Journal reference: Zoungas S, Patel A, Chalmers J, et al. Severe hypoglycemia and risk of vascular events and death. N Engl J Med 2010;363:1410-8 ^[1]

Link: http://dx.doi.org/10.1056/NEJMoa1003795

Evidence cookie says...

Severe hypoglycaemia is strongly associated with increased risk of vascular events and death (~ 350% ↑ risk). This association may be due to common confounding factors rather than a causative relationship.  Intensive glucose treatment in type 2 diabetes (target HbA1c ≤ 6.5%) did not seem to worsen outcomes despite increasing hypoglycaemia. Prudent HbA1c targets for type 2 diabetes should remain at ≤ 7.0% until more definitive evidence exists.  There is, however, no need to raise the HbA1c for patients with HbA1c ≤ 6.5% if clinically stable.

More details:

Article details

Study design:

re-analysis of data from a randomised controlled trial

Study aim:

examine the associations between severe hypoglycaemia and adverse outcomes

Methods summary:

ADVANCE study had two randomised arms:

• perindopril–indapamide vs placebo for lowering blood pressure
• intensive glucose lowering (with gliclazide MR) (target HbA1c ≤ 6.5%) compared with standard guideline-based glucose lowering

This study:

• mean follow up of 5 years
• hypoglycaemia defined as BSL < 2.8 mmol/L or signs or symptoms typical of hypoglycaemia where there was no other cause
• severe hypoglycaemia was defined as hypoglycaemic events where the participants were unable to treat themselves
• primary clinical outcomes:
  • first major macrovascular event (death from cardiovascular causes, non-fatal MI or stroke)
  • first major microvascular event (new or worsening nephropathy or retinopathy)
• primary and secondary outcomes were validated by an independent adjudication committee who were blinded of the treatment assignments
• statistical analysis of severe and minor hypoglycaemia
  • baseline risk factors
  • associations with clinical outcomes

Results summary:

Rates of severe hypoglycaemia:

• standard group: 1.5% of participants with rates stable over time
• intensive treatment group: 2.7% of participants with rates increasing over time (P < 0.001 for trend)

Independent risk factors for severe hypoglycaemia on univariate and multivariate analysis (P < 0.05 for all):

• older age
• longer duration of diabetes
• higher creatinine levels
• lower body mass index
• lower cognitive function
• use of two or more oral hypoglycaemic drugs
• history of smoking or microvascular disease
• assignment to intensive treatment group

Association between severe hypoglycaemia and outcomes:

• severe hypoglycaemia vs no episodes of severe hypoglycaemia (hazard ratios adjusted for multiple covariates):
  • macrovascular event: HR 3.45, CI 2.34-5.08
  • microvascular event: HR 3.55, CI 1.32-9.54
  • death from CV cause: HR 3.78, CI 2.34-6.11
  • death from all causes: HR 3.30, CI 2.31-4.72
• proportion of deaths from cardiovascular causes and non-cardiovascular causes were similar regardless of episodes of severe hypoglycaemia (P = 0.009)
• participants with severe hypoglycaemia had lower annual death rates if receiving intensive treatment (3.6% vs 5.1%)
• in participants not reporting severe hypoglycaemia, annual death rates were similar between the two treatment groups
• no evidence of a dose-response relationship between repeated episodes of severe hypoglycaemia and vascular outcomes and death (note: very few patients had repeated severe hypoglycaemia in the study population)
• the mean time between the onset of severe hypoglycaemia and the primary outcome was 1.56 years

Study conclusion:

Severe hypoglycemia was strongly associated with increased risks of a range of adverse clinical outcomes. It is possible that severe hypoglycemia contributes to adverse outcomes, but these analyses indicate that hypoglycemia is just as likely to be a marker of vulnerability to such events.

Participants:

• total population 11,140 patients
• aged at least 55 years
• 215 centres over 20 countries between June 2001 and March 2003
• received diagnosis of type 2 diabetes after age 30
• history of either major macrovascular or microvascular disease or at least one cardiovascular risk factor
• patients with “clear indication for long-term insulin use” at baseline were excluded

Methodological weaknesses

• Total number of participants with severe hypoglycaemia was not large (231 patients)
• Total number of participants with multiple severe hypoglycaemic episodes was small (only 12 patients with three or more episodes)
  • this limits the ability to make any firm conclusions about a “dose-response effect”
• The accuracy of reporting of hypoglycaemic episodes is uncertain
• patient demographics and recruitment procedure not explicitly reported in this study (however, one can review previous articles reporting the ADVANCE study)

Methodological strengths

• large total cohort of participants with a large number of recorded primary outcome events
• multiple centres and countries
• data collection and general methodology appears to have been rigorous
• results are likely externally valid to other primary health care populations

Biases and conflicts of interests

• Declared: the ADVANCE study was supported by grants from Servier (manufacturer of gliclazide, trade name “Diamicron”) and the National Health and Medical Research Council of Australia.
• No other obvious biases or conflicts of interests obvious.

Clinical relevance to primary health care

Severe hypoglycaemia is strongly associated with poorer outcomes in patients with type 2 diabetes but it may be a marker of risk rather than a cause.

Type 2 diabetes mellitus is a commonly treated condition by Australian GPs.  Recently, there has been suggestions that intensive glucose control might increase the rate of mortality.  The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial demonstrated an increase in mortality by 20% in their intensive treatment arm (target HbA1c < 6%) compared to their standard treatment arm (HbA1c 7.0-7.9%) ^[2].  There was speculation that this excess mortality is secondary to hypoglycaemic episodes from the intensive glucose control.  A meta-analysis later found that intensive glucose control reduced the risk of myocardial infarction by 15%, but did not appear to improve all cause mortality and it increased the rate of hypoglycaemia ^[3].  This mix of evidence places appropriate management in primary health care in a quandary; is intensive glucose management a better or even valid choice in the management of type 2 diabetes?

This article demonstrated that severe hypoglycaemia was strongly associated with poorer outcomes, both cardiovascular and non-cardiovascular.  It is unclear whether there is a causative component, though the results seem to point to the presence of uncontrolled confounding factors.  That is, factors the lead to severe hypoglycaemia are responsible for poorer outcomes; the severe hypoglycaemia is a marker of increased risk.  Interestingly, those with severe hypoglycaemia had better outcomes if they were on the intensive treatment group.  The causal hypothesis that:

Intensive glucose treatment → Severe hypoglycaemia → Poor outcomes

… is not supported by the results of this study and seems to be less likely to be valid (there is no close temporal association between severe hypoglycaemia and the poor outcome and no dose-response relationship).  It should be noted that this hypothesis has not been confidently rejected.  The low number of participants with multiple recorded episodes of severe hypoglycaemia limits the analysis.

It is reasonable that the target  HbA1c for people with type 2 diabetes should remain ≤ 7%.  Lower targets may achieve better cardiovascular targets but at present have not been shown to clearly improve mortality ^[3].  There is no imperative to raise the HbA1c of patients who are already “intensively controlled” (HbA1c < 6.5%) if they are clinically stable. The study confirms the clinical impression that patients with episodes of severe hypoglycaemia are at much greater risk of a range of poor cardiovascular and non-cardiovascular outcomes.

References

1. Zoungas S, Patel A, Chalmers J, et al. Severe hypoglycaemia and risk of vascular events and death. N Engl J Med 2010;363:1410-8
2. Skyler JS, Bergenstal R, Bonow RO, et al. Intensive Glycemic Control and the Prevention of Cardiovascular Events: Implications of the ACCORD, ADVANCE, and VA Diabetes Trials: A Position Statement of the American Diabetes Association and a Scientific Statement of the American College of Cardiology Foundation and the American Heart Association. Circulation. 2009;119:351-357
3. Turnbull FM, Abraira C, Anderson RJ, et al. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia 2009;52:2288-98.