Footnotes

• *
  The tablets should be swallowed whole with water. SYNJARDY^® can be used down to an eGFR of 45 mL/min/1.73 m². The dose should be adjusted or maintained at a maximum daily dose of 10 mg. Do not initiate below 60 mL/min/1.73 m². SYNJARDY^® is not indicated for use in patients with type 1 diabetes.^1,3
• †
  SYNJARDY^® is contraindicated in patients with hypersensitivity to the active substances or any of the excipients, any type of acute metabolic acidosis, and diseases that may cause tissue hypoxia. SYNJARDY^® should not be used in patients with type 1 diabetes. In patients where DKA is suspected or diagnosed, treatment with empagliflozin should be discontinued immediately. SYNJARDY^® should be used with caution in patients who may be at higher risk of ketoacidosis while taking SYNJARDY^®. For use in renally impaired patients, please refer to the SmPC. Lactic acidosis, a very rare but serious metabolic complication, most often occurs at acute worsening of renal function or cardiorespiratory illness or sepsis. Metformin accumulation occurs at acute worsening of renal function and increases the risk of lactic acidosis. SYNJARDY^® was approved based on clinical studies of empagliflozin and metformin as separate co-administered tablets and bioequivalence studies. The results of bioequivalence studies in healthy subjects demonstrated that SYNJARDY^® 5 mg/850 mg, 5 mg/1000 mg, 12.5 mg/850 mg, and 12.5 mg/1000 mg combination tablets are bioequivalent to co-administration of corresponding doses of empagliflozin and metformin as individual tablets.¹
• ‡
  Gastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal pain, and loss of appetite occur most frequently during initiation of therapy and resolve spontaneously in most cases.¹
• §
  Initiation of empagliflozin led to an initial drop in eGFR (mean: 3 mL/min/1.73 m²). Thereafter, empagliflozin maintained kidney function for the duration of treatment.^1,4
• ||
  For empagliflozin + metformin vs placebo + metformin.¹
• ¶
  Unless metformin not tolerated.
• **
  The effect of GLYXAMBI^® on CV outcomes has not been established.⁵
• ††
  Please see the SmPC for dosing details. In patients tolerating GLYXAMBI^® 10/5 mg, the dose may be increased for additional glycaemic control. Patients switching from JARDIANCE^® 10 mg or 25 mg to GLYXAMBI^® should receive the same daily dose of JARDIANCE^® in the fixed-dose combination. GLYXAMBI^® tablets are for oral use and can be taken with or without a meal at any time of the day at regular intervals. The tablets should be swallowed whole with water. This medicinal product does not require any special storage conditions. For patients with mild to moderate renal impairment: GLYXAMBI^® should not be initiated in patients with eGFR <60 mL/min/1.73 m²; GLYXAMBI^® should be discontinued when eGFR is persistently <45 mL/min/1.73 m².⁵
• ‡‡
  EMPA-REG OUTCOME^® trial: primary composite outcome was 3-point MACE, composed of CV death from CV causes, nonfatal MI, or nonfatal stroke, in patients with T2D and established CV disease (N=7020), on top of standard of care; as analysed in the pooled JARDIANCE^® group vs the placebo group. The 14% RRR in 3-point MACE (HR=0.86; 95% CI: 0.74, 0.99) was driven by a reduction in the risk of CV death (HR=0.62; 95% CI: 0.49, 0.77 p<0.001). The primary outcome occurred in 490 of 4687 patients in the pooled JARDIANCE^® group and in 282 of 2333 patients in the placebo group.⁶
• §§
  CARMELINA^® trial: primary outcome was time to first occurrence of CV death, nonfatal MI, or nonfatal stroke (3P-MACE) in patients with T2D and high CV and renal risk (N=6979), on top of standard of care.⁷
• ##
  CAROLINA^® trial: primary outcome was time to first occurrence of CV death, nonfatal MI, or nonfatal stroke (3P-MACE) in patients with T2D and high CV risk (N=6033), on top of standard of care.⁸
• ¶¶
  Overall, the safety profile of GLYXAMBI^® was in line with the safety profiles of the individual active substances (empagliflozin and linagliptin). The established CV safety profiles of JARDIANCE^® and TRAJENTA^® are presumed to indicate a similar CV safety profile with GLYXAMBI^®.⁵

References

1. SYNJARDY^® [summary of product characteristics]. Ingelheim am Rhein, Germany: Boehringer Ingelheim International GmbH.

2. Schorling OK, Clark D, Zwiener I, Kaspers S, Lee J, Iliev H. Pooled safety and tolerability analysis of empagliflozin in patients with type 2 diabetes mellitus. Adv Ther. 2020;37(8):3463-3484.

3. JARDIANCE^® [summary of product characteristics]. Ingelheim am Rhein, Germany: Boehringer Ingelheim International GmbH.

4. Wanner C, Inzucchi SE, Lachin JM, et al; EMPA-REG OUTCOME Investigators. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375(4):323-334.

5. GLYXAMBI^® [summary of product characteristics]. Ingelheim am Rhein, Germany: Boehringer Ingelheim International GmbH.

6. Zinman B, Wanner C, Lachin JM, et al; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128.

7. Rosenstock J, Perkovic V, Johansen OE, et al; for the CARMELINA Investigators. Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk. JAMA. 2019;321(1):69-79.

8. Rosenstock J, Kahn SE, Johansen OE. Effect of linagliptin vs glimepiride on major adverse cardiovascular outcomes in patients with type 2 diabetes: the CAROLINA randomized clinical trial. JAMA. 2019;322(12):1155-1166.