Excess mortality in Finnish diabetic subjects due to alcohol, accidents and suicide: a nationwide study

Introduction

Patients with diabetes mellitus are known to have markedly higher mortality attributable to cardiovascular diseases, cancer and renal causes, whereas the mental strain imposed by chronic diseases and substance abuse as well as accidental causes of excess mortality have attracted relatively little attention.

In particular, diabetic patients treated with daily injections of insulin have a heavy, unremitting burden: how they eat, move and sleep affect plasma glucose levels. Miscalculation or omission in terms of self-care exposes the patient to hypoglycemia, and consequent neuroglycopenic symptoms up to the loss of consciousness may increase the risk of accidental death. Mental symptoms and diseases such as depression and suicidal ideation are common among diabetic patients (1, 2, 3). However, in cases of type 2 diabetes, the relationship with depression may be bidirectional: depression increases the risk of diabetes (4) and the concomitant depression hampers its treatment via multiple mechanisms (2). It was found in a recent meta-analysis (5) and a national cohort study from Sweden (6) that diabetic subjects showed a significantly increased risk of suicide, especially those with insulin-deficient (type 1) diabetes.

Excess alcohol consumption is a major contributor to the burden of diseases and to mortality, and it is associated with an increased risk of accidental and suicidal causes of death (7). Among diabetic patients, it is also associated with an increased risk of severe hypoglycemia (8). Suicide, alcohol-related and accidental causes of death are often interwoven and therefore their simultaneous assessment gives a broader view on the fatality burden associated with diabetes.

For this report, we analyzed mortality attributable to alcohol-related causes, accidents and suicide in a large national cohort including all insulin-treated diabetic patients and a 50% random sample of those treated with OAD, as well as a matched control group from the general population.

Subjects and methods

Results

The study population consisted of 434 629 individuals: 226 372 men and 208 257 women (Table 1). The diabetes population comprised 208 148 subjects, of whom 76% were treated only with OAD. The mean follow-up time was 7.1 years. We observed 2832 deaths attributable to alcohol-related causes (1981 in the diabetic subjects), 3187 from accidents (1707 in the diabetic subjects) and 853 from suicide (499 in the diabetic subjects) (Table 2). The most frequent alcohol-related cause of death was alcoholic cirrhosis of the liver (ICD 10 K70.3; 45% of all deaths). There were no substantial differences between the diabetes treatment groups in this regard (Supplementary Table 1, see section on supplementary data given at the end of this article). The most frequent accidental cause of death (36%) was a fall on some level from slipping, tripping or stumbling (W01; Supplementary Table 2). The most frequent cause of death by suicide was intentional self-harm by hanging, strangulation or suffocation (X70), accounting for 30% of all deaths (Supplementary Table 3). The second most frequent suicide method (17%) was intentional self-poisoning by antiepileptic, sedative-hypnotic, antiparkinsonism and psychotropic drugs, not elsewhere classified (X61). Diabetic individuals were more likely to use this suicide method.

The unadjusted and adjusted analyses revealed consistently higher alcohol-related mortality among diabetic patients in all treatment groups and in both genders (Table 2). Although the mortality rates in this category were lower among the women than among the men, the unadjusted and adjusted MRRs were higher among the women (from 2.10 to 10.60 vs from 1.68 to 6.92 among the men). With regard to accidents, the adjusted MRRs were higher among men and women in the insulin-treated group (2.06 for men and 1.53 for women treated with insulin only; 2.42 for women treated with OAD + insulin). Suicide mortality was substantially lower among women than among men (MRR: 0.35, 95% CI: 0.30–0.41). Men with diabetes treated with OAD faced a similar suicide risk as men without diabetes, whereas the risk was somewhat higher among men taking OAD + insulin (adjusted MRR: 1.68; 1.00, 2.82 of borderline significance), and markedly higher in the insulin-only treatment group (MRR: 2.10; 1.60, 2.75). There was a higher suicide risk among diabetic women (MRR: 1.62; 1.21, 2.17) in the OAD-only group and among those taking OAD + insulin (4.49; 1.95, 10.31). However, the increased risk in the insulin-only group attenuated to a non-significant level after adjustment (1.49; 0.89, 2.50), as well as in the case-cohort setting.

In general, the results from the cohort study and the case-cohort study were similar (Table 2). The largest difference was between the MRRs and the ORs among the insulin-only group in the case of alcohol-related deaths. The odds ratio in the case-control study was about double that in the cohort study. The probable interpretation is that a recent (during the previous year) diabetes status is clearly a better predictor of mortality than diabetes at baseline (further back in the patient’s medical history).

We evaluated changes in mortality across the follow-up time using Aalen’s regression model. The only clear time-dependent effect of diabetes was in alcohol-related mortality among men (Fig. 1): mortality increased more quickly in the insulin-only group than in the other treatment groups. Aalen’s regression reveals any differences in incidence rates in relation to the follow-up time.

Alcohol-related mortality among men; cumulative regression coefficients with 95% confidence intervals based on Aalen’s model: only OAD (continuous line), OAD and insulin (dashes), only insulin (dots) compared to the reference group. Adjusted for age, calendar period, cancer and statin usage.

Citation: European Journal of Endocrinology 179, 5; 10.1530/EJE-18-0351

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Alcohol-related mortality among men; cumulative regression coefficients with 95% confidence intervals based on Aalen’s model: only OAD (continuous line), OAD and insulin (dashes), only insulin (dots) compared to the reference group. Adjusted for age, calendar period, cancer and statin usage.

Citation: European Journal of Endocrinology 179, 5; 10.1530/EJE-18-0351

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Alcohol-related mortality among men; cumulative regression coefficients with 95% confidence intervals based on Aalen’s model: only OAD (continuous line), OAD and insulin (dashes), only insulin (dots) compared to the reference group. Adjusted for age, calendar period, cancer and statin usage.

Citation: European Journal of Endocrinology 179, 5; 10.1530/EJE-18-0351

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Discussion

The risk of suicide, and alcohol-related and accidental death was elevated in this nationwide cohort among diabetic subjects compared with their matched controls. In particular, male diabetic subjects and those treated with insulin were at the highest risk, but in the case of alcohol-related deaths, female subjects with diabetes showed excess mortality regardless of treatment modality.

Suicide is not an uncommon cause of death globally, affecting about one million people annually. Chronic major diseases such as diabetes predispose to mental-health problems, but psychiatric illness as clinical comorbidity has received relatively little attention in guidelines on diabetes treatment (19). Studies assessing the risk of suicide among diabetic individuals have yielded controversial findings. It was found in a recent comprehensive systematic review and meta-analysis that the overall risk of suicide was markedly increased among diabetic individuals (RR: 16; 95% CI: 1.29–1.89) and was especially pronounced in patients with type 1 diabetes (RR: 2.25; 95% CI: 1.50–3.38) (5). The risk among those with type 2 diabetes appeared to be increased (RR: 1.65; 95% CI: 0.95–2.85), but this estimate was based on quite a small number of subjects, and a further problem was the apparent misclassification of intoxication and drug poisoning. Thus, suicide risk among diabetes patients is probably underestimated, and more large-scale population-based studies are needed.

Intentional overdoses of insulin may underlie acute admissions for severe hypoglycemia of ‘unknown’ etiology, and this may also lead to the underestimation of suicide as a cause of death among patients with diabetes (20). However, the majority of suicides among the diabetic subjects in this study were attributable to psychotrophic drugs, as in the Swedish study (6) in which the use of insulin or hypoglycemic agents was identified as contributing to suicide in nine per cent of the cases. Nevertheless, according to the above-mentioned meta-analysis (5), the incidence ratio of suicide among diabetics was 2.85 per 10 000 person-years, on the basis of which it is estimated that globally there are about 94 000 suicides each year among diabetic individuals. In our study, female patients treated with OAD emerged as a risk group in terms of suicide. Although this finding is somewhat difficult to explain, diabetes-related distress is particularly pronounced among females with type 2 diabetes, and the relationship between depression and type 2 diabetes is bidirectional (3).

A high proportion of alcohol- and drug-related deaths was found in a nationwide Finnish study comprising a large cohort of patients with type 1 diabetes (diagnosed before the age of 30 years) (21). One in four deaths was associated with alcohol use or drugs in an early-onset cohort (diagnosis at the age of 0–14 years). In a late-onset cohort (diagnosis at the age of 15–29 years); however, there was a conspicuous increase in such deaths among those diagnosed after 1985. The standardized mortality ratio for alcohol-related deaths was 1.5, and alcohol use or drugs accounted for 39% of the deaths (21). Furthermore, the standardized mortality ratio for ischemic heart disease was up to 17.4 (12.6–22.1) in the early-onset cohort, which is attributable to the rare occurrence of death from ischemic heart disease among young people in the general population (21).

Heavy drinking is associated with clinical depression (22). About 25% of patients with type 1 diabetes investigated in a large Finnish survey were moderate or heavy consumers of alcohol, and they also showed a higher frequency of microvascular diabetic complications (23). Not only does excessive alcohol consumption negatively affect diabetes self-care adherence, it also affects the course of the illness and increases the risk of severe hypoglycemia via multiple mechanisms. Alcohol consumption among patients with diabetes is frequently inadequately assessed in the first place, and neglected thereafter in everyday medical care (8).Validated brief interventions to reduce risky drinking are available and offer the potential to improve adherence to diabetes treatment, and thereby probably the outcome as well (24). Accidental causes of death were likewise higher among the diabetic patients in our study. One obvious explanation is treatment-related hypoglycemia, and hypoglycemia is known to increase the risk of accidents. Other causes may have included microvascular or macrovascular complications, which predispose to accidents via multiple mechanisms, including impaired vision, gait unsteadiness, tiredness and cardiac problems. However, we could not assess the role of complications in this study. As discussed, some accidental deaths may also be suicides.

The strengths of this study include the large nationwide sample and the assessment of three groups of causes of death, which are usually overshadowed by an emphasis on cardiovascular and diabetic complications. Studies on mortality among diabetic individuals should be population-based. In many countries, however, the information on death certificates does not allow the identification of patients with diabetes, especially with type 2 diabetes (25).

On the other hand, among the weaknesses of our study is the lack of access to information on the use of antidepressant and other psychoactive drugs among the participants. It has been shown previously that the use of antidepressants is associated with a lowered (26) risk of death from suicide in the general population. It was found among a large cohort of patients with type 1 diabetes in which purchases of antidepressants were used as a marker of depression (27) that about eight per cent of the patients had bought them. Additional cases were observed during the follow-up increasing the percentage to 18, and in the adjusted Cox’s regression models, the purchase of antidepressants at baseline was associated with mortality among women, but not among men. Among those purchasing antidepressants, chronic diabetic complications were the most frequent underlying cause of death and only a small minority was suicides. The men in our study had a higher risk for every accidental cause of death, and it is conceivable that those seeking professional help for depression or other mental disorder are more problematic. We adjusted for the use of statins and HRT because these medications are suspected risk factors for cancer (9) (the original end-point of the CARING study), and the information was obtainable from the SII database. In addition, their use is indicative of health-service patronage, and probably of health awareness in general, related in part to socioeconomic status.

Another weakness of our study is that we could only assess the type of diabetes in accordance with the type of therapy. However, those treated only with insulin comprise type 1 diabetics and some long-term type 2 patients whose disease could be classified as insulin-requiring, and the demarcation between the types of diabetes in individual cases may also be rather arbitrary in clinical practice. A third problem is that we were not able to assess socioeconomic status or the presence of diabetic complications, or their contributions to the increased mortality. Finally, the follow-up was relatively short.

To conclude, we found in this large nationwide cohort that patients with diabetes have higher mortality attributable to suicide, alcohol-related causes and accidents than the rest of the population and that this premature mortality is associated with insulin use, which reflects the severity of the illness. This effect was most consistent among diabetic men, but in cases of alcohol-related death female diabetic patients showed excess mortality regardless of treatment modality. These findings underscore the importance of effective psychosocial support and interventions in diabetes, especially among high-risk individuals.

Supplementary data

This is linked to the online version of the paper at https://doi.org/10.1530/EJE-18-0351.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this study.

Author contribution statement

All the authors have made substantial contributions: conception and design (all), data acquisition and analysis (J H, A A), data interpretation (all). They all participated in drafting the article or revising it critically for important intellectual content, and all have approved the final version.

Acknowledgements

The authors would like to thank the CARING study (EU grant agreement number 282526) group for their co-operation during the project (28) that made these data available to the authors (A A and J H are members of the CARING group).