The field of organ transplantation has expanded significantly over the last decade but whilst transplantation for complications of diabetes (including renal transplants) are well established, treating the underlying issue in Type 1 diabetes – specifically the loss of pancreatic islets has been a problem. Whole pancreas transplants, usually performed as a combined kidney/ pancreas transplant have been an option for some time. However, it is associated with significant complications on top of rejection; including pancreatitis and issues with the exocrine function of the pancreas especially as only the islets are required. Transplantation of the islets themselves has proven difficult due to issues separating them from the pancreas and the choice of immunosuppressive agent – the use of corticosteroids being a major problem. In 2000 however, the publication of a study of 7 patients who had achieved euglycaemia using a steroid free protocol (of Sirolimus, Tacrolimus and Daclizumab) – the Edmonton regime – has significantly changed the outlook.

In order to obtain sufficient islets, up to 2 donor pancreas are required to provide the 1 million islets which are released via purified collagenases.  Under local anaesthesia (sometimes with sedation) and using imaging guidance, a catheter is inserted percutaneously into the portal vein and the grafted islet cells infused into the liver. More than one infusion may be required following which lifelong immunosuppression is required.

Whilst the concept of islet transplantation may seem a panacea to patients, the shortage of donors and need for long term immunosuppression are major blocks, hence guidance from NICE regarding suitability (essentially those patients who are difficult to control often due to severe hypos despite education, pumps therapy etc.). Furthermore, an islet transplant does not automatically result in freedom from insulin. A variety of studies, usually registry or case series, have shown that insulin independence is achieved in 24-85% of patients up to 2 years following transplant. More importantly however, the incidence of severe hypoglycaemia was significantly reduced (a registry study showed a reduction in severe hypos from 82% to 4.5%) – a major improvement in quality of life.

In the UK, there are 7 centres performing these transplants with referral criteria being >2 severe hypos in the last year and impaired awareness of hypoglycaemia as well as patients who have already received a renal transplant experiencing issues with hypoglycaemia.

Although the rapid development and increasing sophistication of glucose sensing and insulin delivery devices the ultimate goal of a closed loop system may eventually reduce the need for transplants, they still have a place for a small number of patients.

Dr Mark Freeman

SGLT2 inhibitors have been rapidly taken up due to their ideal properties of lowering blood glucose with accompanying weight loss, a positive impact on blood pressure and the fact that they do not cause hypoglycaemia. In fact, despite only being launched in 2012, they have been justified as a second line agent by NICE.

However, not long after launch, anecdotal evidence emerged regarding the potential association of diabetic ketoacidosis (in particular euglycaemic ketoacidosis) with the drugs – possibly as a result of reducing insulin doses or elevated glucagon levels. Whilst being licensed for treatment in Type 2 Diabetes, their insulin independent mode of action has resulted in them being used in some patients with Type 1 Diabetes. By May 2015, the fact that approximately 100 cases had been reported, lead to a review by the European Medicines Agency (EMA). As a result of these cases, the EMA has recommended updating the product information of SGLT2 inhibitors to list diabetic ketoacidosis as a rare adverse reaction (affecting up to 1 in 1,000 patients). Furthermore, it is advised that patients are counselled about the symptoms of DKA. There is a firming up of the licence regarding their specific use in T2DM only. However, it is increasingly recognised that patient do not always obligingly fit nicely into a diagnosis of T1 or T2, with some patients having a slow onset of T1 – now recognised in the NICE T1DM guidance. Advice is given regarding these and other patients who have risk factors for ketoacidosis. These include low insulin producing capacity in the pancreas and increased insulin requirement such as due to illness or alcohol abuse as well as conditions linked with reduced food intake or dehydration. In addition, EMA recommends temporarily stopping SGLT2 inhibitors in patients who are undergoing major surgery or are in hospital due to serious illness.

Whilst the benefit of SGLT2 inhibitors outweighs the risks, this guidance is a cautionary tale. Following their rapid uptake, it has not been the first time that a new class of diabetes drug has received caution following launch.

Dr Mark Freeman