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Patients with type 1 diabetes at increased risk for all-cause, CVD mortality
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The likelihood of dying from any cause or cardiovascular causes is two times higher in patients with type 1 diabetes and an HbA1c level ≤6.9% compared with individuals in the general population, according to research published in The New England Journal of Medicine.
Results from an observational study of patients with type 1 diabetes registered in the Swedish National Diabetes Register after Jan. 1, 1998, demonstrated even more dramatic rates for patients with type 1 diabetes who are unable to control their glucose levels.
“Patients with very poor glycemic control had eight times increased risk of all-cause mortality and 10 times increased risk of CV death,” Marcus Lind, MD, PhD, of the University of Gothenburg and Uddevalla Hospital, Sweden, told Endocrine Today.
Marcus Lind
Study results
Lind, with colleagues from Europe and the United States, matched patients with type 1 diabetes with randomly selected controls from the general population (mean age, 35.8 and 35.7 years, respectively; 45.1% women per group) in a 1:5 ratio according to age, sex and county.
Through the Swedish Register for Cause-Specific Mortality, the researchers followed the diabetes and control groups until Dec. 31, 2011, (8 and 8.3 years, respectively) to determine the excess risk of death according to the level of glycemic control.
The proportion of patients with diabetes who died was higher compared with controls (2,701 of 33,915 patients, or 8% vs. 4,835 of 169,249, or 2.9%; HR=3.52; 95% CI, 3.06-4.04); corresponding death rates from CV causes were 2.7% and 0.9% (HR=4.6; 95% CI, 3.47-6.1).
Multivariable-adjusted HRs showed death from any cause was more likely among patients with diabetes compared with controls at all HbA1c levels, with risk rising correspondingly:
- HR=2.36 (95% CI, 1.97-2.83) for HbA1c ≤6.9% (≤52 mmol/mole);
- HR=2.38 (95% CI, 2.02-2.8) for HbA1c 7% to 7.8% (53-62 mmol/mole);
- HR=3.11 (95% CI, 2.66-3.62) for HbA1c 7.9% to 8.7% (63-72 mmol/mole);
- HR=3.65 (95% CI, 3.11-4.3) for HbA1c 8.8% to 9.6% (73-82 mmol/mole);
- HR=8.51 (95% CI, 7.24-10.01) for HbA1c ≥9.7% (≥83 mmol/mole).
HRs for death from CV causes corresponding to HbA1c levels were: 2.92 (95% CI; 2.07-4.13); 3.39 (95% CI, 2.49-4.61); 4.44 (95% CI, 3.32-5.96); 5.35 (95% CI, 3.94-7.26); and 10.46 (95% CI, 7.62-14.37).
Excess death due to CVD, diabetes
“It has been debated whether cancer is more common in patients with type 1 diabetes; in this study, we found no increased risk of cancer death due to type 1 diabetes, but the excess risk of mortality was principally due to increased CV disease mortality and diabetes-related death,” Lind said.
A clear excess risk for mortality was observed in patients with type 1 diabetes and without microalbuminuria, contrary to earlier smaller studies, according to Lind. Those investigations were generally not population-based and lacked adjustments for background CVD risks and educational levels in the general population, he said.
The size of this study, Lind said, further allowed quantification of excess mortality for patients with severe renal complications (stage 5). “We found 30 to 40 times increased risk of mortality in this patient group.”
Although CVD death was common, hypoglycemia and ketoacidosis were common causes of death in individuals younger than 40 years and represented more than one-third of deaths in individuals younger than 30 years, Lind said.
Reducing risk
With sparse epidemiologic data on the excess risk of mortality and CVD associated with type 1 diabetes, along with its relationship with glycemic control, relative to type 2, addressing this gap in knowledge is critical, Mikhail Kosiborod, MD, of the University of Missouri–Kansas City School of Medicine and Saint Luke’s Mid America Heart Institute, told Endocrine Today.
Mikhail Kosiborod
“The prevalence of type 1 diabetes is increasing, with as many as 3 million patients in the US alone,” Kosiborod, another investigator for the study, said.
“While we know that CVD is the No. 1 cause of mortality and morbidity in patients with type 1 diabetes, what is less clear is the exact magnitude of the difference in risk of mortality and CVD in patients with type 1 diabetes as compared with the general population; whether and to what extent good glycemic control mitigates this risk; and whether the advances in management of type 1 diabetes have had an impact on reducing the risk gap between type 1 diabetes and the general population over time,” he said.
The examination of data from the Swedish National Diabetes Register provided an ideal opportunity to address these critically important questions, Kosiborod said.
Further research needed
Because the mechanisms of capturing detailed information on demographic, clinical and treatment characteristics and outcomes of patients with type 1 diabetes on a national scale do not exist in the United States, it is not currently feasible to conduct large epidemiologic studies similar to the Swedish one, Kosiborod said.
“Efforts are currently ongoing to create an infrastructure that could be used to collect prospective data on a large cohort of patients with type 1 diabetes in the US, such as the Type 1 Diabetes Exchange,” he said.
Although this observational study provides statistical associations rather than cause-and-effect relationships, Kosiborod said their findings suggest that glycemic control is imperative in this patient population to prevent diabetes complications.
“Maximizing efforts to optimize glycemic control in type 1 diabetes is of major importance, not just based on this study, but also on the findings of prior clinical trials, such as the Diabetes Control and Complications Trial (DCCT) and the Epidemiology of Diabetes Interventions and Complications (EDIC) study,” Kosiborod said.
With results from the Sweden registry showing even patients with optimal glucose control still at increased risk for CV events, Kosiborod underscored that further research is needed to better understand what factors beyond blood glucose may be adversely influencing outcomes in type 1 diabetes.
“More research investment in this patient population is critical,” Kosiborod said. “We once again demonstrate that renal disease is a major driver of poor outcomes in type 1 diabetes and therefore prevention of renal complications of type 1 diabetes is very important.” – by Allegra Tiver
For more information:
Mikhail Kosiborod, MD, can be reached mikhail.kosiborod@gmail.com.
Marcus Lind, MD, PhD, can be reached at the Department of Medicine, Uddevalla Hospital, 451 80 Uddevalla, Sweden; email: lind.marcus@telia.com.
Disclosure: Please see the study for a full list of researchers’ financial disclosures.
Perspective
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Luigi Meneghini, MD, MBA
The study published by Lind et al in the NEJM adds to our understanding of the morbidity and mortality associated with type 1 diabetes. This observational study based on a large, robust diabetes registry presents data that demonstrate an association between having type 1 diabetes and being at increased risk for dying, compared with the general population (matched for age and gender). While even subjects with well-controlled HbA1C (<6.9%) had an increased risk for death from cardiovascular events or “any cause,” patients with higher mean HbA1C had an even greater risk for dying. Interestingly, there was no increased risk for cancer death in subjects with diabetes compared with controls. The presence of renal disease (nephropathy) considerably increased mortality risk, and that risk was even higher with elevated HbA1C levels. In younger people (<30 years old) diabetic ketoacidosis and hypoglycemia accounted for more than 30% of the mortality.
The conclusions from this data are as follows:
1. Having type 1 diabetes is associated with a higher risk for dying (CV and all-cause) compared with the general population;
2. In people with type 1 diabetes, a lower HbA1C is associated with a lower mortality risk compared with those with a higher HbA1C;
3. Having kidney disease greatly increases the mortality risk.
It would have been very interesting to also evaluate whether there was an association between mortality from hypoglycemia and mean HbA1C levels, especially in the younger patient population where CV mortality was very low.
Finally, the title of the article and the abstract conclusion could confuse the inattentive reader, who might interpret the general message as being that lower HbA1C levels are associated with higher mortality risk; this is definitely not the case when comparing people with type 1 diabetes having higher HbA1C levels.
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