SGLT2 Inhibitors in Type 2 Diabetes Management: Key Evidence and Implications for Clinical Practice

Abstract

Management of type 2 diabetes mellitus (T2DM) is complex and challenging, particularly for clinicians working in primary care who are faced with many competing clinical priorities. The range of available T2DM treatments has diversified significantly in recent years, generating a busy and data-rich environment in which evidence is rapidly evolving. Sodium-glucose cotransporter-2 inhibitor (SGLT2i) agents are a relatively new class of oral glucose-lowering therapy that have been available in the UK for approximately 5 years. These agents reduce the reabsorption of glucose in the kidney and increase its excretion via the urine. Conflicting messages and opinions within the clinical community have led to misconceptions concerning the efficacy, safety and appropriate position of SGLT2i therapies within the T2DM treatment pathway. To help address some of these concerns and provide advice regarding the appropriate place of these medicines in clinical practice, the Improving Diabetes Steering Committee was formed. The Committee worked together to develop this review article, providing a summary of relevant data regarding the use of SGLT2i medicines and focusing on specific considerations for appropriate prescribing within the T2DM management pathway. In addition, a benefit/risk tool has been provided (see Fig. 3) that summarises many of the aspects discussed in this review. The tool aims to support clinicians in identifying the people most likely to benefit from SGLT2i treatments, as well as situations where caution may be required.

Funding: Napp Pharmaceuticals Limited.

Keywords: Clinical guidance; Glucose-lowering medicines; Oral glucose-lowering medicines; Prescribing tools; Risk/benefit; SGLT2 inhibitors; Therapy choice; Type 2 diabetes.

Fig. 1

NICE treatment algorithm for blood glucose-lowering therapy in adults with T2DM [5]. © NICE (2015) NG28 Type 2 diabetes in adults: management [5]. Available from: http://www.nice.org.uk/guidance/ng28. All rights reserved. Subject to Notice of rights. Requests to reuse NICE content outside of the United Kingdom should be sent to nice@nice.org.uk. NICE guidance is prepared for the National Health Service in England. All NICE guidance is subject to regular review and may be updated or withdrawn. NICE accepts no responsibility for the use of its content in this product/publication. (Abbreviations: DPP-4i dipeptidyl peptidase-4 inhibitor, GLP-1 glucagon-like peptide-1, SGLT2i sodium-glucose cotransporter-2 inhibitors, SU sulfonylurea). Recommendations that cover DPP-4is, GLP-1 mimetics and SUs refer to these groups of drugs at a class level. ^aWhen prescribing pioglitazone, exercise particular caution if the person is at high risk of the AEs of the drug. Pioglitazone is associated with an increased risk of heart failure, bladder cancer and bone fracture. Known risk factors for these conditions, including increased age, should be carefully evaluated before treatment: see the manufacturers’ summaries of product characteristics for details. MHRA guidance (2011) advises that ‘prescribers should review the safety and efficacy of pioglitazone in individuals after 3–6 months of treatment to ensure that only those deriving benefit continue to be treated’. ^bSee NICE Technology Appraisal Guidance 288 and 418, 315 and 336 on dapagliflozin, canagliflozin and empagliflozin, respectively. All three SGLT-2 inhibitors are recommended as options in dual therapy regimens with metformin under certain conditions, as options in triple therapy regimens and in combination with insulin. All three are also options as monotherapies in adults in whom metformin is contraindicated or not tolerated. Serious and life-threatening cases of DKA have been reported in people taking SGLT2is (canagliflozin, dapagliflozin or empagliflozin) or shortly after stopping the SGLT2i. MHRA guidance (2015) advises testing for raised ketones in people with symptoms of DKA, even if plasma glucose levels are near normal. ^cOnly continue GLP-1 mimetic therapy if the person has a beneficial metabolic response [a reduction of HbA1c by at least 11 mmol/mol (1.0%) and a weight loss of at least 3% of initial body weight in 6 months]. ^dIf metformin is contraindicated or not tolerated, repaglinide is both clinically effective and cost effective in adults with type 2 diabetes. However, discuss with any person for whom repaglinide is being considered that there is no licensed non-metformin-based combination containing repaglinide that can be offered at first intensification. ^eDrugs in dual therapy should be introduced in a stepwise manner, checking for tolerability and effectiveness of each drug. ^fMHRA guidance (2011) notes that cases of cardiac failure have been reported when pioglitazone was used in combination with insulin, especially in individuals with risk factors for the development of cardiac failure. People should be observed for signs and symptoms of heart failure, weight gain, and oedema. Pioglitazone should be discontinued if any deterioration in cardiac status occurs. ^gThe recommendations in this guideline also apply to any current and future biosimilar product(s) of insulin glargine that have an appropriate Marketing Authorisation that allows the use of the biosimilar(s) in the same indication

Fig. 2

SIGN treatment algorithm for T2DM management [6]. Algorithm summarises evidence from the guideline in the context of the clinical experience of the Guideline Development Group. It does not apply in severe renal or hepatic insufficiency. ¹Consider dose reduction. ²Do not delay if first line options not tolerated/inappropriate. ³See guideline pages 23 and 26–27. ⁴See BNF: specific agents can be continued at reduced dose. ⁵See BNF: no dose reduction required for linagliptin. ⁶Pioglitazone is contraindicated in people with (or with a history of) heart failure or bladder cancer. ⁷Do not combine dapagliflozin with pioglitazone. ⁸Caution with exenatide when eGFR < 50 ml/min/1.73 m². ⁹Adjust according to response. ¹⁰Driving, occupational hazards, risk of falls, previous history. Prescribers should refer to the British National Formulary (www.medicinescomplete.com), the Scottish Medicines Consortium (www.scottishmedicines.org.uk) and Medicines and Healthcare products Regulatory Agency (MHRA) warnings for updated guidance on licensed indications, full contraindications and monitoring requirements. *Continue medication at each stage if EITHER individualised target achieved OR HbA1c falls more than 0.5% (5.5 mmol/mol) in 3–6 months. Discontinue if evidence that it is ineffective. CKD 3A chronic kidney disease stage 3A (estimated glomerular filtration rate 45–59 ml/min/1.73 m²); CV cardiovascular

Fig. 3

Benefit/risk tool. (Abbreviations: T2DM type 2 diabetes mellitus, SGLT2i sodium-glucose cotransporter-2 inhibitor, ADA American Diabetes Association, RCT randomised controlled trial, BMI body mass index, LLAs lower leg amputations, PAD peripheral arterial disease, CV cardiovascular, CVD cardiovascular disease, eGFR estimated glomerular filtration rate, UTIs urinary tract infections, DKA diabetic ketoacidosis, CKD chronic kidney disease). ¶ SGLT2i therapies should be prescribed with caution in people requiring a rapid reduction in insulin dose, due to insulinopenia, which may increase DKA risk [–4]. *Decisions should be based upon recent eGFR measurement, rather than historical tests. ^‡SGLT2i therapies may be initiated in people with eGFR [3] 60 mL/min/1.73m². Individuals already treated with canagliflozin or empagliflozin who demonstrate renal decline may continue treatment until eGFR reaches < 45 mL/min/1.73m². Dapagliflozin should be discontinued for those who demonstrate eGFR < 60 mL/min/1.73m² [–4]. Urinary symptoms, due to glucosuria, can be an issue for people prescribed SGLT2i medicines [–4]. However, UTIs are relatively rare and these medicines may be prescribed for people with a history of UTIs. ◆Monitor HbA1c levels regularly and cease SGLT2is if elevated levels continue, following treatment initiation. **SGLT2i treatments are not currently recommended for use alongside loop diuretics. However, this may be subject to change as the evidence-base evolves. EMPA-REG and CANVAS CV outcome trials included subgroups of people with T2DM who were receiving loop diuretics and ongoing trials aim to evaluate co-prescribing of these agents [12, 16, 27]. ^†SGLT2i treatment should be suspended in individuals with acute illness until fully recovered [–4, 41, 42]