SGLT2 inhibitors in older adults: A valid therapeutic option

Case: 

Margaret is an 80-year-old woman with moderate dementia, managed with donepezil. Her medical history includes hypertension, a prior myocardial infarction (MI) and heart failure with reduced ejection fraction (HFrEF), for which she takes furosemide, bisoprolol and perindopril. She is also being treated for dyslipidemia with atorvastatin. Her type 2 diabetes mellitus (T2DM) is managed with canagliflozin and saxagliptin, and her most recent hemoglobin A1c was 7.0%. Over the past year, she has experienced two falls related to orthostatic hypotension and has unintentionally lost 15 pounds. She presented to hospital with acute cholecystitis requiring an urgent cholecystectomy. Post-operatively, she developed euglycemic diabetic ketoacidosis.

Issue:

Sodium glucose cotransporter 2 inhibitors (SGLT2is) are a game-changing addition to the therapeutic arsenal of T2DM, offering strong heart and kidney protection with a low risk of hypoglycemia. Yet, their use in older adults — especially those who are frail — remains cautious. What makes prescribing these medications in this population particularly challenging?

Background: 

Owing to their numerous benefits, SGLT2is are widely prescribed, even to those without T2DM. Metformin remains the first-line agent for the treatment of T2DM, as recommended by Diabetes Canada. However, SGLT2is are recommended as second-line in adults with T2DM and atherosclerotic cardiovascular disease (ASCVD), HFrEF or chronic kidney disease (CKD) with an eGFR > 30 mL/min/1.73m². They are also recommended in adults aged 60 years or older with T2DM and at least two cardiovascular risk factors.¹  

Glucagon-like peptide-1 receptor agonists (GLP1-RA) could also be considered, except for those with HF.²

The Canadian Cardiovascular Society recommends integration of SGLT2i or GLP1-RA in patients with T2DM and either ASCVD or multiple risk factors for ASCVD. This recommendation applies to patients without HF or CKD and is made irrespective of HbA1c, to reduce cardiorenal risk.³ However, these recommendations are based on studies in the general population and do not specifically address the needs of older adults. 

Diabetes Canada recommends that dipeptidyl peptidase-4 inhibitors (DPP4is) be used before SGLT2is as add-on therapy after metformin in older adults, due to a larger body of evidence supporting their use within this group.¹ In certain cases, such as an older adult under 75 years of age with evidence of cardiovascular disease, adequate renal function and no other complex comorbidities, empagliflozin may be considered after metformin.¹

A common perception exists that evidence-based therapies are less effective in frail individuals alongside concerns regarding increased risk for adverse side effects.⁴ In general, dedicated randomized controlled trials assessing both efficacy and safety of SGLT2is in patients aged 75 years or older are lacking. The current studies use patients without complex comorbidities; therefore, outcomes in frailer older patients remain unclear. 

Evidence: 

Post-hoc analyses of large cardiovascular outcome trials show that the efficacy profile of SGLT2is versus placebo is unchanged across age groups.⁵ A meta-analysis of EMPA-REG OUTCOMES, DECLARE TIMI 58 and CANVAS trials prove the effect of SGLT2is on cardiovascular outcomes among patients with T2DM did not differ by age subgroup.⁵ A meta-analysis of EMPA-REG OUTCOMES, DECLARE TIMI 58 and CREDENCE trials found that the reduction in major adverse cardiovascular events associated with SGLT2is was even greater in older adults than in younger individuals.⁶

Furthermore, outcome benefits can be observed relatively quickly following drug initiation – as early as 24 days with dapagliflozin.⁷ The DAPA-CKD trial showed that in patients with CKD, dapagliflozin significantly reduced composite endpoints – including both cardiac and renal outcomes – compared to placebo, regardless of whether they had concomitant T2DM. However, the time to observe these outcome benefits was approximately 13 months.⁸ This suggests that for older adults who are severely frail, benefits are unlikely to be seen within their anticipated life expectancy.⁹ 

A post-hoc analysis of the DAPA-HF trial showed that dapagliflozin reduced the risk of worsening HF or cardiovascular death in all frailty groups, with the largest absolute reductions seen in frailer patients. Importantly, adverse events were not more frequent than with placebo, regardless of frailty status.¹⁰  

The DELIVER trial specifically evaluated efficacy and safety of dapagliflozin according to frailty status, utilizing The Clinical Frailty Scale.¹¹ This study included patients with either HFrEF or HF with preserved ejection fraction.⁴ Treatment efficacy was not diminished in patients with the greatest degree of frailty, and improvements in health-related quality of life were greater among frailer patients.⁴ Although, the proportion of patients who discontinued SGLT2i therapy or experienced adverse events increased with greater frailty, the incidence of adverse events was not higher in those taking dapagliflozin compared to placebo, irrespective of frailty class.⁴ 

The safety profiles of SGLT2is (e.g., empagliflozin,¹² dapagliflozin,¹³ canagliflozin¹⁴ and ertugliflozin¹⁵) in those aged 65 years or older are adequate.¹⁶ Compared to younger populations, older patients experience similar rates of hypoglycemia and genitourinary infections, lower rates of volume depletion and no increased risk of bone fractures.¹⁷  

Weight loss is a serious side effect to consider in older patients due to its association with falls, increased morbidity and mortality. The EMPA-ELDERLY trial will be the first randomized controlled trial in older patients with T2DM to evaluate the effects of SGLT2is on skeletal muscle mass, muscle strength and physical performance.¹⁸  

SGLT2is may also be associated with volume loss due to diuretic action, which can lead to orthostatic hypotension, especially in patients on antihypertensive or diuretic medications, where dose adjustments may be necessary.^19,20  

Consensus on fracture risk remains conflicting. Only canagliflozin has been associated with a non-significant increase in low-trauma fractures, possibly due to a higher incidence of falls, as volume-related adverse events were more frequent with canagliflozin than placebo.²¹  

SGLT2i use does not appear to increase genitourinary infection incidence in older individuals, though precaution is recommended for female patients with poorly controlled diabetes due to higher infection risk.²⁰  

Although the incidence of euglycemic diabetic ketoacidosis during SGLT2i therapy is low and does not appear to increase with age, its frequency may be approximately double that compared to other antihyperglycemics.²² However, this should not preclude SGLT2i use in older adults.  

SGLT2is act favorably on blood pressure, even in CKD patients, which may help control hypertension burden in older patients.²³  

Recommendation: 

The cardiorenal benefits of SGLT2is do extend to include patients 75 years or older,¹⁹ and the frequency of adverse events suggests there are no absolute contraindications to their use in older patients. They should be considered as a valid therapeutic option in older adults. The “SGLT2 Rx Tool”²⁴ and the algorithm proposed by Custodio et al.²⁵ may help clinicians better assess the risks and benefits of SGLT2i therapy in various patient profiles.  

However, extra caution is still required in real-life situations, where older individuals are often less robust than those in randomized controlled trials. These patients may be more vulnerable to serious adverse effects such as weight loss and orthostatic hypotension, which may drive reluctance to initiate these evidence-based agents in frail older adults.²⁶ 

Case Outcome: 

The patient was maintained on the canagliflozin for cardio protection. Her bisoprolol was able to be reduced helping the orthostatic hypotension. Her weight was followed.  

Acknowledgement: 

This article is a collaboration with the Canadian Geriatrics Society (CGS). For more articles from CGS, visit www.geriatricsjournal.ca/journalarticles or www.canadiangeriatrics.ca. 

References: 

1. Meneilly GS, Knip A, Miller DB, et al. Diabetes Canada 2018 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada: Diabetes in Older People. Can J Diabetes [Internet]. 2018 [cited 2024 Jul 25];42:S283-S295. Available from: https://www.diabetes.ca/health-care-providers/clinical-practice-guidelines/chapter-37#panel-tab_FullText  
2. Lipscombe L, Butalia S, Dasgupta K, et al. Diabetes Canada 2018 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada: Pharmacologic Glycemic Management of Type 2 Diabetes in Adults: 2020 Update. Can J Diabetes [Internet]. 2020 [cited 2024 Jul 25];44:575-591. Available from: https://guidelines.diabetes.ca/cpg/chapter-13-2020-update  
3. Mancini GBJ, O'Meara E, Zieroth S, et al. 2022 Canadian Cardiovascular Society Guideline for Use of GLP-1 Receptor Agonists and SGLT2 Inhibitors for Cardiorenal Risk Reduction in Adults. Can J Cardiol [Internet]. 2022 Aug [cited 2024 Jul 25];38(8):1153-1167. Available from: https://onlinecjc.ca/article/S0828-282X(22)00335-X/fulltext    
4. Butt JH, Jhund PS, Belohlávek J, et al. Efficacy and Safety of Dapagliflozin According to Frailty in Patients With Heart Failure: A Prespecified Analysis of the DELIVER Trial. Circulation [Internet]. 2022 Oct 18 [cited 2024 Jul 25];146(16):1210-1224. Available from: https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.122.061754  
5. Giugliano D, Longo M, Maiorino MI, et al. Efficacy of SGLT-2 inhibitors in older adults with diabetes: Systematic review with meta-analysis of cardiovascular outcome trials. Diabetes Res Clin [Internet]. 2020 Apr [cited 2024 Jul 25];162:108114. Available from: https://www.diabetesresearchclinicalpractice.com/article/S0168-8227(20)30364-8/abstract  
6. Strain WD, Griffiths J. A systematic review and meta-analysis of the impact of GLP-1 receptor agonists and SGLT-2 inhibitors on cardiovascular outcomes in biologically healthy older adults. Br J Diabetes [Internet]. 2021 [cited 2024 Jul 25]; 21: 30–5. Available from: https://bjd-abcd.com/index.php/bjd/article/view/647  
7. Packer M, Anker SD, Butler J, et al. Effect of Empagliflozin on the Clinical Stability of Patients With Heart Failure and a Reduced Ejection Fraction: The EMPEROR-Reduced Trial. Circulation [Internet]. 2021 Jan 26 [cited 2024 Jul 25];143(4):326-336. Available from: https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.051783  
8. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med [Internet]. 2020 Oct 8 [cited 2024 Jul 25];383(15):1436-1446. Available from: https://www.nejm.org/doi/full/10.1056/NEJMoa2024816  
9. Evans M, Morgan AR, Davies S, et al. The role of sodium-glucose co-transporter-2 inhibitors in frail older adults with or without type 2 diabetes mellitus. Age Ageing [Internet]. 2022 Oct 6 [cited 2024 Jul 25];51(10):afac201. Available from: https://academic.oup.com/ageing/article/51/10/afac201/6749364?login=false  
10. Butt JH, Dewan P, Merkely B, et al. Efficacy and Safety of Dapagliflozin According to Frailty in Heart Failure With Reduced Ejection Fraction: A Post Hoc Analysis of the DAPA-HF Trial. Ann Intern Med [Internet]. 2022 Jun [cited 2024 Jul 25];175(6):820-830. Available from: https://www.acpjournals.org/doi/10.7326/M21-4776  
11. Moorhouse P, Rockwood K. Frailty and its quantitative clinical evaluation. J R Coll Physicians Edinb [Internet]. 2012 [cited 2024 Jul 25];42(4):333-40. Available from: https://www.rcpe.ac.uk/journal/issue/journal_42_4/moorhouse.pdf  
12. Kinduryte Schorling O, Clark D, Zwiener I, et al. Pooled Safety and Tolerability Analysis of Empagliflozin in Patients with Type 2 Diabetes Mellitus. Adv Ther [Internet]. 2020 Aug [cited 2024 Jul 25];37(8):3463-3484. Available from: https://link.springer.com/article/10.1007/s12325-020-01329-7  
13. Fioretto P, Mansfield TA, Ptaszynska A, et al. Long-Term Safety of Dapagliflozin in Older Patients with Type 2 Diabetes Mellitus: A Pooled Analysis of Phase IIb/III Studies. Drugs Aging [Internet]. 2016 Jul [cited 2024 Jul 25];33(7):511-22. Available from: https://link.springer.com/article/10.1007/s40266-016-0382-1  
14. Sinclair AJ, Bode B, Harris S, et al. Efficacy and Safety of Canagliflozin in Individuals Aged 75 and Older with Type 2 Diabetes Mellitus: A Pooled Analysis. J Am Geriatr Soc [Internet]. 2016 Mar [cited 2024 Jul 25];64(3):543-52. Available from: https://agsjournals.onlinelibrary.wiley.com/doi/10.1111/jgs.14028  
15. Pratley R, Dagogo-Jack S, Charbonnel B, et al. Efficacy and safety of ertugliflozin in older patients with type 2 diabetes: A pooled analysis of phase III studies. Diabetes Obes Metab [Internet]. 2020 Dec [cited 2024 Jul 25];22(12):2276-2286. Available from: https://dom-pubs.pericles-prod.literatumonline.com/doi/10.1111/dom.14150
16. Scheen AJ. Pharmacodynamics, efficacy and safety of sodium-glucose co-transporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus. Drugs [Internet]. 2015 Jan [cited 2024 Jul 25];75(1):33-59. Available from: https://link.springer.com/article/10.1007/s40265-014-0337-y  
17. Fioretto P, Mansfield TA, Ptaszynska A, et al. Long-Term Safety of Dapagliflozin in Older Patients with Type 2 Diabetes Mellitus: A Pooled Analysis of Phase IIb/III Studies. Drugs Aging [Internet]. 2016 Jul [cited 2024 Jul 25];33(7):511-22. Available from: https://link.springer.com/article/10.1007/s40266-016-0382-1  
18. Yabe D, Shiki K, Suzaki K, et al. Rationale and design of the EMPA-ELDERLY trial: a randomised, double-blind, placebo-controlled, 52-week clinical trial of the efficacy and safety of the sodium-glucose cotransporter-2 inhibitor empagliflozin in elderly Japanese patients with type 2 diabetes. BMJ Open [Internet]. 2021 Apr 7 [cited 2024 Jul 25];11(4):e045844. Available from: https://bmjopen.bmj.com/content/11/4/e045844  
19. Abdelhafiz AH, Sinclair AJ. Cardio-renal protection in older people with diabetes with frailty and medical comorbidities - A focus on the new hypoglycaemic therapy. J Diabetes Complications [Internet]. 2020 Sep [cited 2024 Jul 25];34(9):107639. Available from: https://www.sciencedirect.com/science/article/abs/pii/S1056872720303986?via%3Dihub  
20. Cintra R, Moura FA, Carvalho LSF, et al. Inhibition of the sodium-glucose co-transporter 2 in the elderly: clinical and mechanistic insights into safety and efficacy. Rev Assoc Med Bras (1992) [Internet]. 2019 Jan [cited 2024 Jul 25];65(1):70-86. Available from: https://www.scielo.br/j/ramb/a/RWqwfK4xzwscCqMV74wFTcD/?lang=en  
21. Watts NB, Bilezikian JP, Usiskin K, et al. Effects of Canagliflozin on Fracture Risk in Patients With Type 2 Diabetes Mellitus. J Clin Endocrinol Metab [Internet]. 2016 Jan [cited 2024 Jul 25];101(1):157-66. Available from: https://academic.oup.com/jcem/article/101/1/157/2806681  
22. Erondu N, Desai M, Ways K, et al. Diabetic Ketoacidosis and Related Events in the Canagliflozin Type 2 Diabetes Clinical Program. Diabetes Care [Internet]. 2015 Sep [cited 2024 Jul 25];38(9):1680-6. Available from: https://diabetesjournals.org/care/article/38/9/1680/37313/Diabetic-Ketoacidosis-and-Related-Events-in-the  
23. Kohan DE, Fioretto P, Tang W, et al. Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int [Internet]. 2014 Apr [cited 2024 Jul 25];85(4):962-71. Available from: https://www.kidney-international.org/article/S0085-2538(15)56274-1/fulltext
24. Fralick M, Zhao A, Gyenes M, et al. SGLT2 Rx Tool [Internet] [Publisher unknown]; 2022 [cited 2024 Jul 25]. Available from: https://www.sglt2rx.com/  
25. Custódio JS Jr, Roriz-Filho J, Cavalcanti CAJ, et al. Use of SGLT2 Inhibitors in Older Adults: Scientific Evidence and Practical Aspects. Drugs Aging [Internet]. 2020 Jun [cited 2024 Jul 25];37(6):399-409. Available from: https://link.springer.com/article/10.1007/s40266-020-00757-y
26. Scheen AJ. Efficacy / safety balance of DPP-4 inhibitors versus SGLT2 inhibitors in elderly patients with type 2 diabetes. Diabetes Metab [Internet]. 2021 Nov [cited 2024 Jul 25];47(6):101275. Available from: https://www.sciencedirect.com/science/article/abs/pii/S1262363621000586?via%3Dihub