ARTICLE The new class war: SGLT2 inhibitors versus DPP-4 inhibitors Merlin Thomas Over 90% of people with type 2 diabetes will need more than metformin monotherapy Citation: Thomas M (2017) The new class war: SGLT2 inhibitors versus to achieve their targets for optimal glucose levels. There are many second-line options for DPP-4 inhibitors. Diabetes & Primary glucose management in type 2 diabetes, including the sodium–glucose cotransporter 2 Care Australia 2: 119 –23 (SGLT2) inhibitor and dipeptidyl peptidase-4 (DPP-4) inhibitor classes. This article provides Article points a framework for Australian general practices to compare the associated benefits and risks 1. Over 90% of people with of SGLT2 inhibitors and DPP-4 inhibitors when added to metformin for the management type 2 diabetes will require of type 2 diabetes. additional medication after metformin. 2. Dipeptidyl peptidase-4 ver 90% of people with type 2 Question #1: efficacy inhibitors and sodium–glucose diabetes will need more than The most obvious first question when deciding cotransporter 2 inhibitors metformin monotherapy to achieve between an SGLT2 and a DPP-4 inhibitor is how provide an alternative O to the older glucose- their targets for optimal glucose levels. Dual well does each class lower glucose? Across clinical lowering medications. therapy may begin early in their management, trials, SGLT2 inhibitors have been shown to lower 3. Drug regimens should when it is clear that metformin is insufficient HbA1c by 7.2 mmol/mol (−0.66%; 95% confidence be individualised and (primary failure) or later as the efficacy of interval [CI], −0.73%, −0.58%; Vasilakou et patient-centred. metformin gradually wanes (secondary failure). al, 2013). Very similar results have also been The Royal Australian College of General reported for DPP-4 inhibitors in participants Key words Practitioners (RACGP) and Diabetes Australia who were not achieving their glycaemic target – DPP-4 inhibitors (2014) guidelines recommend that when on metformin alone (7.2 mmol/mol [−0.69%] – Dual therapy optimal glycaemic levels are not met, no more 95% CI, −0.79%, −0.61%; Liu et al, 2012). It – SGLT2 inhibitors than 3–6 months should pass before a second- has been considered that there is no significant line agent is added. Of course, earlier initiation difference in glucose lowering achieved by either of combination therapy may be appropriate in drug class (Goring et al, 2014). However, recent some cases, especially when diabetes is clearly head-to-head studies have suggested that SGLT2 managed suboptimally. inhibitors may result in a greater glucose-lowering There are many second-line options for effect than DPP-4 inhibitors in people with type 2 glucose management of type 2 diabetes, diabetes very suboptimally managed diabetes at including the sodium–glucose cotransporter 2 baseline (HbA1c >75 mmol/mol [9%]; Rosenstock (SGLT2) inhibitor and dipeptidyl peptidase-4 et al, 2014; DeFronzo et al, 2015). In contrast, for (DPP-4) inhibitor classes. These newer classes people with type 2 diabetes who have an HbA1c have a number of advantages compared around 53 mmol/mol (7%), a DPP-4 inhibitor to older classes, including reduced risk of may achieve a greater glucose-lowering effect. hypoglycaemia and weight gain, and no need The effect of DPP-4 inhibitors on fasting plasma for dose-titration. So the question, rather than glucose may be modestly greater than with SGLT2 whether to use them, is which agent will be inhibitors in combination with metformin, while best for the patient you have in front of you? the converse may be true for post-prandial glucose This article provides a framework to compare levels (Rosenstock et al, 2014; DeFronzo et al, the associated benefits and risks of SGLT2 2015). In people with type 2 diabetes who have Author inhibitors and DPP-4 inhibitors, when added renal impairment, there may be a reduction in Merlin Thomas is Professor, Department of Diabetes, to metformin for the management of type 2 SGLT2 inhibitor efficacy. The glucose-lowering Central Clinical School, Monash diabetes in Australian general practice. effects of DPP-4 inhibitors are unaffected or University, Melbourne. Diabetes & Primary Care Australia Vol 2 No 3 2017 119 © OmniaMed SB and the Primary Care Diabetes Society of Australia – www.pcdsa.com.au The new class war Page points even modestly improved in people with renal The modest volume losses associated with 1. DPP-4 inhibitors have highly impairment (Thomas et al, 2016). SGLT2 inhibition should not cause dehydration, favourable tolerability. This is constipation or dizziness in the long term (Vasilakou important, as most Australians with type 2 diabetes are over Question #2: tolerability et al, 2013). However, alternative glucose-lowering 65 years of age, and for whom All treatments have the potential for adverse strategies should be considered for individuals polypharmacy, inconstant effects, so the doctor’s mantra must be prius minus prone to postural hypotension, fainting or dizziness. health and comorbidities are common. noceant (first do least harm). The key advantage of About 1 in 12 women with diabetes using 2. Because of their mode of using DPP-4 inhibitors is their highly favourable an SGLT2 inhibitor will develop genital thrush action, SGLT2 inhibitors are tolerability (Karagiannis et al, 2012; Kawalec et (candidiasis), usually in the first 3–4 months of not recommended for glucose al, 2014). This is critical, given that the most treatment (Wilding, 2014). Thrush is easy to lowering in people with renal Australians with type 2 diabetes are over 65 years recognise and treat with short courses of standard impairment. of age, in whom polypharmacy, inconstant health antifungal therapies (topical creams, suppositories 3. While some antidiabetes medications are potentially and comorbidities are common. Recent studies or oral “azoles”). Once treated, recurrent infections weight promoting, DPP-4 have confirmed a very small risk of pancreatitis with are uncommon. Although SGLT2 inhibitors inhibitors are weight neutral DPP-4 inhibitors (DeVries et al, 2017). add glucose to the urine, surprisingly, urinary and SGLT2 inhibitors are weight negative. SGLT2 inhibitors block the SGLT2 protein tract infections (UTIs) are not significantly more involved in 90% of glucose reabsorption in the common or more severe in participants receiving proximal renal tubule, resulting in increased renal SGLT2 inhibitors, even in women with a previous glucose excretion and lower blood glucose levels. history of chronic or recurrent UTIs (Vasilakou et SGLT2 inhibitors also increase the urine output, al, 2013). This is possibly because people taking an especially when therapy has just been started and SGLT2 inhibitor empty their bladder more often, glucose levels are high. This can be a positive and just like encouraging drinking, this reduces experience for people using an SGLT2 inhibitor, as bladder stasis and offsets the risk of UTIs. within hours of taking the drug, it begins to take effect. As glucose levels improve, the amount and Question #3: optimising body weight frequency of urination usually settles down. Optimising body weight is a key element of the The glucose-lowering efficacy of SGLT2 management of type 2 diabetes in overweight or obese inhibitors is dependent on sufficient glomerular people, especially in early diabetes when weight loss is filtration to deliver a glucose load to the proximal a high priority and can be hard to achieve, reinforce tubule. SGLT2 inhibitors are not recommended or sustain. When glucose levels are suboptimal, it is for glucose lowering in patients with renal common to recommend intensification of lifestyle impairment (estimated glomerular filtration rate interventions to lose weight while also adding in [eGFR] <45 mL/min/1.73 m2 for empagliflozin or additional glucose-lowering agents. It is important <60 mL/min/1.73 m2 for dapagliflozin), although to be aware that some antidiabetes medications are action on weight, renal and cardiac outcomes potentially weight promoting (sulfonylureas, insulin appear to be maintained even in patients with and thiazolidinediones), and so will be antagonist severe renal impairment. with the advice to intensify lifestyle interventions In the long-term, people with type 2 diabetes for weight loss. DPP-4 inhibitors are weight neutral taking SGLT2 inhibitors will void on average an while SGLT2 inhibitors are weight negative. Glucose extra 300–400 mL/day (Kilov et al, 2013). This is loss and thus calorie loss in the urine, as a result of the same volume as a can of soft drink and taking an an SGLT2 inhibitor, can result in rapid, significant SGLT2 inhibitor will generally mean individuals will and sustained weight loss (approximately 2–3 kg go to the toilet once or maybe twice more every day, in 6 months). Most of the weight loss seen with especially if the medication is taken in the morning SGLT2 inhibition is loss of fat, including visceral (Johnsson et al, 2013). Individuals with type 2 fat (Bolinder et al, 2012), which is important for diabetes who have pre-existing bladder, pelvic floor the waistline and overall health. Interestingly, after or prostate problems may not feel comfortable with 6 months of SGLT2 inhibition, weight loss stops any increase in their urine output, and other glucose- even though glycosuria continues. SGLT2 inhibition lowering strategies should be considered. can contribute to weight loss, but is not the solution. 120 Diabetes & Primary Care Australia Vol 2 No 3 2017 © OmniaMed SB and the Primary Care Diabetes Society of Australia – www.pcdsa.com.au The new class war Question #4: cardiovascular safety of Vascular Outcomes Recorded in Patients with Page points Reducing the risk of cardiovascular events is a Diabetes Mellitus – Thrombolysis in Myocardial 1. Cardiovascular safety data for priority of diabetes management as heart attacks Infarction; Mosenzon et al, 2017) and TECOS DPP-4 inhibitors suggest that the class does not pose an and strokes account for over a third of all deaths (Trial Evaluating Cardiovascular Outcomes with unacceptable cardiovascular in people with type 2 diabetes.