Diabetes mellitus is a chronic condition resulting in increased concentrations of glucose in the blood, which in turn damage many of the bodys systems, in particular blood vessels and nerves, which may lead to diabetic foot disease that often leads to ulceration and subsequent limb amputation. Lower limb amputation is substantially more common among patients with Type 2 Diabetes Mellitus (T2DM) when compared to those without T2DM. Furthermore, T2DM patients who suffer from Diabetic Foot Ulcers (DFU) have a considerable increase in mortality in comparison to T2DM patients without DFU.
Sodium-glucose co-transporter-2 inhibitors (SGLT-2Is) are a useful addition to the already existing glucose-lowering drugs since they provide a better control of hyperglycemia and subsequently a reduction of diseases associated with T2DM. However, the results of the Canagliflozin Cardiovascular Assessment Study (Canvas) program showed that patients on canagliflozin had a greater risk of amputation especially of the foot. As a result, a safety alert regarding amputations associated with canagliflozin use was issued. In clinical trials with other SGLT-2-Is the increased risk of amputation was not observed. Moreover, observational studies have produced conflicting results. This may be a result of using different comparison groups and methods. None of these observational studies evaluated the increased risk of amputation and the relevant association of an underlying pharmacological mechanism. In view of this scenario, this study is aimed to investigate the association of SGLT-2Is versus other antidiabetic drugs and the risk of amputation of the lower limb and foot, whilst exploring the potential underlying mechanism.
The objective of this study is to investigate the association between the use of sodium-glucose co-transporter-2 inhibitors (SGLT-2-Is) in comparison to other antidiabetic drugs and the risk of amputation of the lower limb by different sites. A possible mechanism for lower limb amputations is that SGLT-2-I use increases osmotic diuresis together with a reduction in extravascular volume which may lead to reduced tissue perfusion. We aim to investigate hypovolemia as a possible mechanism in this study.
We will first create a base cohort including all patients aged >18 starting with metformin only between 1998 and 2019. From this base cohort we will select all patients with a first ever prescription for a SU, DPP4-I or SGLT-2-I between 1-1-2013 and 30-6-2018. This study period is chosen as SGLT-2-Is have been available from 1-1-2013 in the UK. The date of the first prescription for a SU, SGLT-2-I, or DPP4-I will determine the indexdate. Every patient will be followed from his/her indexdate collection, death, or the outcome of interest, whichever comes first. The total follow-up will be divided into intervals of 30 days. At the start of each interval we will determine exposure to non-insulin anti-diabetic drugs (NIADs). Based on the time since the most recent prescription an interval will be classified as current (1-90 days) or past (> 90 days) NIAD use. Current use will be further stratified into current use of SUs (reference group), DPP4-Is, SGLT-2Is and other NIADs.
The primary outcome will be the risk of lower limb amputation. When volume restriction is the mechanism by which SGLT-2-Is increase the risk of amputation, we expect that patients using SGLT-2-Is will also have a higher risk of other foot problems, including an elevated risk of amputations of the lower limb, foot (toes) and a high risk of DFU.
Primary:
- Lower limb amputations (read codes are listed in appendix 6)
Secondary:
- amputation of the foot (including ankle) (read codes are listed in appendix 4)
- amputation of the metatarsal bones and one or more toes (read codes are listed in appendix 3)
- amputation of the one or more toes (read codes are listed in appendix 5)
- diabetic foot ulcer (read codes are listed in appendix 1)
- ischaemic diabetic foot ulcer (read codes are listed in appendix 2)
Frank de Vries - Chief Investigator - Utrecht University
Johanna Driessen - Corresponding Applicant - Utrecht University
Bernardette Rossi - Collaborator - Maastricht University Medical Centre
Johan Roikjer - Collaborator - Aalborg University Hospital
Johannes T.H. Nielen - Collaborator - Utrecht University
Joop van den Bergh - Collaborator - Maastricht University
Nicolaas Schaper - Collaborator - Maastricht University
Niels Ejskjaer - Collaborator - Aalborg University Hospital
Nikki Werkman - Collaborator - Utrecht University
Olaf Klungel - Collaborator - Utrecht University
Peter Vestergaard - Collaborator - Aalborg University Hospital