Diabetes in special situations: Sodium-glucose co-transporter-2 inhibitors in acute coronary syndrome
Sodium-glucose co-transporter-2 (SGLT2) inhibitors have progressively evolved a key role in the clinical management of type 2 diabetes. Following the results of the EMPA-REG OUTCOME study, the standard clinical guidelines have recommended evidence-based use of SGLT2 inhibitors in patients with stable coronary artery disease. At present, there is limited evidence to suggest the utility of these agents in a setting of acute coronary syndrome (ACS).
The widespread usage of these medications leads to frequent situations where one has to consider whether to initiate or continue SGLT2 inhibitor therapy during ACS. To answer this question, I have reviewed the prescribing information, indirect evidence, and trial data. With this background, I will share guidance for the appropriate use of SGLT2 inhibitors during and after ACS.
SGLT2 inhibitors in modern diabetes care
The SGLT2 inhibitor class of glucose-lowering medications is extensively used in modern diabetes care. In the updated American Association of Clinical Endocrinologists/American College of Endocrinology's algorithm for glycemic control, the SGLT2 inhibitor class is recommended next only to metformin and glucagon-like peptide-1 receptor agonists in the suggested hierarchy for using antidiabetic therapies . Increasing confidence about their efficacy, coupled with emerging evidence supportive of their cardiovascular benefits, has led to an increase in clinical usage of these agents.
SGLT2 inhibitors and cardiovascular outcomes
While EMPA-REG OUTCOME has demonstrated the cardiovascular benefits of empagliflozin , the CANVAS trial supports the beneficial effect of canagliflozin .The use of dapagliflozin is supported by real-world evidence, which reveals a mortality-lowering effect . The US Food and Drug Administration label for empagliflozin includes an indication for its use to reduce the risk of cardiovascular death in adult patients with type 2 diabetes and established cardiovascular disease . The European Medicines Agency’s summary of product characteristics for empagliflozin also supports the positive cardiovascular outcomes observed in the EMPA-REG OUTCOME study .
Evidence gap: SGLT2 inhibitors in ACS
Though there is broad consensus regarding the use of SGLT2 inhibitors in stable coronary artery disease [7, 8], there is no clear-cut agreement regarding their use during and immediately after ACS. In fact, no study has evaluated the use of SGLT2 inhibitors in the early post-ACS period. In the EMPA-REG OUTCOME trial, patients having a history of an ACS event within the past 2 months were excluded . Similarly, in the CANVAS program, patients having an ACS within 3 months prior to screening were excluded . In fact, among the cardiovascular outcome trials for newer antidiabetic therapies, early post-ACS patients have been assessed in only the EXAMINE and ELIXA trials. In the EXAMINE trial, the effect of alogliptin was assessed in patients up to 90 days post-ACS . In ELIXA, patients up to 180 days post-ACS were assessed for the cardiovascular safety of lixisenatide .
Use of SGLT2 inhibitors during and after ACS
To answer the question of whether to use SGLT2 inhibitors during and after ACS, I suggest the following framework, based upon the prescribing information of the three main SGLT2 inhibitors [5, 6, 11, 12] and good clinical sense . To discuss this topic further, I classify all patients with type 2 diabetes and ACS as being SGLT2 inhibitor naïve or on current SGLT2 inhibitor therapy. I reiterate that modern guidelines promote the use of insulin in hospitalized patients with diabetes . SGLT2 inhibitors should not be viewed as an alternative to insulin, but rather as an adjunct.
SGLT2 inhibitor-naïve patients
- Do not start SGLT2 inhibitor therapy during hospitalization for ACS.
- Do not start SGLT2 inhibitor therapy on the day of discharge from hospitalization for ACS.
- Consider prescribing SGLT2 inhibitors for glycemic control and cardiovascular risk reduction upon first outpatient follow-up visit after an ACS event.
SGLT2 inhibitor users
- Temporarily discontinue SGLT2 inhibitor therapy, as acute severe illness or a surgical procedure may predispose the patient to euglycemic diabetic ketoacidosis.
- Reinstate SGLT2 inhibitor therapy in patients who are hemodynamically stable, are volume replete, who have an estimated glomerular filtration rate (eGFR)>45 mL/min per 1.73m2, and who accept regular oral feeds.
- Temporarily reduce the dose of canagliflozin from 300 to 100 mg, in patients with an acute drop in eGFR to below 60 mL/min per 1.73m2.
- Respect all contraindications and caveats for SGLT2 inhibitor prescription.
- Monitor SGLT2 inhibitor therapy as per routine protocol.
- Observe caution in patients with congestive cardiac failure and chronic renal insufficiency, and in the elderly.
- Note that patients on SGLT2 inhibitors may require lower doses of antihypertensive medications, particularly loop diuretics, to avoid excessive volume depletion.
- Patients on canagliflozin 300 mg and digoxin therapy may exhibit an increase in digoxin concentrations, and should be monitored appropriately.
- If the patient is receiving sulfonylurea or insulin, the dose of sulfonylurea or insulin should be reduced to avoid the risk of hypoglycemia.
- Regularly monitor for symptoms and signs of hypotension.
- Regularly monitor eGFR and urine output.
- Monitor for ketosis and ketoacidosis by symptoms, signs, and laboratory tests.
- Educate staff that patients on SGLT2 inhibitors will have positive urine glucose tests.
- Educate staff that 1, 5-anhydroglucitol assays cannot be used to monitor glycemic control in patients on SGLT2 inhibitors.
- Note that SGLT2 inhibitors may marginally increase the low-density lipoprotein cholesterol and hematocrit levels.
Long-term follow up
- The potential utility and safety of SGLT2 inhibitors should be re-evaluated at the first outpatient follow-up visit, and monitored at each outpatient visit, based upon routine protocol.
- Concomitant dapagliflozin and pioglitazone therapy is not recommended, in view of their uncertain additive effects on bladder cancer.
- Predisposing factors for amputations should be considered before initiating canagliflozin. Canagliflozin should be discontinued if such a complication is suspected.
Based upon prescribing information and published trial data, I suggest that SGLT2 inhibitors should not be initiated during or upon discharge from ACS care. However, they should continue if they have already been prescribed, provided there are no contraindications to use. SGLT2 inhibitors should be viewed as an adjunct to, and not as an alternative to, insulin. Use of SGLT2 inhibitors should be considered at first outpatient follow-up visit, and monitored as per routine practice. Physicians should be aware of the contraindications, potential medication interactions, and possible side effects of these medications.
- Garber AJ, Abrahamson MJ, Barzilay JI et al. Consensus statement by the American Association of Clinical Endocrinology and American College of Endocrinology on the comprehensive type-2 diabetes management algorithm - 2017 executive summary. Endocr Pract 2017; 23: 207–238.
- Zinman B, Wanner C, Lachin JM et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373: 2117–2128.
- Neal B, Perkovic V, Mahaffey KW et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017; 377: 644–657.
- Birkeland KI, Jørgensen ME, Carstensen B et al. Cardiovascular mortality and morbidity in patients with type 2 diabetes following initiation of sodium-glucose co-transporter-2 inhibitors versus other glucose-lowering drugs (CVD-REAL Nordic): A multinational observational analysis. Lancet Diabetes Endocrinol 2017; 5: 709–717.
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