title sub title SGLT2 and DPP4 Inhibition: An Ideal Combination

EXPERT MONOGRAPH ISSUE 47

Introduction

Few patients with type 2 diabetes can successfully manage their glucose levels, and the risk of complications associated with them, using only monotherapy. Most will need to take at least two, more often three glucose-lowering agents to

achieve and maintain optimal glucose control. Although each single agent will have some limitations as monotherapy, this is seldom a failing of any individual strategy. Rather, it reflects the complex multifactorial pathogenesis of hyperglycaemia1 and the progressive nature of type 2 diabetes.

So instead of accepting the traditional ‘treat-to-fail’ approach for managing diabetes that uses combination therapy only as a last resort, an early proactive use of combination therapies for glucose lowering may offer a number of advantages. This review will explore the potential benefits and limitations of combination therapy with SGLT2 and DPP4 inhibitors and their role in managing type 2 diabetes.

Take Home Messages

į SGLT2 inhibitors and DPP4 inhibitors can be safely and effectively used together in patients with type 2 diabetes.

į The glucose lowering achieved using combination therapy is better than each agent individually.

į Therapy combining SGLT2 inhibitors with DPP4 inhibitors are now subsidised through the Pharmaceutical Benefits Scheme (PBS) as triple therapy (added to metformin or a sulphonylurea).

į A range of fixed-dose formulations combining different SGLT2 inhibitors with DPP4 inhibitors are now available and subsided by the PBS.

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PROFESSOR MERLIN THOMAS MBChB, PhD, FRACP

Prof Merlin Thomas is a Professor of Medicine at Monash University, Melbourne. Prof Thomas is both a physician and a research scientist. He has published over 300 articles in many of the world’s leading medical journals, as well as several books including The Longevity List and Fast Living, Slow Ageing. He is an internationally recognised speaker, opinion-leader, teacher and medical storyteller. His research focuses on discovering new ways to prevent and treat the complications of diabetes.

This article discusses the evidence for the combination use of SGLT2 inhibitors and DPP4 inhibitors, in addition to standard care, in the management of type 2 diabetes.

FEBRUARY 21, 2020

This article was supported by an independent educational sponsorship provided by Merck Sharp & Dohme.

title sub title

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Hormonal Contraception Trouble-shooting Part One: The Overweight Woman

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SGLT2 and DPP4 Inhibition: An Ideal Combination

More medication = better glucose control

Good glucose control is still important for the management of

diabetes. Although recent cardiovascular outcome trials have

demonstrated that some of the benefits of SGLT2 inhibitors2 and

GLP-1 receptor agonists3 are independent of glucose lowering,

achieving and maintaining the HbA1c at or close to the target

appropriate for that individual is still fundamental and clearly has

long-term benefits for preventing diabetic complications4, especially

if undertaken without delay and early in the course of the disease.

RACGP guidelines specifically recommend adding additional glucose

lowering therapy after no more than six months when patients are

not achieving their desired level of control5.

The addition of SGLT2 inhibitors to DPP4 inhibitors and vice versa,

achieves a valuable reduction in HbA1c in most patients. Overall,

across a large number of clinical trials, the use of SGLT2 inhibitors

is associated with reduction in HbA1c between 0.6 to 0.9%

when compared to placebo, regardless of background therapy6.

Specifically, adding an SGLT2 inhibitor onto background therapy

with a DPP4 inhibitor reduces HbA1c by 0.62%, [95% CI: 0.73 to

0.51%; P < 0.001] compared to placebo7.

For example, in patients inadequately controlled on sitagliptin and

metformin, treatment with ertugliflozin 5mg or 15mg lowered

HbA1c by 0.7% [95% CI 0.9, 0.5] and 0.8% [95% CI 0.9, 0.6],

respectively (P <0.001 for both comparisons; Figure 1)8.

However, patients with poor glucose control (HbA1c>8%) can

achieve a greater response than those starting an SGLT2 inhibitor

when closer to 7%8-10. This is simply because the amount of glucose

that can be lost into the urine when using SGLT2 inhibitors is

proportional to the ambient glucose6.

A key advantage of combining DPP4 inhibition and SGLT2 inhibition

in an individual patient is that the fundamental differences in

glucose-lowering by these two agents offer an opportunity for

broader coverage. For example, in a patient with poor glucose

control, treatment with an SGLT2 inhibitor reduces plasma glucose

levels effectively, but their glycosuria wanes as HbA1c levels

approach 7.0%. To achieve target control, adding in DPP4 inhibitors

is a great way to get over the line, because unlike SGLT2 inhibitors,

their efficacy is less glucose-dependent. Indeed, DPP4 inhibitors may

be more effective for glucose lowering than SGLT2 inhibitors when

the HbA1c is less than 7.5%7,11. Equally, in patients inadequately

controlled on a DPP4 inhibitor, the better effects of SGLT2 on post-

prandial glucose and insulin-independent glucose lowering can

facilitate improved glucose control.

Figure 1. Change over time in glycated haemoglobin (HbA1c) from baseline with ertuglifozin or placebo in patients inadequately controlled with metformin and sitagliptin (VERTIS-SITA2)

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Dagogo-Jack S,et al. Diabetes Obesity and Metabolism (2018) Mar;20(3):530-540.

Overall, the effect of adding a DPP4 inhibitor onto background therapy with an SGLT2 inhibitor in recent trials is slightly less than the other way around [weighted mean difference 0.37%; 95% CI: 0.50 to 0.25%; P < 0.001]. However, this most likely reflects differences in glucose control at baseline. This is also why the glucose-lowering effects of simultaneously combining a DPP4 inhibitor together with an SGLT2 inhibitor are not additive with respect to HbA1c reduction, as each agent reduces the baseline glucose for the other to work off.

Importantly, the likelihood of achieving a target HbA1c <7% is increased to the same extent by adding a DPP4 inhibitor to an SGLT2 inhibitor, or by adding an SGLT2 inhibitor to a DPP4 inhibitor7.

More medication ≠ more side effects

The first reason why most patients and doctors dislike combination therapy is the notion that adding more medication will unnecessarily expose patients to more side effects. Take for example what happens when sulphonylurea is added to metformin, the addition opens up a whole world of monitoring and mitigation of hypoglycaemia risks. However, a perfect combination would add little or no extra risks to the patient (alongside the potential benefits).

One advantage of using DPP4 inhibitors in combinations is their highly favourable tolerability when added to background therapy, including SGLT2 inhibitors12,13.

Avoiding the worry of potential hypoglycaemia and weight gain helps for adherence when starting out as well as in the long term. But while the safety and tolerability of DPP-4 inhibitors is favourable compared to other glucose lowering agents, all DPP-4 inhibitors

may be associated with an increased risk of acute pancreatitis13 and bullous pemphigoid14 (although the absolute risk remains very low).

Adding an SGLT2 inhibitor to background therapy with a DPP4 inhibitor does not increase the risk of hypoglycaemia or weight gain. In fact, taking SGLT2 inhibitors results in rapid, significant and sustained weight loss (approximately two to three kilograms in six months of treatment6), regardless of background therapy. For example, adding ertugliflozin 5mg or 15mg onto background therapy with a sitagliptin 100mg reduced body weight by 2.0 kg and 2.1 kg respectively more than placebo (p<0.001)15.

Clinical experience suggests patients don’t forget that this was the drug that helped them lose some weight, even if the weight loss subsequently plateaus after six months of therapy.

On the downside, adding an SGLT2 inhibitor to background therapy with a DPP4 inhibitor can be associated with increased urine output and frequency, especially if baseline plasma glucose levels are high. This is not usually a problem, and settles down quickly as glucose control improves and glycosuria declines16. Starting the SGLT2 inhibitor early, while patients have an HbA1c below 8%, can also minimise polyuria at initiation. Subjects with pre-existing bladder, pelvic floor or prostate problems may be less accommodating to any increase in their urine output, and other glucose lowering strategies might be preferable in these contexts.

SGLT2 inhibition can also increase the risk of developing genital thrush (candidiasis), especially in women with urinary incontinence and/or poor genital hygiene. Although painful and unpleasant, thrush generally settles quickly with short courses of standard antifungal therapies (topical creams, suppositories or oral ‘azoles’). Furthermore, focused education programs to improve genital hygiene can significantly reduce the risks of thrush in patients with diabetes. Like polyuria, genital mycoses are glucose-dependent and minimised when starting therapy from an HbA1c of less than 8%. Some studies have reported that SGLT2/DPP4 inhibitor combinations resulted in a slightly lower risk of genital infection compared with an SGLT2 inhibitor alone (RR: 0.42, 95% CI: 0.18 to 0.99; P = 0.046)7 . Whether this is due to less glycosuria or other actions of DPP4 inhibitors is unclear.

Ketoacidosis has been rarely reported in patients using SGLT2 inhibitors17. Where it has occurred, it has almost always been when SGLT2 inhibitors have continued to be taken in stressful metabolic settings, like prolonged starvation, after surgery, excess alcohol intake or major intercurrent illness.

Inappropriate and excessive reductions of insulin doses may also increase ketone production. Although DPP4 inhibition may prevent the rise in glucagon following SGLT2 inhibition, it does not appear to prevent ketogenesis or lower the risk of ketoacidosis18.

Combinations for patients with diabetes and renal impairment

At least one in four of all adult patients(>55 years)19 with type 2 diabetes in Australian general practice have moderate to severe renal impairment, denoted by the presence of an estimated GFR less than 60 mL/min/1.73m2. Managing these patients can be challenging. Patients with diabetes and renal impairment are at increased risk for poor health outcomes including adverse drug reactions, cardiovascular disease, heart failure, and premature mortality. This makes the use SGLT2 inhibitors with their proven cardiovascular, heart failure and renoprotective benefits2 highly desirable, compared to other strategies that, at best, have demonstrated safety in this setting20.

At the same time, the glucose-lowering effects of SGLT2 inhibitors are reduced in patients with an eGFR between 45-60 mL/min/1.73m2 (Stage 3A CKD) (Figure 2) and are non-significant in patients with reduced kidney function below this level. This is the reason that SGLT2 inhibitors are not currently recommended for use in patients with an eGFR less than 45 mL/min/1.73m2, and are contraindicated in patients with an eGFR <30 mL/min/1.73m2 or an eGFR persistently lower than 45 mL/min/1.73m2. In fact, they are still working but too little glomerular filtration means insufficient urinary glucose loss, so little or no plasma glucose lowering. In order to achieve glucose control, as well as end organ protection, a combination of SGLT2 inhibition with an appropriate dose of DPP4 inhibitor in patients with renal impairment is therefore preferred. Empagliflozin/linagliptin is contraindicated in patients with an eGFR persistently below 45 mL/min/1.73m2. Saxagliptin/dapagliflozin should not be used in patients with an eGFR persistently lower than 60 mL/min/1.73m2.

DPP4 inhibition allows for safe and effective glucose control in patients with diminished renal function, with efficacy comparable to that observed in patients with normal renal function and a low incidence of adverse drug reactions including hypoglycaemia6. Reductions in albuminuria with DPP4 inhibitors have also been reported in large trials21. At the same time, SGLT2 inhibition can protect the heart and the kidneys2, independent of glucose lowering.

Combinations for patients with diabetes and heart failure

Heart failure is an unwelcome companion to type 2 diabetes.

Patients with type 2 diabetes have over twice the risk of incident heart failure as people without diabetes22.

Although historically-associated with comorbid ischaemic heart disease (e.g. a prior heart attack), increasingly patients are presenting with shortness of breath or ankle swelling as their first sign of cardiac disease.

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SGLT2 and DPP4 Inhibition: An Ideal Combination

Treatment with SGLT2 inhibitors has been shown to be associated with a substantial reduction in hospitalisation for heart failure, both in those with known heart failure and those without known cardiac disease2. Recent European guidelines recommend the use of SGLT2 inhibitors in all patients with diabetes and heart failure, as well as those at increased risk from heart failure, including those with cardiovascular disease and chronic kidney disease23.

By contrast, some DPP4 inhibitors have been associated with a borderline increase in the risk for hospitalisation from heart failure24, and have been generally discouraged for use in patients with heart failure. However, the large Cardiovascular Outcome Trial using sitagliptin showed no safety signal, including patients with known heart failure25. Limiting any risk from heart failure by combining SGLT2 and DPP4 inhibition is an attractive proposition, although there is currently no evidence to support this.

Combinations for patients with diabetes and cardiovascular disease

The burden of cardiovascular disease among people with diabetes is substantial.

Almost two in three adults with type 2 diabetes report having cardiovascular disease26. Reducing the risk of cardiovascular events, and certainly not adding to it, is a top priority of diabetes management.

Overall, data suggests that DPP4 inhibitors are generally a safe way to lower glucose levels in patients with type 2 diabetes27. Clinical trials including patients with established CVD have been completed with empagliflozin, canagliflozin (not available in Australia) and dapagliflozin (EMPA-REG Outcomes, CANVAS and DECLARE-TIMI53, respectively) and the VERTIS-CV trial with ertugliflozin is due to be reported in 2020.

Despite some variability between studies, taken as a whole these data suggest that all SGLT2 inhibitors have the potential to reduce the risk of major acute cardiovascular events, myocardial infarction, heart failure and mortality, when used in addition to standard care (Figure 3)2. As a consequence, recent global guidelines recommend the use of SGLT2 inhibitors in all patients with diabetes and atherosclerotic cardiovascular disease20,23.

Fixed-dose combinations make a difference

One of the major keys to long term therapy is adherence. The best medication does not work if it does not continue to be taken! One determinant of non-adherence is a medication’s tolerability and perceived safety, which is one reason why adherence with DPP4 inhibitors is greater than with other glucose-lowering agents.

Another factor that contributes to non-adherence is dosing complexity and the overall pill burden.

Fixed dose combinations of glucose lowering medications have a strong potential to improve adherence by consolidating therapy to reduce the pill burden of separate pills as well encouraging adherence with a stronger combination therapy28. Generally, fixed-dose combinations are also associated with better patient satisfaction29. And better adherence and satisfaction generally means better control. For example, the GIFT study observed a 0.3% to 0.4% reduction in HbA1c after a switch to a fixed dose combination from separate metformin and DPP4 inhibitor therapy30.

What combination?

As most patients with type 2 diabetes will need dual or triple therapy to achieve and maintain glucose control, almost everyone should consider some fixed-dose combination or another. Consolidating the SGLT2 and DPP4 inhibitor into a single once daily tablet, and

SGLT2 and DPP4 Inhibition: An Ideal Combination

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Figure 2. The glucose-lowering efficacy of SGLT2 inhibitors is reduced in patients with moderate renal impairment eGFR 45-60mL/min/1.73m2 (CKD stage 3A)

1. Fioretto et al. Diabetes Obesity and Metabolism (2018); 2. Barnett et al. Lancet (2014); 3. Grunberger et al. Diabetes Ther. (2018).

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taking the metformin separately has marginal cost advantages for the patient compared to fixed-dose combinations with metformin. However, as most patients will be using metformin combinations as second line before using both SGLT2 and DPP4 inhibition together, it is often simpler to add one (of DPP4 or SGLT2 inhibitor), rather than change two.

Whether you are starting with an SGLT2 inhibitor and then adding an DPP4 inhibitor or the other way around will be dependent upon the patient and their individual needs. In high risk patients with comorbidities including cardiovascular disease, heart failure and chronic kidney disease, SGLT2 inhibition is now widely recommended after metformin as first or second line therapy20,23. Additional control can be easily achieved with the addition of a DPP4 inhibitor as needed, to safely reach the desired target without hypoglycaemia or weight gain.

Equally, in low-risk patients the priority is to reduce barriers to long-term adherence by choosing agents with a reduced risk of side effects like hypoglycaemia and weight gain. Generally, DPP4 inhibition is a safe, well-tolerated second line agent. SGLT2 inhibition can then be added for patients who are non-responsive with the added reinforcement of early weight loss.

In the future, it may well be that an early combination approach will be the norm for managing type 2 diabetes. We are already seeing a move away from a traditional glucose-centric approach, to assessing the risks from comorbidities and complications which influence the choice of a particular glucose-lowering medication or medications20,23. But even in early disease the sooner and better the glucose is controlled, the more durable this control will be31.

Declaration of Interest

Prof Merlin Thomas was commissioned by Healthed for this article. The ideas, opinions and information presented are solely those of the author. The advertiser does not necessarily endorse or support the views expressed in this article. Prof Thomas has received from support for travel and honoraria from pharmaceutical companies involved in the manufacture of SGLT2/DPP4i including AstraZeneca, Boehringer Ingelheim, Lilly, Merck Sharp & Dohme, Novartis and Servier.

References

1. Defronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009 Apr; 58(4): 773-95. DOI: 10.2337/db09-9028

2. Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet. 2019 Jan 5; 393(10166): 31-9. DOI: 10.1016/S0140-6736(18)32590-X

3. Kristensen SL, Rørth R, Jhund PS, Docherty KF, Sattar N, Preiss D, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol. 2019 Oct; 7(10): 776-85. DOI: 10.1016/S2213-8587(19)30249-9

4. Thomas MC. Glycemic exposure, glycemic control, and metabolic karma in diabetic complications. Adv Chronic Kidney Dis. 2014; 21(3): 311-7. DOI: 10.1053/j.ackd.2014.03.004

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SGLT2 and DPP4 Inhibition: An Ideal Combination

Figure 3. Pooled analysis of completed trials demonstrates a reduction in major cardiac outcomes associated with SGLT2 inhibitors in patients with established atherosclerotic cardiovascular disease (*3P-MACE = time to first myocardial infarction, stroke or cardiovascular death)2.

Outcome Hazard Ratio (95% CI)FE Model p-value

3P-MACE* 0.86 (0.80, 0.93) 0.0002

Myocardial infarction 0.85 (0.76, 0.95) 0.0045

Stroke 0.98 (0.84, 1.14) 0.78

Hospitalisation for heart failure 0.71 (0.62, 0.82) <0.0001

Cardiovascular death 0.80 (0.71, 0.91) 0.0005

All-cause mortality 0.83 (0.75, 0.92) 0.0003

Zelniker et al. Lancet 2016;10.1016/S0140-6736(18)32590-X

0.5 0.7 0.9

SGLT2 better Placebo better

1.1 1.3 1.5

5. The Royal Australian College of General Practitioners. General practice management of type 2 diabetes: 2016-18 [Internet]. East Melbourne, VIC: RACGP; 2016. 192 p. Available from: https://www.racgp.org.au/FSDEDEV/media/documents/Clinical%20Resources/Guidelines/Diabetes/General-practice-management-of-type-2-diabetes_1.pdf

6. Zaccardi F, Webb DR, Htike ZZ, Youssef D, Khunti K, Davies MJ. Efficacy and safety of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes mellitus: systematic review and network meta-analysis. Diabetes Obes Metab. 2016 Aug; 18(8): 783-94. DOI: 10.1111/dom.12670

7. Cho YK, Kang YM, Lee SE, Lee J, Park JY, Lee WJ, et al. Efficacy and safety of combination therapy with SGLT2 and DPP4 inhibitors in the treatment of type 2 diabetes: A systematic review and meta-analysis. Diabetes Metab. 2018 Nov; 44(5): 393-401. DOI: 10.1016/j.diabet.2018.01.011

8. Dagogo-Jack S, Liu J, Eldor R, Amorin G, Johnson J, Hille D, et al. Efficacy and safety of the addition of ertugliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sitagliptin: The VERTIS SITA2 placebo-controlled randomized study. Diabetes Obes Metab. 2018 Mar; 20(3): 530-40. DOI: 10.1111/dom.13116

9. Rosenstock J, Hansen L, Zee P, Li Y, Cook W, Hirshberg B, et al. Dual Add-on Therapy in Type 2 Diabetes Poorly Controlled With Metformin Monotherapy: A Randomized Double-Blind Trial of Saxagliptin Plus Dapagliflozin Addition Versus Single Addition of Saxagliptin or Dapagliflozin to Metformin. Diabetes care. 2015 Mar; 38(3): 376-83. DOI: 10.2337/dc14-1142

10. DeFronzo RA, Lewin A, Patel S, Liu D, Kaste R, Woerle HJ, et al. Combination of Empagliflozin and Linagliptin as Second-Line Therapy in Subjects With Type 2 Diabetes Inadequately Controlled on Metformin. Diabetes Care. 2015 Mar; 38(3): 384-93. DOI: 10.2337/dc14-2364

11. Abe T, Matsubayashi Y, Yoshida A, Suganami H, Nojima T, Osawa T, et al. Predictors of the response of HbA1c and body weight after SGLT2 inhibition. Diabetes Metab. 2018 Mar; 44(2): 172-4. DOI: 10.1016/j.diabet.2017.10.003

12. Karagiannis T, Paschos P, Paletas K, Matthews DR, Tsapas A. Dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: systematic review and meta-analysis. BMJ. 2012 Mar 12; 344: e1369. DOI: 10.1136/bmj.e1369

13. Kawalec P, Mikrut A, Lopuch S. The safety of dipeptidyl peptidase-4 (DPP-4) inhibitors or sodium-glucose cotransporter 2 (SGLT-2) inhibitors added to metformin background therapy in patients with type 2 diabetes mellitus: a systematic review and meta-analysis. Diabetes Metab Res Rev. 2014 May; 30(4): 269-83. DOI: 10.1002/dmrr.2494

14. Nishie W. Dipeptidyl peptidase IV inhibitor-associated bullous pemphigoid: a recently recognized autoimmune blistering disease with unique clinical, immunological and genetic characteristics. Immunol Med. 2019 Mar; 42(1): 22-8. DOI: 10.1080/25785826.2019.1619233

15. Miller S, Krumins T, Zhou H, Huyck S, Johnson J, Golm G, et al. Ertugliflozin and Sitagliptin Co-initiation in Patients with Type 2 Diabetes: The VERTIS SITA Randomized Study. Diabetes Ther. 2018 Feb; 9(1): 253-68. DOI: 10.1007/s13300-017-0358-0

16. Johnsson KM, Ptaszynska A, Schmitz B, Sugg J, Parikh SJ, List JF. Urinary tract infections in patients with diabetes treated with dapagliflozin. Journal of diabetes and its complications. 2013 Sep-Oct; 27(5): 473-8. DOI: 10.1016/j.jdiacomp.2013.05.004

17. Scheen AJ. An update on the safety of SGLT2 inhibitors. Expert Opin Drug Saf. 2019 Apr; 18(4): 295-311. DOI: 10.1080/14740338.2019.1602116

18. Chaplin S. DPP4/SGLT2 Inhibitor combined therapy for type 2 diabetes. Prescriber; 2017 Nov 13: 28(11); 32-8. Available from: https://www.prescriber.co.uk/article/dpp-4sglt2-inhibitor-combined-therapy-type-2-diabetes/

19. Razavian M, Heeley EL, Perkovic V, Zoungas S, Weekes A, Patel AA, et al. Cardiovascular risk management in chronic kidney disease in general practice (the AusHEART study). Nephrol Dial Transplant, 2012 Apr; 27(4): 1396-402. DOI: 10.1093/ndt/gfr599

20. Davies MJ, D’Alessio DA, Fradkin J, Kernan WN, Mathieu C, Mingrone G, et al. Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018 Dec; 41(12): 2669-2701. DOI: 10.2337/dci18-0033

21. Cornel JH, Bakris GL, Stevens SR, Alvarsson M, Bax WA, Chuang LM, et al. Effect of Sitagliptin on Kidney Function and Respective Cardiovascular Outcomes in Type 2 Diabetes: Outcomes From TECOS. Diabetes Care. 2016 Dec; 39(12): 2304-10. DOI: 10.2337/dc16-1415

22. Dei Cas A, Khan SS, Butler J, Mentz RJ, Bonow RO, Avogaro A, et al. Impact of diabetes on epidemiology, treatment, and outcomes of patients with heart failure. JACC Heart Fail. 2015 Feb; 3(2): 136-45. DOI: 10.1016/j.jchf.2014.08.004

23. Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V, et al. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J. 2019 Aug 31. pii: ehz486. DOI: 10.1093/eurheartj/ehz486 [Epub ahead of print]

24. Li L, Li S, Deng K, Liu J, Vandvik PO, Zhao P, et al. Dipeptidyl peptidase-4 inhibitors and risk of heart failure in type 2 diabetes: systematic review and meta-analysis of randomised and observational studies. BMJ. 2016 Feb 17; 352: i610. DOI: 10.1136/bmj.i610

25. Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, et al. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2015 Jul 16; 373(3): 232-42. DOI: 10.1056/NEJMoa1501352

www.healthed.com.au Page 6

SGLT2 and DPP4 Inhibition: An Ideal Combination

26. Australian Bureau of Statistics. National Health Survey: First Results, 2014-15 [Internet]. Canberra, ACT: ABS; 2015. 51 p. Cat No.: 4364.0.55.001. Available from: https://www.ausstats.abs.gov.au/ausstats/subscriber.nsf/0/CDA852A349B4CEE6CA257F150009FC53/$File/national%20health%20survey%20first%20results,%202014-15.pdf

27. Patil HR, Al Badarin FJ, Al Shami HA, Bhatti SK, Lavie CJ, Bell DS, et al. Meta-analysis of effect of dipeptidyl peptidase-4 inhibitors on cardiovascular risk in type 2 diabetes mellitus. Am J Cardiol. 2012 Sep 15; 110(6): 826-33. DOI: 10.1016/j.amjcard.2012.04.061

28. Schlosser R. Fixed-Dose and Fixed-Ratio Combination Therapies in Type 2 Diabetes. Can J Diabetes. 2019 Aug; 43(6): 440-4. DOI: 10.1016/j.jcjd.2019.05.005

29. Hutchins V, Zhang B, Fleurence RL, Krishnarajah G, Graham J. A systematic review of adherence, treatment satisfaction and costs, in fixed-dose combination regimens in type 2 diabetes. Curr Med Res Opin. 2011 Jun; 27(6): 1157-68. DOI: 10.1185/03007995.2011.570745

30. Bajaj HS, Ye C, Jain E, Venn K, Stein E, Aronson R. Glycemic Improvement with a Fixed-dose combination of DPP-4 inhibitor + metformin in patients with Type 2 diabetes (GIFT study). Diabetes Obes Metab. 2018 Jan; 20(1): 195-9. DOI: 10.1111/dom.13040

31. Matthews DR, Paldánius PM, Proot P, Chiang Y, Stumvoll M, Del Prato S, et al. Glycaemic durability of an early combination therapy with vildagliptin and metformin versus sequential metformin monotherapy in newly diagnosed type 2 diabetes (VERIFY): a 5-year, multicentre, randomised, double-blind trial. Lancet. 2019 Oct 26; 394(10208): 1519-29. DOI: 10.1016/S0140-6736(19)32131-2

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SGLT2 and DPP4 Inhibition: An Ideal Combination

Editorial TeamMedical Editors: Dr Linda Calabresi, Dr Vivienne Miller Managing Editor: Neil Harris Production Editor: Amanda Bryan Editorial Assistant: Sai Machiraju Executive Editor: Dr Ramesh Manocha