SGLT2i in patients with diabetes: translating an evolving body of evidence to the nuances of practice

Please also see our past article on heart failure and SGLT2i’s: Sodium Glucose Cotransporter 2 (SGLT2) Inhibitors: New drug class in the treatment of Heart Failure with Reduced Ejection Fraction — DAPA-HF and EMPEROR-Reduced trials, January 13, 2021, by Tanveer Brar, Doson Chua, and Laura Atiyeh

Author

Dr. Jamie Falk (biography and disclosures)

Disclosures: Received speaker honoraria from the Health Education Collaboration (not-for-profit organization) and the Canadian Society of Hospital Pharmacists (not-for-profit organization). Mitigating potential bias: Recommendations are consistent with current practice patterns. Treatments or recommendations in this article are unrelated to products/services/treatments involved in disclosure statements. No conflicts of interest.

What I did before

What is touted as the next big thing in disease management may be big in promotion but often small in advancement of patient care. As a result, in general, with the introduction of new medications, we gauge and revise perceptions as evidence becomes available. Although the sodium-glucose cotransporter 2 inhibitors (SGLT2i) class came onto my decision-making radar early after they were marketed, the uncertainty and lack of confidence that they would provide the patient-relevant outcomes I hoped for, while minimizing potential burdens to an already burdened patient population, prevented SGLT2i agents from attaining a prominent spot in the diabetes management line-up in my practice.

What changed my practice

Considering the goals for diabetes care in the patients I work with, assuming they are two-fold, i.e., risk reduction and symptom reduction, then there are two key parameters by which I assess diabetes medications: 1) ability to reduce risk of micro- and macro-vascular complications, and 2) ability to reduce hyperglycemia in those experiencing day-to-day symptoms of hyperglycemia.

As the SGLT2i cardiovascular trials were completed in patients with diabetes, it became clear that they a) reduced the risk of cardiovascular disease events^1,2,3 and b) that this benefit was likely patient risk related (i.e., absolute benefit increases with increased baseline risk or disease). As the results of the SGLT2i trials in patients with CKD have been revealed, a similar pattern has emerged.^4,5,6

Within the last year or so, large systematic reviews such as Palmer et al.⁷ have provided an overarching view of this risk-based benefit profile for SGLT2i. For example, for very low-risk patients with diabetes (up to 2 cardiovascular disease risk factors), there is negligible benefit in cardiovascular, renal, or mortality outcomes (~0–4 fewer events/1000 patients over 5 years). In those with diabetes at low risk (more risk factors but still no existing vascular disease), the potential benefits continue to be modest (~1–10 fewer events/1000 patients over 5 years). This paints a convincing picture showing that even for our highest-risk primary prevention patients with diabetes, few will benefit from a vascular complication standpoint. As the picture shifts to those with existing cardiovascular and/or renal disease, we see the absolute ballpark benefits increase to up to ~20–40 events saved/1000 patients over 5 years. Although this still means the vast majority won’t benefit, these are fairly impressive numbers by current preventative intervention standards.

The modest vascular outcome benefits in primary prevention patients noted above, however, caused me to take a closer look at my standard therapeutic approach to blood glucose lowering beyond metformin (e.g., addition of sulphonylureas or insulin). While I’ve been hard on newer medications like SGLT2i for their relatively small benefit in these lower-risk patients, recent systematic reviews such as Tsapas et al⁸, show that our traditional interventions are no better (and may be worse) at reducing risks of hard outcomes like mortality in these cohorts of patients. And, after decades of experience with these standard therapeutic options, while attempting to lower blood glucose with the often false assumption of reduced complications, issues of hypoglycemia, subsequent need for blood glucose monitoring, and weight gain have continued to burden patients. Conversely, SGLT2i are associated with weight loss and minimal risk of hypoglycemia while producing similar A1c reductions as traditional agents like sulphonylureas.⁸

The same safety microscope of course is needed to examine our newer medications to determine the implications of swapping one set of adverse events for another. Although there is often less certainty in the true incidence of adverse events than there is certainty from efficacy reporting, the large volume of safety data over the recent years of diabetes clinical trial publications has increased my confidence in the adverse events profile of SGLT2i. While they have minimal risk for hypoglycemia and are associated with potential weight loss (mean ~1.8 kg⁹) instead of gain, they come with their own list of issues to navigate. The most common of these being genital infections and volume depletion, with numbers needed to harm of approximately 7–15 and 30 over 5 years, respectively.^2,5,7,10 While these may not be perceived as common events, and one could argue they are more “acceptable” than the hypoglycemia or weight gain associated with traditional antihyperglycemics, they can have significant effects on broader patient safety and quality of life, requiring clinicians to be diligent in attention to existing baseline characteristics that would predispose to these adverse events as we make decisions on whether or not to use this class of medications in an individual patient.

Although the high level of importance I place on shared decision making hasn’t changed, the confidence with which I can engage patients in an informed decision about SGLT2i initiation has certainly increased over the last several years as this evidence has surfaced and been rigorously synopsized. Knowing that this large body of evidence shows that even for the higher-risk patients, most won’t benefit from the cardiovascular or kidney attributes of this class, some will be harmed, and various forms of burden (e.g., cost) will exist for all, these medications shouldn’t be viewed as “must prescribe” interventions (nor should preventative medications in general).¹¹ However, the evidence certainly does point to this class as an important consideration in the next steps after metformin for patients with diabetes with and without comorbid micro- or macro-vascular disease. While it is reasonable that clinicians and patients would look at this evidence and conclude that the benefits outweigh the risks, the key in this consideration is determining the potential net benefit of taking this next step along with the individual patient in front of us, considering their clinical circumstances, values, and preferences in order to ensure careful and kind care.

What changed my practice in this area wasn’t one or two studies, but it was the story of SGLT2i agents being revealed over time, through careful attention to an expanding body of evidence, as a class of medications that have the potential to reduce the risk of clinically important outcomes for the patients I care for.

What I do now

• Discuss the option of adding an SGLT2i for patients with diabetes and pre-existing cardiovascular or renal disease with the aim of lowering future event risk.
• Discuss the option of adding an SGLT2i for patients with symptomatic hyperglycemia where blood glucose reduction would be expected to reduce day-to-day symptoms.
• In those willing to start an SGLT2i, discontinue or reduce doses of other antihyperglycemic medications (e.g., sulphonylureas or insulin) if possible.
• Educate patients about genital mycotic infections (especially females), increased urinary frequency, and orthostatic hypotension (especially if on concomitant diuretics or other antihypertensives)¹².
• In those who start an SGLT2i, ask about genital infections in follow-up as they may be self-treated in many cases.
• In those who start an SGLT2i, measure for postural BP drop if the patient is symptomatic (e.g., dizzy or lightheaded) and consider backing off on antihypertensive and/or diuretic doses if necessary.
• Use the lowest studied doses. Cardiovascular and CKD trials have not shown higher doses to result in greater vascular event reduction nor are there clinically important reductions in surrogate markers (e.g., HbA1c, weight loss, BP lowering) with higher versus lower doses¹³. (Note: empagliflozin 10 mg and 25 mg tablets are the same price so cutting 25 mg in half (12.5 mg) will also cut the patient’s cost in half).
• Continue to promote and creatively implement safer and more broadly effective therapies including exercise¹⁴ and a healthy (and tasty) diet.

Resources

Ministry of Health – Province of British Columbia. Special Authority forms by condition. Government of British Columbia. Updated January 23, 2023. Accessed June 21, 2023. (View)

Log in to eForms.

Special Authority Requests. Revised December 7, 2022. Accessed June 21, 2023.

• Form 5826: empagliflozin, semaglutide: Second-Line Anti-Diabetic Medications (PDF 747KB)
• Form 5481: linagliptin, saxagliptin, pioglitazone: Third-Line Anti-Diabetic Medications (PDF, 633KB)

Current BC provincial special authority for SGLT2i (only empagliflozin) only takes into account glycemic lowering, not end-organ events or benefits, thus having CAD or renal disease and diabetes does not qualify patients for special authority coverage.

References

1. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128. doi:10.1056/NEJMoa1504720 (View)
2. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644-657. doi:10.1056/NEJMoa1611925 (View)
3. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347-357. doi:10.1056/NEJMoa1812389 (Request with CPSBC or view with UBC)
4. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380(24):2295-2306. doi:10.1056/NEJMoa1811744 (Request with CPSBC or view with UBC)
5. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383(15):1436-1446. doi:10.1056/NEJMoa2024816 (Request with CPSBC or view with UBC)
6. The EMPA-KIDNEY Collaborative Group. Empagliflozin in patients with Chronic kidney disease. N Engl J Med. 2023;388(2):117-127. doi:10.1056/NEJMoa2204233 (View)
7. Palmer SC, Tendal B, Mustafa RA, et al. Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: Systematic review and network meta-analysis of randomised controlled trials. 2021;372:m4573. (View)
8. Tsapas A, Avgerinos I, Karagiannis T, et al. Comparative effectiveness of glucose-lowering drugs for type 2 diabetes: A systematic review and network meta-analysis. Ann Intern Med. 2020;173(4):278-286. doi:10.7326/M20-0864 (Request with CPSBC or view with UBC)
9. Tsapas A, Karagiannis T, Kakotrichi P, et al. Comparative efficacy of glucose-lowering medications on body weight and blood pressure in patients with type 2 diabetes: A systematic review and network meta-analysis. Diabetes Obes Metab. 2021;23(9):2116-2124. doi:10.1111/dom.14451 (Request with CPSBC or view with UBC)
10. QiuM, Ding LL, Zhang M, et al. Safety of four SGLT2 inhibitors in three chronic diseases: A meta-analysis of large randomized trials of SGLT2 inhibitors. Diab Vasc Dis Res. 2021;18(2):14791641211011016. doi:10.1177/14791641211011016 (View)
11. Montori VM, Brito JP, Murad MH. The optimal practice of evidence-based medicine incorporating patient preferences in practice guidelines. JAMA. 2013;310(23):2503-2504. doi:10.1001/jama.2013.281422 (Request with CPSBC or view with UBC)
12. Getting the most from your Sodium Glucose Co-transporter-2 Inhibitors (SGLT2i). Imperial College Healthcare NHS Trust. February 2023. Accessed June 21, 2023. (View)
13. Shi FH, Li H, Shen L, et al. High-dose sodium-glucose co-transporter-2 inhibitors are superior in type 2 diabetes: A meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2021;23(9):2125-2136. doi:10.1111/dom.14452 (Request with CPSBC or view with UBC)
14. Get Active! Centres for Disease Control and Prevention. Accessed June 21, 2023. (View)

Vote

Please indicate how this article will change your practice:

SGLT2i in patients with diabetes: translating an evolving body of evidence to the nuances of practice

• I disagree with this approach
• I will consider changing my practice, but need more information/time
• I will likely change my practice
• I will definitely change my practice
• I already do this

View Results

 Loading ...