Excess risk of lower extremity amputations in people with type 1 diabetes compared with the general population: amputations and type 1 diabetes
Arndís Finna Ólafsdóttir, Ann-Marie Svensson, Aldina Pivodic, Soffia Gudbjörnsdottir, Thomas Nyström, Hans Wedel, Annika Rosengren, Marcus Lind
Objective This study investigates how the excess risk of lower extremity amputations (amputations) in people with type 1 diabetes mellitus (DM) differs from the general population by diabetes duration, glycemic control, and renal complications.
Research design and methods We analyzed data from people with type 1 DM from the Swedish National Diabetes Register without prior amputation from January 1998 to December 2013. Each person (n=36 872) was randomly matched with five controls by sex, age, and county (n=184 360) from the population without diabetes. All were followed until first amputation, death or end of follow-up.
Results The overall adjusted HR for all amputation was 40.1 (95% CI 32.8 to 49.1) for type 1 DM versus controls. HR increased with longer diabetes duration. The incidence of amputation/1000 patient-years was 3.18 (95% CI 2.99 to 3.38) for type 1 DM and 0.07 (95% CI 0.05 to 0.08) for controls. The incidence decreased from 1998–2001 (3.09, 95% CI 2.56 to 3.62) to 2011–2013 (2.64, 95% CI 2.31 to 2.98). The HR for major amputations was lower than for minor amputations and decreased over the time period (p=0.0045). Worsening in glycemic control among patients with diabetes led to increased risk for amputation with an HR of 1.80 (95% CI 1.72 to 1.88) per 10 mmol/mol (1%) increase in hemoglobin A1c.
Conclusions Although the absolute risk of amputation is relatively low, the overall excess risk was 40 times that of controls. Excess risk was substantially lower for those with good glycemic control and without renal complications, but excess risk still existed and is greatest for minor amputations
Already known about this subject?
► Earlier studies have shown decreasing incidence of lower extremity amputations (amputations) and that they are related to hemoglobin A1c (HbA1c) and to diabetes complications.
What are the new findings?
► This nationwide study of virtually all people with type 1 diabetes mellitus (DM) in Sweden and their matched controls found that there was a high excess risk of amputation for people with type 1 DM compared with the general population (40-fold), and only the risk for major amputations (above knee) has decreased substantially during the 1998–2013 study period.
► There was a much lower excess risk for persons with good glycemic control and no renal complications, but the risk was still over six times greater than for the general population.
How might these results change the focus of research or clinical practice?
► Special focus has to be given to persons with very poor glycemic control and renal complications, but it is important to screen all people with type 1 DM as even those who reach the target HbA1c level and without renal complications have an excess risk of lower extremity amputation compared with the general population.
► The uniquely strong relationship found between HbA1c and amputations indicates that amputations would substantially decrease if the long-term glycemic control can be at least moderately improved in the population of people with type 1 DM and if the proportion of patients with very poor glycemic control could be reduced.
From the article
People with diabetes have higher risk for lower extremity amputations (amputations), and 40%–50% of all non-traumatic amputations have reportedly been due to diabetes.1 2 People with type 1 diabetes mellitus (type 1 DM) and amputation have reduced survival rates.2 Amputation also leads to high medical and social costs.3 Several studies have evaluated the risk of amputation in people with type 2 diabetes, but limited population-based studies have been performed in type 1 DM.4–7 In people with diabetes poor glycemic control has been associated with amputation8 as well as renal complications.9 Diabetes renal failure and foot ulcers are often coexisting complications. People with diabetes renal failure have a higher incidence of foot ulcers and increased risk of amputation,10 a risk strongly associated with declining estimated glomerular filtration rates.11 Renal complications, resulting from history of poor glycemic control, might be a marker for advanced complications such as foot ulcers and amputations, although other crucial pathophysiologic mechanisms may play a role.12
With improved glucose-lowering therapies for people with type 1 DM and stricter guidelines for controlling risk factors such as lipids and blood pressure in recent decades, it is important to determine the current prognosis for amputations in people with type 1 DM. However, it is unknown whether people with type 1 DM who achieve the recommended glycemic control and avoid renal complications, which are thought to be associated with lower risk of complications,13 have prognoses similar to the general population.
In this study, we evaluated the overall excess risk for amputation by glycemic control, renal complications, and duration of diabetes in people with type 1 DM versus controls.
This nationwide study including 36 577 people with type 1 DM and 182 617 matched controls from the general population in Sweden shows a 40-fold excess risk of lower extremity amputations in people with type 1 DM. The excess risk of amputations approached that of the general population with better glycemic control and fewer renal complications, but an excess risk remained for people with type 1 DM at normoalbuminuria and who reached the target levels of HbA1c. Excess risk was greater for minor than major amputations and only decreased over time for major amputations. The incidence of amputations was also higher for men than women and in older compared with younger individuals.
To our knowledge this is the first study of principally all people with type 1 DM in a single country and comparing the risk of amputations with the general population in relation to risk factors.
Earlier studies have also identified an excess risk of amputations in people with versus without type 1 DM,4 7 and others performing analyses within the diabetes group found that impaired glycemic control and renal complications were associated with increased risk of amputations.8 9 The current incidence of amputations (3.18/1000 patient-years) is within the same range of that from similar cohorts evaluating coronary events (5.7/1000 patient-years) and heart failure (4.0/1000 patient-years).16 23 Hence, it is notable that although the relative risk of amputations in people with type 1 DM compared with the general population is around 40 times compared with 4 times for coronary events and heart failure, the risk of experiencing an amputation for people with type 1 DM is somewhat lower. These results also show that amputation is a diabetes-specific complication to a greater extent than cardiovascular disease, which is more common in the general population.
People with normoalbuminuria and mean HbA1c levels below targets had an excess risk for all amputations that was approximately 8 times at 40 years diabetes duration and increased with longer diabetes duration, this was 7 times greater for major amputations and 13 times greater for minor amputations. These findings should be interpreted with caution with regard to whether targeting HbA1c and avoiding renal complications is sufficient to reducing the risk of amputations to that of the general population. The current data include information on HbA1c levels for approximately 10 years, and it is possible that people with diabetes had worse glycemic control before participating in NDR. Although we used normoalbuminuria as a marker for earlier glycemic control, this is only a rough measure of historic glucose levels. However, in clinical practice it is important for caregivers to be aware that people with on-target HbA1c and no renal complications still have an excess risk of amputation, although it is considerably lower than for other people with diabetes.
Although there were some indications of lower risk of amputations in people with type 1 DM over time as shown by numerically lower rates and a significant reduction in a post-hoc analysis, this was due to a significant change in major amputations and not in minor amputations. Therefore, improved prevention of amputations in people with type 1 DM is urgently needed. Glycemic control seems to be of special concern for preventing amputations. Besides the high excess risk of amputations in people with type 1 DM compared with the general population, indicating a diabetes-specific condition, the 80% increase in risk of all and minor amputations by 10 mmol/mol (1%) higher HbA1c estimated within the diabetes group was considerably higher than for coronary events (30% for men and 41% for women) and heart failure (30%) reported in similar cohorts.15 23 An earlier meta-analysis showed a 15% increase in risk of myocardial infarction for a similar increase in HbA1c,24 and few analyses of microvascular complications have shown such a high gradient of risk as found here for amputation.21 Since hyperglycemia is a prerequisite for renal complications, the dramatic increase in risk of amputation with severity of renal complications indicates the same phenomenon. Therefore, from a longer term perspective, improving glycemic control in people with type 1 DM may lead to a substantial decrease in amputations. Not only hyperglycemia, but other risk factors for diabetes complications such as hypertension and smoking cessation are also important strategies to control for in people with type 1 DM to decrease the incidence of amputations both from a medical and health economics perspective.13
Although the relative risk in type 1 DM is higher for younger people due to few events in the general population, the risk of amputations increases substantially with age, and the mean age and diabetes duration were 59 and 44 years, respectively, at the time of first amputation in the current study. Why renal complications are such a strong risk factor for amputations may be partly due to being a marker of high historic glycemic control and an overall high risk of complications. However, it is also possible that other mechanisms associated with renal complications such as hypertension, reduced albumin levels, inflammatory processes, and factors of the dialysis process may play an essential role for lower extremity amputations.8 9 25–27 To prevent amputations, screening for neuropathy and ulcers and performing preventive foot care are of importance, which often require specialist foot teams for people with diabetes and severe ulcers.13
A strength of this study is the large cohort, both for people with type 1 DM and the availability of five matched controls. Further adjustment for several variables could be performed, including comorbidities when comparing the risk of amputations in people with type 1 DM with that of the general population. Moreover, well-known risk factors for diabetes complications existed for virtually all people with type 1 DM and during a long time period, which are essential when estimating the excess risk of amputations compared with controls and the risk gradient between HbA1c and amputations within the diabetes group. Limitations include that some potential risk factors for amputations such as BMI, blood pressure levels, lipid-lowering medication, and smoking were not available among controls. Moreover, since this is an observational study, residual confounding cannot be excluded.
In conclusion, the absolute risk of experiencing an amputation for people with type 1 DM is relatively low, especially at younger ages, whereas the relative risk compared with that of the general population remains high. To reduce the excess risk of amputations, improving glycemic control in people with type 1 DM is crucial. Longer diabetes duration, renal complications, and poor glycemic control are strong risk factors for amputations. Although people with diabetes, good glycemic control and no renal complications have considerably lower risks for amputations, excess risk of amputations remains, and thus this group also requires continued prevention.
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