Severe hypoglycaemia is associated with increased risk of adverse cardiovascular complications in adults with type 1 diabetes:
risk mitigation using intermittently scanned continuous glucose monitoring
Katarina Eeg‑Olofsson · David Nathanson · Tim Spelman · Mattias Kyhlstedt · Alexander Seibold · Fleur Levrat‑Guillen · Jan Bolinder
Vol.:(0123456789)Diabetologia
https://doi.org/10.1007/s00125-025-06438-y
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Abstract
Aims/hypothesisIt has been proposed that severe hypoglycaemia events (SHE) may increase the risk of adverse CVD complications in adults with type 1 diabetes.
The aim of this study was to evaluate the risk of CVD complications following SHE in a large cohort of adults with type 1 diabetes, and to compare the risk of post-SHE CVD complications for users of intermittently scanned continuous glucose monitoring (isCGM) vs users of blood glucose monitoring (BGM).
Methods
This comparative retrospective cohort study used data from the Swedish National Diabetes Register and the Swedish National Patient Register. We identified people with type 1 diabetes who had a hospitalisation for CVD complications. Rates of hospitalisation were compared between those with an index SHE and those without, and within isCGM or BGM subgroups. The study baseline was date of the first SHE prior to the isCGM index date.
Results
We identified 14,829 adults with type 1 diabetes with up to 2 years of follow-up, of which 1313 had an index SHE. In the full cohort, the relative rate of hospitalisations for CVD complications was 2.06-fold (95% CI 1.48, 2.85) in those with prior SHE. Of these 1313 participants with prior SHE, 970 were using isCGM and 343 were using BGM.
Hospitalisations for post-SHE CVD complications were significantly lower for isCGM users (5.40 per 100 person-years of follow-up; 95% CI 4.59, 6.31) compared with BGM control participants (14.23 per 100 person-years of follow-up; 95% CI 11.95, 16.82), which represents a 78% relative reduction in rates of post-SHE CVD complications for isCGM users (relative rate 0.22; 95% CI 0.11, 0.43; p<0.001), after adjustment for confounders.
Conclusions/interpretation
In adults with type 1 diabetes, SHE is associated with an increased risk of hospitalisation for adverse CVD complications.
This risk is significantly reduced in isCGM users compared with BGM control participants.
From the article
Introduction
Despite advances in glycaemic management, people with type 1 diabetes remain at higher risk of CVD and CVD-related mortality than people without diabetes [1].
Data from the Swedish National Diabetes Register (NDR) reveal that people with type 1 diabetes and HbA1c ≤52 mmol/mol (≤6.9%) have a twofold greater risk of CVD death than a matched population without diabetes [2].
For individuals with type 1 diabetes and HbA1c ≥82 mmol/mol (≥9.7%), this risk is estimated to be 8–10-fold [2].
The Diabetes Control and Complications Trial (DCCT) and the Epidemiology of Diabetes Interventions and Complications (EDIC) study have shown that more-intensive glucose control for people with type 1 diabetes is associated with a 42% reduced risk of any cardiovascular event and a 57% risk reduction of death from CVD [3] over a mean of 6.5 years.
However, prior severe hypoglycaemia events (SHEs) are reported to increase the risk of adverse CVD complications in people with type 1 diabetes [4], and SHEs are independently associated with accelerated ath-erosclerosis, increased risk of CVD events and all-cause mortality [5–7].
Acute or recurrent hypoglycaemia episodes are known to induce proinflammatory mediators, platelet activation and markers of vascular endothelial stress in type 1 diabetes [8, 9].
Continuous glucose monitoring (CGM) technologies have enabled people with type 1 diabetes to significantly improve their glucose levels and reduce exposure to hypoglycaemia, compared with using blood glucose monitoring (BGM) test strips [10–13].
We have previously shown that the use of intermittently scanned CGM (isCGM) is associated with lowered HbA1c within 6 months of initiation, and that these levels persist for at least 2 years of follow-up, in addition to lower rates of SHEs compared with BGM control participants [14].
Using data from the NDR, linked with hospital admissions data from the Swedish National Patient Register (NPR), we have also reported that, com-pared with a matched cohort of BGM users, isCGM users with type 1 diabetes have a 36–75% relative reduction in rates of hospitalisation for CVD events, including acute myocardial infarction (AMI), stroke, heart failure and atrial fibrillation, as well as a relative reduction in hospitalisation for acute diabetes events (68% relative reduction in rates of SHE and 45% relative reduction for diabetic ketoacidosis) over a 24-month follow-up period, together with an HbA1creduction of approximately 0.3% [15].
Mechanistically, it seems unlikely that reductions in CVD events were linked to improved glucose control, considering the short observation period and modest difference in HbA1c.
Instead, we speculate that the reductions in CVD events may be associated with the observed risk reduction for SHEs. Studies in healthy individuals and in people with type 1 diabetes indicate that acute hypoglycaemia leads to increased proinflammatory cytokines, mobilisation of inflammatory leukocytes and increased platelet reactivity [16–18].
Such consequences are hypothesised to promote atherogenesis and plaque instability in people with diabetes.
To investigate this hypothesis, the current study uses linked data from the NDR and NPR to examine the association between prior SHE and hospital admissions for non-fatal CVD complications and CVD-related death in adults with type 1 diabetes, and compared the rate of CVD complica-tions following a prior SHE for isCGM users vs a control group of BGM users.
Discussion
This comparative retrospective study demonstrates that prior SHE is associated with an increased risk of hospitalisation for CVD complications in adults with type 1 diabetes, and reveals important changes in the risk of post-SHE CVD complications for isCGM users.
Our data confirm that risk of hospital admission for CVD complications is approximately doubled among adults with type 1 diabetes who had a previous SHE, compared to those without a recorded SHE (Fig. 1a).
The highest rate of hospital admissions for CVD complications was in the cohort of adults with type 1 diabetes who were BGM users (Fig. 1b). Adults with type 1 diabetes who were isCGM users had a lower rate of hospitalisation for CVD complications (Fig. 1c), in both the group with and those without a prior SHE. In keeping with the wider observation that a prior SHE episode confers an approximately doubled risk of hospitalisation for CVD complications, the post-SHE cohort of isCGM users exhibited a 1.89-fold relative increase in rate of admission for CVD complications (Fig. 1c).
The most notable outcome is that isCGM users with a prior SHE had a greatly reduced frequency of admission for CVD complications compared to BGM users with a previous SHE (Fig. 2).
Equally notable are the significant reductions in risk of CVD complications for isCGM users with no prior SHE, compared with BGM users.
Use of isCGM has been shown to reduce less-severe hypoglycaemia in type 1 diabetes [12, 13], which may contribute to the lower incidence of CVD complications shown here. These outcomes were replicated when using a narrower composite definition of CVD complications, including AMI, stroke and cardiovascu-lar death (ESM Fig. 2).
This aligns with our previous study showing that isCGM users have a significant relative reduction in rates of hospital admissions for cardiovascular com-plications of type 1 diabetes, compared with BGM control participants, including stroke, AMI, heart failure and atrial fibrillation [15].
Our subgroup analysis showed that risk of CVD complications was significantly higher in the subgroup of adults with type 1 diabetes and a history of CVD (Fig. 3), and that using isCGM significantly reduced this risk.Our study has several noteworthy outcomes. These include demonstration of the association of at least one prior SHE with a significantly increased risk of CVD complications for people with type 1 diabetes, using the composite endpoint of hospitalisation for CVD complications, rather than CVD mortality alone.
A 2014 study using NDR data to show an association of prior SHE with CVD mortality in type 1 diabetes [4] concluded that, although prior SHE was associated with reduced survival following a major CVD event, it was not associated with an increased risk of a subsequent fatal CVD event.
Our data, using hospital admissions data, suggest an association between prior SHE and an increased risk of composite CVD complications, for people with type 1 diabetes using either BGM or isCGM.
This finding must be reconciled with the EURODIAB study outcomes, which did not find that prior SHE increased the risk of fatal or non-fatal cardiovascular events [24] and the finding of a prospective observational study on two cohorts of people with type 1 diabetes, one Danish (n=269) and one Dutch (n=482), neither of which found an association between episodes of SHE or impaired awareness of hypo-glycaemia and CVD mortality when not part of a composite outcome [25].
The difference in outcomes between the previous NDR study on CVD mortality following SHE [4] and the current study may also reflect different selection criteria and reporting aims. The 2014 study included risk factor data from the NDR between January 1987 and December 2010, and reported risk equations for survival after myocardial infarction and stroke only, in 1839 adults with type 1 diabetes.
Thus, their conclusion that prior SHE was not associated with an increased risk of subsequent CVD was based only on myocardial infarction and stroke.
Our study used a composite outcome comprising occurrence of hospital admissions with a primary diagnosis of non-fatal AMI, coronary heart disease, non-fatal stroke, atrial fibrillation or heart failure, or recorded cardiovascular death.
The different methodology and the wider selection of CVD-related primary diagnoses is likely to influence comparisons with earlier studies, as each of these primary diagnoses have been associated with increased hospitalisation for adults with type 1 diabetes using BGM, and with reductions in relative rates for isCGM users [15].
An assessment of atherosclerosis in type 1diabetes in the DCCT cohort found that SHE is associated with increased coronary artery calcification scores for indi-viduals with HbA1c <58 mmol/mol (<7.5%) [26].
During acute hypoglycaemia, heart rate, systolic BP and blood flow (which are associated with risk of CVD) all increase [27]. The association with atherosclerotic disease is also supported by one study showing that repeated hypoglycaemia in type 1 diabetes, including in individuals with impaired awareness of hypoglycaemia, may be an aggravating fac-tor for markers of preclinical atherosclerosis [6].
Prior SHE may also be a marker for increased frequency of non-severe hypoglycaemia, which has a cumulative effect on cardiac structures, as hypoglycaemia is implicated in cardiac arrythmias in type 1 diabetes [28–30].
More directly, studies have shown that acute hypoglycaemia can have proinflammatory sequelae that may contribute to atherogenesis in type 1 diabetes [16, 17]. Repeated hypoglycaemia is also associated with enhanced coagulation, oxidative stress, vascular inflammation, endothelial dysfunction and platelet activa-tion [31], which are features of CVD.
However, we should point out that isCGM has also been shown to reduce time in hyperglycaemia and glucose variability [12, 13], which are not recorded in the NDR. The influence of these variables on CVD complications should be examined in future trials.
The association of prior SHE with increased CVD out-comes in type 1 diabetes is a clinically important finding of the current and previous studies [4, 15] using the NDR and NPR datasets.
Notably, our findings do not prove a causal link between severe or recurrent hypoglycaemia and CVD complications but only an association between the two phenomena.
However, in our study, the use of isCGM was certainly associated with a lower risk of CVD complications as a composite outcome in adults with type 1 diabetes, both for those with and without a prior SHE, compared with use of BGM, with the reduction being most noticeable in those with a prior SHE (Fig. 2).
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