Life expectancy in a large cohort of type 2 diabetes patients treated in primary care (ZODIAC-10).
ABSTRACT Most longitudinal studies showed increased relative mortality in individuals with type 2 diabetes mellitus until now. As a result of major changes in treatment regimes over the past years, with more stringent goals for metabolic control and cardiovascular risk management, improvement of life expectancy should be expected. In our study, we aimed to assess present-day life expectancy of type 2 diabetes patients in an ongoing cohort study.
We included 973 primary care type 2 diabetes patients in a prospective cohort study, who were all participating in a shared care project in The Netherlands. Vital status was assessed from May 2001 till May 2007. Main outcome measurement was life expectancy assessed by transforming actual survival time to standardised survival time allowing adjustment for the baseline mortality rate of the general population. At baseline, mean age was 66 years, mean HbA(1c) 7.0%. During a median follow-up of 5.4 years, 165 patients died (78 from cardiovascular causes), and 17 patients were lost to follow-up. There were no differences in life expectancy in subjects with type 2 diabetes compared to life expectancy in the general population. In multivariate Cox regression analyses, concentrating on the endpoints 'all-cause' and cardiovascular mortality, a history of cardiovascular disease: hazard ratio (HR) 1.71 (95% confidence interval (CI) 1.23-2.37), and HR 2.59 (95% CI 1.56-4.28); and albuminuria: HR 1.72 (95% CI 1.26-2.35), and HR 1.83 (95% CI 1.17-2.89), respectively, were significant predictors, whereas smoking, HbA(1c), systolic blood pressure and diabetes duration were not.
This study shows a normal life expectancy in a cohort of subjects with type 2 diabetes patients in primary care when compared to the general population. A history of cardiovascular disease and albuminuria, however, increased the risk of a reduction of life expectancy. These results show that, in a shared care environment, a normal life expectancy is achievable in type 2 diabetes patients.
- [show abstract] [hide abstract]
ABSTRACT: Recent studies indicate that the prevalence of type 2 diabetes mellitus is increasing in the United States; less is known about trends in the incidence of type 2 diabetes mellitus. Participants free of diabetes mellitus (n=3104; mean age 47 years; 1587 women) from the Framingham Offspring Study who attended a routine examination in the 1970s, 1980s, or 1990s were followed up for the 8-year incidence of diabetes mellitus. Diabetes was defined as a fasting plasma glucose > or = 7.0 mmol/L or treatment with either insulin or a hypoglycemic agent. Pooled logistic regression was used to compare diabetes incidence across decades for participants between 40 and 55 years of age in each decade. The age-adjusted 8-year incidence rate of diabetes was 2.0%, 3.0%, and 3.7% among women and 2.7%, 3.6%, and 5.8% among men in the 1970s, 1980s, and 1990s, respectively. Compared with the 1970s, the age- and sex-adjusted odds ratio (OR) for diabetes was 1.40 (95% confidence interval [CI], 0.89 to 2.22) in the 1980s and 2.05 (95% CI, 1.33 to 3.14) in the 1990s (P for trend=0.0006). Among women, the OR was 1.50 (95% CI, 0.75 to 2.98) in the 1980s and 1.84 (95% CI, 0.95 to 3.55) in the 1990s (P for trend=0.07) compared with the 1970s, whereas among men, the OR was 1.33 (95% CI, 0.72 to 2.47) in the 1980s and 2.21 (95% CI, 1.25 to 3.90) in the 1990s (P for trend=0.003). Most of the increase in absolute incidence of diabetes occurred in individuals with body mass index > or = 30 kg/m2 (P for trend=0.03). In the present community-based sample of middle-aged adults, we observed a doubling in the incidence of type 2 diabetes over the last 30 years. Careful surveillance of changes in diabetes incidence may be necessary if current trends of excess adiposity continue.Circulation 06/2006; 113(25):2914-8. · 15.20 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Diabetes mellitus is a recognized risk factor for cardiovascular disease (CVD) and mortality. However, limited information exists on the association of diabetes with life expectancy with and without CVD. We aimed to calculate the association of diabetes after age 50 years with life expectancy and the number of years lived with and without CVD. Using data from the Framingham Heart Study, we built life tables to calculate the associations of having diabetes with life expectancy and years lived with and without CVD among populations 50 years and older. For the life table calculations, we used hazard ratios for 3 transitions (healthy to death, healthy to CVD, and CVD to death), stratifying by the presence of diabetes at baseline and adjusting for age and confounders. Having diabetes significantly increased the risk of developing CVD (hazard ratio, 2.5 for women and 2.4 for men) and of dying when CVD was present (hazard ratio, 2.2 for women and 1.7 for men). Diabetic men and women 50 years and older lived on average 7.5 (95% confidence interval, 5.5-9.5) and 8.2 (95% confidence interval, 6.1-10.4) years less than their nondiabetic equivalents. The differences in life expectancy free of CVD were 7.8 and 8.4 years, respectively. The increase in the risk of CVD and mortality from diabetes represents an important decrease in life expectancy and life expectancy free of CVD. Prevention of diabetes is a fundamental task facing today's society in the pursuit of healthy aging.Archives of Internal Medicine 07/2007; 167(11):1145-51. · 11.46 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: The prognosis of a patient with Type 2 (non-insulin-dependent) diabetes mellitus varies considerably from one individual to another. The reasons for the variability in the individual prognoses include (1)the possibility that Type 2 diabetes in a given patient represents a clinically inconsequential metabolic disorder without any sequelae for length and quality of life; (2) the occurrence of severe, life-shortening vascular complications in association with Type 2 diabetes; and (3) the development of acute life-threatening events such as (hyperosomolar or ketoacidotic) coma or iatrogenic complications, e.g. hypoglycaemia. As with other chronic diseases, generalisations of the prognoses of Type 2 diabetes by means of mortality and survival statistics are of limited predictive value for individual outcomes. However, knowledge about its course and natural history characterises the impact of the disease on public health, thus forming an essential basis for improved prevention and therapy strategies.Diabetologia 04/1987; 30(3):123-31. · 6.49 Impact Factor
Life Expectancy in a Large Cohort of Type 2 Diabetes
Patients Treated in Primary Care (ZODIAC-10)
Helen L. Lutgers1., Esther G. Gerrits2.*, Wim J. Sluiter3, Lielith J. Ubink-Veltmaat4, Gijs W. D. Landman2,
Thera P. Links3,5, Reinold O. B. Gans1,5, Andries J. Smit1,5, Henk J. G. Bilo1,2,5
1Department of Internal Medicine, University Medical Center Groningen, Groningen, the Netherlands, 2Diabetes Center, Isala Clinics, Zwolle, the Netherlands,
3Department of Endocrinology, University Medical Center Groningen, Groningen, the Netherlands, 4Family practice’t Veen, Hattem, the Netherlands, 5Department of
Medicine, University of Groningen, Groningen, the Netherlands
Background: Most longitudinal studies showed increased relative mortality in individuals with type 2 diabetes mellitus until
now. As a result of major changes in treatment regimes over the past years, with more stringent goals for metabolic control
and cardiovascular risk management, improvement of life expectancy should be expected. In our study, we aimed to assess
present-day life expectancy of type 2 diabetes patients in an ongoing cohort study.
Methodology and Principal Findings: We included 973 primary care type 2 diabetes patients in a prospective cohort study,
who were all participating in a shared care project in The Netherlands. Vital status was assessed from May 2001 till May
2007. Main outcome measurement was life expectancy assessed by transforming actual survival time to standardised
survival time allowing adjustment for the baseline mortality rate of the general population. At baseline, mean age was 66
years, mean HbA1c7.0%. During a median follow-up of 5.4 years, 165 patients died (78 from cardiovascular causes), and 17
patients were lost to follow-up. There were no differences in life expectancy in subjects with type 2 diabetes compared to
life expectancy in the general population. In multivariate Cox regression analyses, concentrating on the endpoints ‘all-cause’
and cardiovascular mortality, a history of cardiovascular disease: hazard ratio (HR) 1.71 (95% confidence interval (CI) 1.23–
2.37), and HR 2.59 (95% CI 1.56–4.28); and albuminuria: HR 1.72 (95% CI 1.26–2.35), and HR 1.83 (95% CI 1.17–2.89),
respectively, were significant predictors, whereas smoking, HbA1c, systolic blood pressure and diabetes duration were not.
Conclusions: This study shows a normal life expectancy in a cohort of subjects with type 2 diabetes patients in primary care
when compared to the general population. A history of cardiovascular disease and albuminuria, however, increased the risk
of a reduction of life expectancy. These results show that, in a shared care environment, a normal life expectancy is
achievable in type 2 diabetes patients.
Citation: Lutgers HL, Gerrits EG, Sluiter WJ, Ubink-Veltmaat LJ, Landman GWD, et al. (2009) Life Expectancy in a Large Cohort of Type 2 Diabetes Patients Treated
in Primary Care (ZODIAC-10). PLoS ONE 4(8): e6817. doi:10.1371/journal.pone.0006817
Editor: Thorkild I. A. Sorensen, Institute of Preventive Medicine, Copenhagen University Hospital, Denmark
Received October 2, 2008; Accepted July 22, 2009; Published August 28, 2009
Copyright: ? 2009 Lutgers et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This study was supported by a grant from the Dutch Diabetes Research Foundation (project 2000.00.06) and the Medical Research Foundation Zwolle.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: firstname.lastname@example.org
. These authors contributed equally to this work.
The incidence and prevalence of diabetes mellitus has risen
worldwide duringthepastfewdecades.Recentlypublished data from
the Framingham Heart Study showed an absolute increase in the
incidence of diabetes of ,2.5% yearly during the 1990s compared to
the 1970s . The proportion of cardiovascular disease attributable
to diabetes mellitus has increased as well . Other studies over the
last decades of the previous century also showed higher mortality
rates in diabetes mellitus compared to the general population, mostly
due to cardiovascular events [3–7]. However, since the progress in
effective pharmaceutical interventions and more stringent regimens
for the treatment of hyperglycemia, hypertension, dyslipidemia, and
other cardiovascular risk factors, trends towards a reduction of
(cardiovascular) mortality rates amongst diabetic patients have been
reported [8–12]. This improvement of survival was hoped to
eventually be comparable to the decrease in cardiovascular mortality
rates in the general population thanks to aggressive management of
cardiovascular risk factors.
Most published data were extracted from representative
national cohorts in North-America or the United Kingdom. Some
reports showed a decline in mortality rates amongst diabetic men
only, whereas women showed an increase or no change in
mortality rates at all [4,8,11,12]. A recently published Scandina-
vian study showed a substantial decrease in mortality rates from
coronary heart disease in all age groups irrespective of sex and
diabetes status over two consecutive time periods. However, the
more than twofold higher mortality from coronary heart disease in
diabetes patients compared to the non-diabetic population
remained over time. Still, these findings suggested a longer
survival in diabetes patients resulting from intensified treatment of
cardiovascular risk factors .
PLoS ONE | www.plosone.org1August 2009 | Volume 4 | Issue 8 | e6817
Our aim was to investigate present-day life expectancy in a type
2 diabetes population treated in primary care, with additional
support both for patients and health care professionals in a shared
care setting in a Western European country.
In 2001, 973 type 2 diabetes patients participated in a cross-
sectional study with measurements of skin advanced glycation
endproduct (AGE) accumulation as described previously . This
study was embedded in a long-term shared care project (ZODIAC:
Zwolle Outpatient Diabetes project Integrating Available Care)
concerning a primary care treated population-based sample of type
shows an overview of the enrolment of the current study cohort
started from the beginning of the ZODIAC. During this project, 32
general practitioners (GPs) were supported by hospital diabetes
specialist nurses and consultant-physicians . In short, all type 2
diabetes patients were exclusively treated by their GPs and visited
the diabetes specialist nurses for evaluation of metabolic control and
diabetes related complications annually. After these evaluations,
treatment advice for individual patients as well as for benchmarking
was given to the GPs by internists in the Isala Clinics in Zwolle, the
Netherlands. Advices and referrals were based on guidelines of the
Dutch College of General Practitioners .
Patients with a cognitive disability or terminal disease were not
included in the ZODIAC study because of their inability to
undergo educational programs. Furthermore, patients who were
physically unable to visit the diabetes specialist nurse at the
outpatient clinic were not enclosed in the present cohort.
This study was approved by the local ethical committee of the
Isala Clinics, Zwolle, The Netherlands and all patients gave
written informed consent.
Description of Procedures
Methods of clinical data collection and laboratory assessments
have beendescribed in detail elsewhere . Before participation in
our study, based on the 1997 ADA guidelines and the Dutch
primary care standard , diagnosis of diabetes mellitus was
already made in individuals with fasting plasma glucose levels
$7.0 mmol/liter and the following definitions representing diabetic
complications at baseline were: retinopathy, which was defined as
the presence of at least background retinopathy or a history of laser
coagulation for diabetic retinopathy. Albuminuria was defined as an
.2.5 mg/mmol for men. Diminished sensibility at least at one foot
was considered as neuropathy, tested with a 5.07 Semmes-
Weinstein monofilament, applied on three areas of each foot. The
presence of microvascular disease was defined as meeting the
criteria of retinopathy, albuminuria, and/or neuropathy. The
presence of cardiovascular disease at baseline was defined when
meeting at least one aspect of cardiovascular disease: ischemic heart
disease (IHD), International Classification of Diseases ninth revision
(ICD-9), codes 410–414 and/or a history of coronary artery bypass
surgery or percutaneous coronary intervention, cerebrovascular
accidents including transient ischemic attacks (CVAs/TIAs) and/or
peripheral vascular disease (PVD). PVD was defined as surgical
intervention, history of claudication and/or absent pulsations of
ankle or foot arteries (absence of pulsations of the dorsalis pedis
Figure 1. Flowchart of the enrolment of the type 2 diabetes study cohort from 32 general practitioners of a district in The
Life Expectancy in Diabetes
PLoS ONE | www.plosone.org2 August 2009 | Volume 4 | Issue 8 | e6817
arteries bilaterally was not scored as PVD when tibial posterior
artery pulsations were present).
Mortality was registered from the date of inclusion until May
2007. Death was certified according to the following procedure. In
addition to the list of deceased patients reported in the files of the
scheduled annual follow-up visits, survival status of the patients
was obtained from the local hospital information system and
verified with the GPs. Date of death was collected likewise. None
of the GPs had involvement or interest in study outcome. Causes
of death were coded according to ICD–9 and categorised as:
neoplasms (140–239), diseases of the cardiovascular system (390–
459), diseases of the respiratory system (460–519), diseases of the
digestive system (520–579), diseases of the genitourinary system
(580–629), injury and poisoning (800–999). Sudden death, with
symptoms present for less than one hour, was encoded in the
category of coronary heart disease. For the in-hospital deaths, the
medical records were retrieved. For the out-of-hospital deceased
patients, the assigned causes of death by the GPs were obtained
from the medical records of the GPs. The coded causes of death
were combined to all-cause mortality (all codes) and cardiovascular
mortality (390–459 or sudden death).
Life expectancy analysis was performed primarily by the use of
‘standardised survival time’ (SST), which is a novel approach to
survival analysis . SST is another expression of follow-up time
than survival time in years. This method provides survival time,
which is adjusted for the median residual life span of individuals in
the general population with the same age and sex. Due to this
standardisation of survival time there is no influence of the
Table 1. Baseline characteristics of type 2 diabetes patients: total and subdivided in survivors and non-survivors expressed as
mean6SD or n (%).
CharacteristicTotal (N=973)Survivors (N=791)Non-survivors (N=165) p-value
Age in years66.4 (11.3)64.8 (11.1) 73.6 (9.4)
Male gender (%)4746.350.9 0.278
Body mass index in kg/m2
29.38 (4.87) 29.5 (4.8)28.7 (5.1)0.077
Systolic blood pressure in mmHg 146.01 (20.15)145 (20)149 (20) 0.015
Diastolic blood pressure in mmHg81.18 (10.34) 81 (10)80 (11) 0.046
Diabetes duration in years
Creatinine in mmol/l
6.96 (1.3)6.95 (1.32)6.998 (1.23) 0.69
96.0 (19.88) 94.56 (17.6)103.16 (27.69)
Creatinine clearance in ml/min 76.13 (26.91)78.8 (26.6)63.22 (24.75)
Urinary albumin-to-creatinine ratio in mg/mmol
a3.09 (1.23–11.01) 0.001
Total cholesterol in mmol/l. 5.16 (1.01) 5.17 (1.02)5.08 (1.00) 0.302
Cholesterol-to-HDL ratio4.34 (1.23) 4.37 (1.21)4.22 (1.36) 0.171
HDL cholesterol in mmol/l 1.25 (0.33)1.24 (0.32)1.29 (0.35)0.141
LDL cholesterol in mmol/l 2.87 (0.93)2.85 (0.92)2.92 (0.98)0.388
Triglycerides in mmol/l 2.32 (1.36)2.39 (1.40) 2.03 (1.14) 0.002
Microvascular disease (%)54.150.2 70.9
Retinopathy (%)19.6 18.524.80.050
Neuropathy (%)29.1 2640.6
Cardiovascular disease (%)39.534.6 63.6
Ischemic heart disease (%)21.519.6 30.30.002
Cerebrovascular disease (%)7.86.414.5
Peripheral vascular disease (%)23.0 18.147.3
Antiplatelet drugs (%) 24.922.138.2
Diabetes treatment – Diet only (%)20.221.416.4
Oral medication (%)64.164.3 63
Insulin (%) 9.88.315.8
Both (%) 18.104.22.168
Seven patients were lost to follow-up and did not define the baseline characteristics of the survivors/non-survivors.
aMedian and interquartile range.
bAngiotensin-converting enzyme inhibitors and Angiotensin II receptor blockers.
cLarge majority represented by statins (99%). Reference values of the laboratory: HbA1c4.0–6.0%, creatinine 70–110 mmol/l, creatinine clearance (Cockcroft-formula) 80–
120 ml/min, urinary albumin-to-creatinine ratio 0–2.5 for men and 0–3.5 for women, total cholesterol 3.5–5.0 mmol/l.
Life Expectancy in Diabetes
PLoS ONE | www.plosone.org3 August 2009 | Volume 4 | Issue 8 | e6817
interactions between age and the presence or effects of other risk
factors due to age. Furthermore, it allows assessment of the
effectiveness of treatment on regaining a normal residual life span.
SST was calculated as the ratio between the observed survival time
(follow-up time) of an individual and the median residual life span
of individuals with the same age and sex in the general population
at the starting date of the study. The median residual life span was
derived from gender specific reports provided by the Dutch
Central Office of Statistics, which is the national Dutch institution
of statistics and demographics . The SST at baseline is defined
as 0, and a SST ratio of 1 is defined as follow-up time
corresponding with the life expectancy of the general population.
Direct comparisons between study samples and the general
population were done by comparing the 95% confidence interval
(CI) of each median SST with an expected value of 1. The 95% CI
of mortality at a SST of 0.25 and 0.5 were calculated and
compared with the expected mortality as calculated for the age
and gender matched general population, assuming Poisson
distribution of the events. Kaplan-Meier curves were constructed
for survival and for standardised survival. A Cox proportional
hazard model to estimate hazard ratios (HR) and 95% CI was
used in the standard way using survival time in years, and
additionally by using SST. Methodologically, it is allowed to use
SST instead of survival time in years in a Cox-regression model, as
it is consistent with the preconditions of a Cox regression analysis:
an increase in mortality and an increase in follow-up time have to
be present. This new statistical approach underlines the prognostic
value of the mentioned risk factors, irrespective of age and sex.
Eliminating the effects of age and sex excludes the influence of
disease-specific risk of age and sex in the standardised analysis. P
values ,0.05 were considered to be statistically significant.
Clinical and laboratory variables with an expected effect on
mortality risk were first analysed in a univariate analysis, and
secondly, in a multivariate model. Detailed analyses were
performed specifically for two end-points: all-cause mortality and
Characteristics of the 973 type 2 diabetes patients at baseline
(2001) are shown in Table 1. The population had a relatively short
median diabetes duration of 4.2 (interquartile range 1.6–8.3) years
and on average an acceptable to good glycemic control (mean
HbA1c7.0%). Table 1 also shows the baseline characteristics of
patients when subdivided in survivors (791 patients) and non-
survivors. At the end of a median follow-up duration of 5.4 years
(interquartile range 5.1–5.6), 165 patients had died (17%); 17
patients were lost to follow-up. Minimum follow-up duration of all
survivors was 5.0 years. Ten of the lost to follow-up persons had a
last visit to the outpatient clinic between baseline and the end of
follow-up; this last registered visit date was defined as the end of
follow-up for these patients. The remaining 7 persons lost to
follow-up had a mean age of 68 years, were non-smokers, and 2
patients had cardiovascular disease at baseline. Their median
diabetes duration was 9.7 years with a mean HbA1cof 7.5%.
The proportion of prescribed lipid-lowering drugs, renin-
angiotensin system (RAS) inhibitors and antiplatelet therapy at
baseline, is shown at the end of Table 1. At baseline, antiplatelet
drugs were significantly more prescribed in the non-survivors
compared to the survivors. The proportion of cardiovascular
deaths in the study population (47%) was increased compared to
the general population. In 2007, 31% of all deaths in the general
Dutch population were due to cardiovascular disease, with a
highest relative incidence of 38% cardiovascular deaths in the
population above 85 years .
Figure 2 shows the Kaplan-Meier curve of the cumulative
proportion of survivors in our type 2 diabetes population against
survival time in years. A Kaplan-Meier plot of the cumulative
proportion of deaths in our study population against standardised
survival time is shown in figure 3; the expected mortality for the
age- and gender-matched general population is also shown. The
Figure 2. Kaplan-Meier survival curve for survival in years in
the entire type 2 diabetes group.
Figure 3. Kaplan-Meier plot of the cumulative proportions of
deaths against Standardised Survival Time. Survival curve for
survival expressed as Standardised Survival Time (SST) in the entire type
2 diabetes group. The median SST in type 2 diabetes mellitus (T2DM)
1.00 is not different from the general Dutch population 1.00 (Expected);
the observed mortality (all-cause) at SST 0.25 and 0.50 of 0.09,
respectively 0.20 does not significantly differ from the general Dutch
population (0.08 respectively 0.18, p.0.1).
Life Expectancy in Diabetes
PLoS ONE | www.plosone.org4August 2009 | Volume 4 | Issue 8 | e6817
median standardised survival time in our study population was
1.00 [95% confidence interval (CI) 0.88–1.12] and did not differ
from the general population. The cumulative proportion of deaths
at half standardised survival time (SST=0.50) was 0.20 (95% CI
0.16–0.23), which again did not differ from the expected value of
0.18 in the general population.
Figure 4 shows the mortality rate in type 2 diabetes patients with
albuminuria at SST 0.25 of 0.15 (95% CI 0.10–0.19), which was
higher than the expected value of 0.076 (p=0.002). At SST 0.50
mortality rate was 0.26 (95% CI 0.19–0.33), which was also higher
than the expected value of 0.18 (p=0.014). This also proved to be
the case for type 2 diabetes patients with a history of
cardiovascular disease, who had a higher mortality at SST 0.25
[0.13 (95% CI 0.096–0.17), p,0.001] and at SST 0.50 [0.25 (95%
CI 0.19–0.30), p,0.0001], figure 5.
Table 2 shows the hazard ratios (HRs) and 95% CI of
univariate and multivariate Cox-regression analyses for all-cause
mortality. The HRs in the univariate analyses are higher for all
cardiovascular disease items compared to the method of using SST
in the model. In the multivariate analysis, predictive factors for all-
cause mortality were comparable for both methods when age and
gender were included in the model of the standard method: a
history of cardiovascular disease (HR 1.79 and 1.71) and,
albuminuria (HR 1.79 and 1.72). Univariate analysis of the
endpoint: cardiovascular mortality (not shown in Table 2) resulted
in the same significant predictive factors, but with higher HRs.
Multivariate analysis of cardiovascular mortality resulted in the
same significant predictive factors with higher HRs (SST) as well:
albuminuria 1.83 (95% CI 1.17–2.89); history of cardiovascular
disease 2.59 (95% CI 1.56–4.28). Smoking, systolic blood pressure,
diabetes duration and HbA1cdid not reach significance in both
This study shows a normal median overall life expectancy in a
defined cohort of type 2 diabetes patients treated in a primary care
setting, during a follow-up period from 2001 till 2007. This finding
strongly suggests that current available treatment strategies may
eventually lead to a life expectancy equal to the general population
in this subset of type 2 diabetes patients. Secondly, in this type 2
diabetes study population, patients with a history of cardiovascular
disease and/or the presence of albuminuria still had an increased
risk to die before their median life expectancy was reached. The
differences in effects of all items of cardiovascular disease on
‘survival in years’ and SST, could be explained by the age
correction enclosed in the SST – method. As the prevalence of
cardiovascular diseases is increasing with increasing age, SST does
have definite advantages compared to the ‘classical survival time’
in identifying premature mortality.
Finally, we still found an increased proportion of deaths due to
cardiovascular disease compared to the general population (47%
versus 31%). This is in agreement with established observations of
increased cardiovascular disease in diabetes, and also with the fact
that the presence of classical cardiovascular risk factors still is most
intimately related to life expectancy reduction [13,19].
The United Kingdom Prospective Diabetes Study reported a 5
years reduction of life expectancy for males aged 45 to 50 years at
diagnosis of diabetes when compared to the general United
Figure 5. Kaplan-Meier plot of the cumulative proportions of
deaths in patients with previous cardiovascular disease
against Standardised Survival Time. Cumulative proportions of
deaths (all causes) against Standardised Survival Time (SST) in type 2
diabetes patients with previous cardiovascular disease (CVD) yes/no
(+/2), compared to the expected deaths of the general population.
Differences in mortality between the type 2 diabetes-subgroups and
the general population are tested at SST=0.25 and SST=0.5. Mortality
rate at SST 0.25 is 0.13 (95% CI 0.096–0.17) and an expected value is
0.076, p,0.001. At SST 0.50 mortality rate is 0.25 (95% CI 0.19–0.30) and
the expected value is 0.18, p,0.0001.
Figure 4. Kaplan-Meier plot of the cumulative proportions of
deaths in patients with albuminuria against Standardised
Survival Time. Cumulative proportions of deaths (all causes) against
Standardised Survival Time (SST) in type 2 diabetes patients with
albuminuria (Alb) yes/no (+/2), compared to the expected deaths of
the general population. Differences in mortality between the type 2
diabetes-subgroups and the general population are tested at SST=0.25
and SST=0.5. Mortality rate at SST 0.25 is 0.15 [95% confidence interval
(CI) 0.10–0.19] and the expected value is 0.076 (p=0.002). At SST 0.50
mortality rate is 0.26 (95% CI 0.19–0.33), which was also higher than the
expected value of 0.18 (p=0.014).
Life Expectancy in Diabetes
PLoS ONE | www.plosone.org5 August 2009 | Volume 4 | Issue 8 | e6817
Kingdom population . Estimations of reduction of life
expectancy for patients with diabetes diagnosed at an older age
are not presented explicitly in this paper, but might be smaller
than 5 years, as other studies showed that reduction of life
expectancy decreases with diagnosis at older age [5,12,20].
A large study of the non institutionalised United States
population, which was conducted between 1971 and 1993,
showed a median reduced life expectancy of 8 years for the
diabetic population aged 55–64 years, and a 4 years reduction for
the diabetic population aged 65–74 years . However, these
studies were all executed in a period during which treatment with
statins, angiotensin-converting enzyme inhibitors and angiotensin-
1 receptor blockers, and antiplatelet medication was much less
common practice. A more recent study, showing slightly increased
mortality in women but no excess mortality in men, included
exclusively patients diagnosed with type 2 diabetes mellitus over
the age of 65 . Our study is of additional value, as we included
primary care type 2 diabetes patients of all ages, representing a
large amount of the type 2 diabetes patients in The Netherlands,
where the majority of subjects with type 2 diabetes is treated in
primary care according to national guidelines. Sixty-four percent
of our study population was diagnosed with type 2 diabetes
mellitus before the age of 65 years.
A previous study in the first ZODIAC-cohort (1998) reported an
annual mortality rate of 4.8% between 1998 and 2000 (the first
three years of the shared care project), definitely higher than the
mortality rate in the present analysis (,3%), which was performed
over the subsequent years within this shared care environment
. This difference could be explained by the fact that the earlier
analysis was performed in a more extended type 2 diabetes cohort,
which also included patients who were referred to secondary care.
It is also possible that the cohort as presented in this first analysis
had yet to benefit from longer term participation in a shared-care
environment with supportive care and monitoring of implemen-
tation of the guidelines.
More than half of our population received either a statin, RAS-
inhibitor or aspirin at baseline. At follow-up, this proportion had
increased to at least 80%. Widespread treatment of the traditional
cardiovascular risk factors resulted in vastly improved blood
pressure readings and lipid levels. This could also be the
explanation for disappearance of systolic blood pressure from the
model to predict mortality. Recent studies, although maybe
underpowered, addressed the importance of statins and blood
pressure lowering drugs in patients with type 2 diabetes mellitus,
showing a reduction in cardiovascular events with these lipid-
lowering drugs compared to placebo [22–24].
HbA1c had also no effect on life expectancy in uni- and
multivariate analysis. This may possibly be explained by the low
number of patients with poor glycemic control (only 7% had a
HbA1c.9%). Alternatively, other mechanisms could be involved
Table 2. Predictors of overall mortality in type 2 diabetes mellitus by univariate and multivariate Cox regression analysis using
‘‘survival in years’’ (=standard method) and using ‘‘standardised survival time’’.
Predictors of all-cause mortalitySurvival in years Standardised survival timea
p-value HR95% CI p-value
Gender (man=reference) 0.840.62–1.14 0.250.910.67–1.24 0.56
Smoking1.100.75–1.60 0.63 1.491.02–2.180.039
Systolic blood pressure1.01 1.00–1.02 0.016 1.000.99–1.010.66
Diabetes duration 1.03 1.02–1.050.001 1.02 1.00–1.04 0.073
1.02 0.91–1.150.71 1.08 0.95–1.220.23
Albuminuria (yes/no) 2.33 1.71–3.17
,0.001 1.81 1.32–2.46
History of cardiovascular disease (yes/no) 2.952.15–4.06
Use of lipid-lowering drugs (yes/no)0.830.59–1.180.301.340.80–1.620.48
Use of antiplatelet drugs (yes/no) 2.001.46–2.74
Smoking (yes/no) NSNS
Systolic bloodpressure NSNS
Diabetes duration NS NS
History of cardiovascular disease (yes/no)1.791.29–2.500.0011.711.23–2.37 0.001
Use of lipid-lowering drugs (yes/no)NS NS
Use of antiplatelet drugs (yes/no)NS NS
Abbreviations: HR, hazard ratio; CI, confidence interval; NS, not significant.
aThe standardised survival time was calculated as the ratio between the observed survival time of an individual and the median residual life span of individuals with the
same age in the general population.
Life Expectancy in Diabetes
PLoS ONE | www.plosone.org6 August 2009 | Volume 4 | Issue 8 | e6817
in the development of diabetes related complications. E.g., we
recently reported increased levels of advanced glycation end-
products (AGEs) rather than HbA1cin the same study group, to be
related to chronic complications .
There are some limitations to our study regarding the possible
general applicability of the results. Diabetic patients who were
referred to the secondary care in the past, mainly for reasons of
poor metabolic control or comorbidity, were not included in this
study and almost certainly will have a reduced life expectancy.
Also, there has been a selection bias by excluding diabetic patients
with a very short life expectancy (terminally ill patients, cognitive
disabled people and patients who were unable to undergo
educational programs), as described in the methods section. Still,
the selection comprised a considerable subset of the total
population known with type 2 diabetes (see figure 1), and 40%
of the included study population were known with cardiovascular
disease at baseline.
Despite this apparent selection bias, we still are able to conclude
that we defined a large subset of patients with a life expectancy
comparable to that of the general population of the same age and
sex. In The Netherlands, the large majority (70–80%) of type 2
diabetes patients is treated in primary care or in a shared-care
setting. Therefore, this study population could be representative
for the majority of type 2 diabetes patients in The Netherlands,
and probably also for a larger part of type 2 diabetes patients in
other countries with structured diabetes care.
Our choice to compare life expectancy of this type 2 diabetes
cohort to the general population can be criticised, since the general
population also includes people with diabetes, cardiovascular
disease, cancer, and other life shortening diseases. We nevertheless
preferred to choose the general population instead of a non-
diabetic control group, since one of the aims of caregivers in
medical practice is to regain a life expectancy for their patients
equal to the general population when life expectancy is reduced
due to a specific disease.
To visualise whether a life expectancy equal to the general
population had been achieved, we used SST. Traditional survival
analysis focuses more on ‘mortality’ within a certain follow-up
time, but with this more conventional method it is not clear
whether it is ‘normal mortality’ or ‘excess mortality’. Using SST,
the mortality rate is adjusted for the median survival of subjects in
the general population of the same age and sex. In this way, we
eliminate the effect of age and sex, by excluding the influence of
disease-specific risk of age and sex in the standardised analysis.
Excess mortality or a reduced life expectancy will be identified
more easily in that way. We consider the results of this study to be
relevant for clinical practice, because they offer a hopeful
perspective of a definitely improved life expectancy in type 2
diabetes patients. We suggest that those results are also (partly) due
to the fact that these patients were and are participating in a care
system promoting adherence to evidence-based guidelines and to a
system emphasizing close cooperation between health care
providers focusing on this patient group.
In summary, this study shows a normal life expectancy in a large
subset of type 2 diabetes patients treated in a primary care setting
compared to the general population. The presence of previous
cardiovascular disease and albuminuria, however, is still associated
with a markedly reduced life expectancy.
Analyzed the data: HLL EGG WJS LJUV GWL. Wrote the paper: HLL
EGG TPL ROG AJS HJB.
1. Fox CS, Pencina MJ, Meigs JB, Vasan RS, Levitzky YS, et al. (2006) Trends in
the incidence of type 2 diabetes mellitus from the 1970s to the 1990s. The
Framingham Heart Study. Circulation 113: 2914–2918.
2. Fox CS, Coady S, Sorlie PD, D’Agostino Sr RB, Pencina MJ, et al. (2007)
Increasing cardiovascular disease burden due to diabetes mellitus. The
Framingham Heart Study. Circulation 115: 1544–1550.
3. Franco OH, Steyerberg EW, Hu FB, Mackenbach J, Nusselder W (2007)
Associations of diabetes mellitus with total life expectancy and life expectancy
with and without cardiovascular disease. Arch Intern Med 167: 1145–1151.
4. Gu K, Cowie CC, Harris MI (1998) Mortality in adults with and without
diabetes in a national cohort of the US population, 1971–1993. Diabetes Care
5. Panzram G (1987) Mortality and survival in type 2 (non-insulin-dependent)
diabetes mellitus. Diabetologia 30: 123–131.
6. Clarke PM, Gray AM, Briggs A, Farmer AJ, Fenn P, et al. (2004) UK
Prospective Diabetes Study (UKDPS) Group. A model to estimate the lifetime
health outcomes of patients with type 2 diabetes: the United Kingdom
Prospective Diabetes Study (UKPDS) Outcomes Model (UKPDS no. 68).
Diabetologia 47: 1747–1759.
7. Roper NA, Bilous RW, Kelly WF, Unwin NC, Connolly VM (2002) Cause-
specific mortality in a population with diabetes. South Tees Diabetes Mortality
Study. Diabetes Care 25: 43–48.
8. Gregg EW, Gu Q, Cheng YJ, Venkat Narayan KM, Cowie CC (2007) Mortality
trends in men and women with diabetes, 1971 to 2000. Annals Int Med 147:
9. Tierney EF, Cadwell EF, Engelgau MM, Shireley L, Parsons SL, et al. (2004)
Declining mortality rate among people with diabetes in North Dakota, 1997–
2002. Diabetes Care 27: 2723–2725.
10. Lipscombe LL, Hux JE (2007) Trends in diabetes prevalence, incidence, and
mortality in Ontario, Canada 1995–2005: a population-based study. Lancet 369:
11. Gu K, Cowie CC, Harris MI (1999) Diabetes and decline in heart disease
mortality in US adults. Journal of the American Medical Association 281:
12. Tan HH, McAlpine RR, James P, Thompson P, McMurdo MET, et al. (2004)
Diagnosis of type 2 diabetes at an older age: effect on mortality in men and
women. Diabetes Care 27: 2797–2799.
13. Dale CA, Vatten LJ, Nilsen TI, Midthjell K, Wiseth R (2008) Secular decline in
mortality from coronary heart disease in adults with diabetes mellitus: cohort
study. British Medical Journal 337: 1–6.
14. Lutgers HL, Graaff R, Links TP, Ubink-Veltmaat LJ, Bilo HJG, et al. (2006)
Skin autofluorescence as a non-invasive marker of vascular damage in patients
with type 2 diabetes mellitus. Diabetes Care 29: 2654–2659.
15. Ubink-Veltmaat LJ, Bilo HJ, Groenier KH, Rischen RO, Meyboom-de Jong B
(2005) Shared care with task delegation to nurses for type 2 diabetes: prospective
observational study. Netherlands Journal of Medicine 63: 103–110.
16. Rutten GEH, De Grauw WJC, Nijpels G, Goudswaard AN, Uitewaal PJM, et
al. (2006) Diabetes mellitus type 2. Huisarts en Wetenschap 49: 137–152. [in
17. Links TP, van Tol KM, Jager PL, Plukker JTM, Piers DA, et al. (2005) Life
expectancy in differentiated thyroid cancer: a novel approach to survival
analysis. Endocrine-Related Cancer 12: 273–280.
18. Data published by the ‘‘Centraal bureau voor de statistiek’’. Available from
http://statline.cbs.nl/StatWeb/. Accessed January 2007.
19. Kannel WB, McGee DL (1979) Diabetes and cardiovascular risk factors: the
Framingham study. Circulation 59: 8–13.
20. Roper NA, Bilous RW, Kelly WF, Unwin NC, Connolly VM (2001) Excess
mortality in a population with diabetes and the impact of material deprivation:
longitudinal, population based study. British Medical Journal 322: 1389–1393.
21. Ubink-Veltmaat LJ, Bilo HJ, Groenier KH, Houweling ST, Rischen RO, et al.
(2003) Prevalence, incidence and mortality of type 2 diabetes mellitus revisited: a
prospective population-based study in The Netherlands (ZODIAC-1).
Eur J Epidemiol 18: 793–800.
22. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HAW, et al.
(2004) Primary prevention of cardiovascular disease with atorvastatin in type 2
diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre
randomised placebo-controlled trial. Lancet 364: 685–696.
23. Sever PS, Poulter NR, Dahlo ¨f B, Wedel H, Collins R, et al. (2005) Reduction in
cardiovascular events with atorvastatin in 2.532 patients with type 2 diabetes:
Anglo-Scandinavian Cardiac Outcomes Trial-lipid-lowering arm (ASCOT-
LLA). Diabetes Care 28: 1151–1157.
24. Patel A, ADVANCE Collaborative Group (2007) Effect of a fixed combination
of perindopril and indapamide on macrovascular and microvascular outcomes
in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised
controlled trial. Lancet 370: 829–840.
Life Expectancy in Diabetes
PLoS ONE | www.plosone.org7 August 2009 | Volume 4 | Issue 8 | e6817