JCI Insight: Autonomic dysfunction and risk of severe hypoglycemia in patients with type 2 diabetes

Background: Type 2 diabetes is common
in the United States.
Hypoglycemia has been a key limiting factor
in glycemic control in patients with type 1 and type 2 diabetes.
Indeed, hypoglycaemia is associated with poorer quality of life and poses a significant morbidity and mortality burden
in people with type 2 diabetes.
Hypoglycemia unconsciousness, defined as hypoglycemia-related autonomic failure, is known to increase the risk of
severe hypoglycemia.
While hypoglycemia consciousness tends to occur at the same time as CAN, the two conditions are distinct and do not necessarily have any causal link
.
It has been suggested that autonomic dysfunction, including cardiac autonomic neuropathy (CAN), directly leads to the development of impaired awareness of
hypoglycemia.
Autonomic dysfunction is a very common complication of type 2 diabetes, with a prevalence of up to 34%.

Data from experimental studies suggest a link
between CAN and hypoglycemic episodes of type 1 diabetes.
However, there are few
large-scale human data on the link between autonomic dysfunction and severe hypoglycemia in patients with type 2 diabetes.
In addition, whether intensive glycemic control alters the relationship between autonomic dysfunction and severe hypoglycemic events in people with type 2 diabetes is unclear
.

Objective: In this study, using data from the Action for Cardiovascular Risk Control of Diabetes (ACCORD) trial, we investigated the association of CAN with the incidence of
severe hypoglycemia, including initial hypoglycemia and recurrent hypoglycemia.
We also assessed whether these associations differed
in the glycaemic therapeutic branch of ACCORD.

Methods: We evaluated the association
of CAN with severe hypoglycemia in 7,421 adult patients with type 2 diabetes mellitus from the Action for the Control of Cardiovascular Risk of Diabetes (ACCORD) study.
Define CAN
using the ECG exported method.
Cox and Andersen-Gill regression models were used to generate risk ratios (HR)
for first and recurrent episodes of severe hypoglycemia, respectively.

Results: There were 558 first hypoglycemic events and 811 recurrent hypoglycemic events
over 4.
7 years.
Patients with CAN are at increased
risk of severe hypoglycemia for the first time (HR 1.
23, 95% CI 1.
01-1.
50) or relapse (HR: 1.
46, 95% CI 1.
16-1.
84).
The intensity of glycemic control changed the correlation between CAN and hypoglycemia (P<0.
05).

In the standard glycemic management group, the RR for first severe hypoglycemia and recurrent hypoglycemia was 1.
58 (95% CI 1.
13~2.
23) and 1.
96 (1.
33~2.
90),
respectively, compared with participants without CAN.
The HR of the first severe hypoglycemia and recurrent hypoglycemia in the intensive hypoglycemic therapy group were 1.
10 (0.
86~1.
40) and 1.
24 (0.
93~1.
65),
respectively.

Table 1 Incidence and risk ratio of severe hypoglycemia by cardiac autonomic neuropathy state

Table 2 Incidence and risk ratio of severe hypoglycemia requiring medical help as shown by evidence of cardiac autonomic neuropathy graded by glycemic intensity

Table 3 Incidence and risk ratio of severe hypoglycemic events by cardiac autonomic neuropathy and intensity of glycemic control

Figure the cumulative incidence of first (A) and recurrent (B) severe hypoglycemic events (ARM and CAN).

Conclusions: In adults with type 2 diabetes, CAN is independently associated with the risk of initial and recurrent hypoglycemia, with the highest risk observed
in patients receiving standard blood glucose therapy.

Original source:

Kaze AD, Yuyun MF, Ahima RS,et al.
Autonomic dysfunction and risk of severe hypoglycemia among individuals with type 2 diabetes.
JCI Insight 2022 Nov 01