SGLT2 inhibitors in type 2 diabetes management: Guidance from the Improving Diabetes Steering Committee

Summary points (1 of 5)

People with type 2 diabetes mellitus (T2DM) and diabetic kidney disease (DKD) are at increased risk of mortality alongside adverse cardiovascular (CV) and renal outcomes, with many progressing to end-stage kidney disease and requiring haemodialysis or kidney transplantation

Summary points (2 of 5)

In recent years, a growing body of evidence has emerged concerning the potential renoprotective effects of the sodium-glucose co-transporter 2 inhibitor (SGLT2i) class of medicines, with data from large T2DM CV outcome trials (CVOTS) demonstrating a significant reduction in markers for progression of kidney disease in addition to CV end points.

Summary points (3 of 5)

In response, a new era of SGLT2i cardio-renal studies was initiated, with the canagliflozin CREDENCE trial (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) being the first to publish data demonstrating the effectiveness of this medicine in reducing the risk of both kidney failure and CV events in a population comprising individuals with T2DM and renal disease.

Summary points (4 of 5)

The evolving evidence base in this area is reflected in the latest international guidelines for the treatment of T2DM, and this article aims to put these recommendations into context for clinicians supporting people with T2DM, outlining the relevant studies that have driven these changes and examining the potential mechanisms that may underlie the renoprotective effect of SGLT2i treatments as well as the implications for clinical practice.

Summary points (5 of 5)

The SGLT2i Prescribing Tool, previously developed by the Steering Committee, has also been updated to reflect much of the evidence discussed in this review and is available above and on the Diabetes Therapy website as a supplementary material.

Summary points (1 of 14)

A large proportion of patients with type 2 diabetes have concurrent cardiovascular disease, which is associated with significant morbidity and mortality; therefore, effective management of cardiovascular disease risk in patients with type 2 diabetes is a priority for healthcare systems and affected patients

There are multiple overlapping risk factors between type 2 diabetes and cardiovascular disease, including insulin resistance, chronic systemic inflammation, elevated blood pressure, obesity, dyslipidaemia and hypercoagulability.

A bidirectional relationship exists between type 2 diabetes and heart failure in terms of disease risk and progression, highlighting the need for effective treatment regimens that recognise both diseases.

Although studies have shown the benefits of reducing glycated haemoglobin (HbA1c) on CV outcomes, treatment strategies are needed that address the independent risk factors for cardiovascular disease, in addition to glycaemic control, in patients with type 2 diabetes

SGLT2 inhibitors modify many cardiovascular disease risk factors beyond HbA1c, including BP, body weight, hyperinsulinaemia, visceral adiposity, albuminuria, plasma uric acid levels, arterial stiffness and oxidative stress.

Proposed mechanisms of action to explain the cardio-protective effects of SGLT2 inhibitors include improved cardiac metabolism and bioenergetics, improved ventricular loading via osmotic diuresis and increased sodium excretion, and inhibition of the sodium/hydrogen exchanger in the myocardium.

Randomised cardiovascular outcomes trials of the SGLT2 inhibitors empagliflozin, canagliflozin and dapagliflozin have shown cardiovascular disease or heart failure benefits with these agents in patients with type 2 diabetes at high risk of cardiovascular disease.

Three large real-world studies in a total of >1 million patients with type 2 diabetes in routine clinical practice have observed cardiovascular benefits with SGLT2 inhibitors, including reductions in the risk of all-cause mortality and/or hospitalisation for heart failure.

Clinical trial data support the benefits of SGLT2 inhibitors in patients with established cardiovascular disease (ie, secondary prevention); however, there is increasing evidence to suggest benefits with SGLT2 inhibitor therapy in patients with cardiovascular disease risk factors but without established cardiovascular disease (ie, primary prevention).

The IDSC recommends early initiation of SGLT2 inhibitors in patients with type 2 diabetes and risk factors for cardiovascular disease, regardless of the presence of established cardiovascular disease or heart failure, as this provides an optimal management strategy by decreasing hyperglycaemia, increasing weight loss and lowering systolic blood pressure

The National Institute for Health and Care Excellence (NICE) guidelines do not yet provide guidance on the selection of type 2 diabetes treatment according to cardiovascular disease risk; however, the IDSC suggests wider implementation of the American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) consensus report, which recommends considering outcomes beyond glycaemic control (ie, atherosclerotic cardiovascular disease, heart failure, chronic kidney disease, weight management and prevention of hypoglycaemia) when selecting glucose-lowering therapy.

There are several challenges to adopting a new treatment approach when managing patients with type 2 diabetes, including a lack of familiarity with newer glucose-lowering agents, a lack of prescribing options through local formularies, and limited flexibility within local guidelines.

SGLT2 inhibitor therapy may represent the best option when escalating from metformin therapy in many patients with type 2 diabetes and risk factors for cardiovascular disease, particularly given the outcome benefits beyond attainment of glycaemic targets and the shared risk factors for type 2 diabetes and cardiovascular disease, including elevated BP, dyslipidaemia and obesity.

The Improving Diabetes Steering Committee provided recommendations for SGLT2 inhibitor use the following groups of patients with type 2 diabetes:

• Patients with type 2 diabetes and established cardiovascular disease;
• patients with type 2 diabetes and a high risk for cardiovascular disease;
• patients with type 2 diabetes and a lower risk for cardiovascular disease; and 
• frail patients with type 2 diabetes.

Based on the evidence for SGLT2 inhibitors summarised in the review, the authors developed a benefit/risk tool that can be used as a quick reference for clinicians in routine practice.

SGLT2 inhibitors reduce the reabsorption of glucose in the kidney in an insulin-independent manner, thereby increasing glucose excretion via urine.

Three SGLT2 inhibitors are approved in the UK: canagliflozin, dapagliflozin and empagliflozin. National Institute for Health and Care Excellence (NICE) and Scottish Intercollegiate Guidelines Network (SIGN) guidelines recommend the use of SGLT2 inhibitors for first intensification of type 2 diabetes treatment after metformin failure.

Guidelines also note that SGLT2 inhibitors can be administered in combination with other anti-diabetic drugs, such as insulin and glucagon-like peptide-1 receptor antagonists.

Randomised controlled trials and real-world evidence have shown that SGLT2 inhibitors achieve and maintain glucose levels, are associated with weight loss (reduce visceral fat), and have cardio- and renoprotective effects.

SGLT2 inhibitors are generally well tolerated; however, there are some patient populations that may be at increased risk of adverse events.

Genital infections are a common adverse event with SGLT2 inhibitors. To achieve optimum treatment benefit, education on the risk of these and practical hygiene advice at the start of treatment are recommended.

There is conflicting evidence for the risk of lower limb amputation and bone fractures with SGLT2 inhibitors; however, high-risk individuals should avoid SGLT2 inhibitors. Preventative footcare advice and ongoing monitoring is recommended.

Patients receiving SGLT2 inhibitors may experience diabetic ketoacidosis, although this is rare. Diabetic ketoacidosis monitoring should be implemented when administering SGLT2 inhibitors.

SGLT2 inhibitors should be discontinued immediately in patients with acute illness or planned surgical procedures, but can be resumed following full recovery.