs), insulin degludec versus insulin glargine (4 RCTs): there was no evidence of a clinically relevant difference for all main outcomes comparing (ultra-)long-acting insulin analogues with each other.
For all outcomes none of the comparisons indicated differences in tests of interaction for children versus adults.