This list of Q&A reflects issues discussed in webinars held early in 2021.
The content has been edited, and reviewed by Waikato DHB endocrinologist/diabetologist Dr Ryan Paul.
Starting empagliflozin in people on insulin and with good glycaemic control
Your patient uses gliclazide and insulin but could still benefit from the additional cardiovascular and renal protections of empagliflozin. How would you manage the change in treatment?
This article was originally printed in New Zealand Doctor Rata Aotearoa, 3 March 2021 issue and has been republished with permission.
Key points
- Empagliflozin reduces the renal and cardiovascular complications of type 2 diabetes, even when blood glucose level is well controlled
- Empagliflozin itself carries a minimal risk of hypoglycaemia, but its introduction often requires dose adjustment of other hypoglycaemic agents – current HbA1c level has a large bearing on what change is required.
- Patient education on benefits and risks of empagliflozin, plus comprehensive blood glucose monitoring in the early weeks of its use, help with a smooth change in management.
Helen is 63 years old and has worked very hard over the last 12 months to control her blood glucose level. She achieved an HbA1c level of 57mmol/mol three months ago, and it is 54mmol/mol today. She has microalbuminuria and her recent estimated glomerular filtration rate is 56ml/min/1.73m2, after a slow downward trend over the last two years.
Further investigations reveal the following:
- BMI – 29.5kg/m2
- blood pressure – 136/78mmHg (average over last six months)
- albumin:creatinine ratio – 23.3mg/mmol
- five-year cardiovascular risk – 7 per cent
- electrolytes, complete blood count, liver function tests – unremarkable.
The table (below) provides a list of Helen’s current prescriptions. In terms of adverse drug reactions, vildagliptin caused her to have a headache.
| Medical Condition | Medicines | Dose | Comment |
|---|---|---|---|
| Type 2 diabetes | metformin 500mg | 2 tablets twice daily | Long term |
| Type 2 diabetes | gliclazide 80mg | 2 tablets twice daily | Long term |
| Type 2 diabetes | insulin glargine | 16 units in the morning | Started 12 months ago and titrated up |
| Type 2 diabetes | cilazapril 5mg | 1 tablet daily | Long term |
| Cardiovascular risk | atorvastatin 40mg | 1 tablet daily | |
| Gastrointestinal | omeprazole 20mg | 1 tablet daily | Takes only if needed |
Helen is an ideal candidate for the sodium-glucose cotransporter-2 (SGLT2) inhibitor empagliflozin, due to her impaired renal function and the benefit of empagliflozin in reducing the risk of progression to end-stage renal disease (ESRD) by approximately 33 per cent. Note, the new Special Authority criteria for empagliflozin specify an HbA1c level >53mmol/mol, reminding us that it can be added even for people with good glycaemic control.
There may be an added benefit of a small reduction in blood pressure (4–5mmHg) and, potentially, some weight loss, though this tends to occur more in people with a higher BMI.
Helen has no history of pancreatitis, excess alcohol intake, very-low-carbohydrate diet or other risk factors for euglycaemic ketoacidosis.
Modifying dose of hypoglycaemics
The benefits of empagliflozin are such that it should be introduced to reduce the renal and cardiovascular complications of type 2 diabetes, regardless of whether the person has good glycaemic control. The focus is on reducing complications.
This does pose a problem for people with good glycaemic control using insulin or a sulphonylurea because empagliflozin, while having minimal risk itself of causing hypoglycaemia, does reduce blood glucose levels; therefore, it does carry a risk if used with hypoglycaemic agents.
Unfortunately, there is no simple algorithm for the dose reduction of sulphonylureas (eg, gliclazide) and/or insulin when starting empagliflozin. Gaining experience with empagliflozin in five to 10 people using only metformin with or without vildagliptin (patients with minimal risk of hypoglycaemia) is helpful for “getting a feel” for the likely reduction in HbA1c that can be expected, although it can vary wildly.
People with a higher HbA1c level are generally expected to have a greater reduction in HbA1c. It is also important to allow for the fact people may be inclined to improve their treatment adherence when started on a new medicine.
Helen starts empagliflozin
Helen is started on empagliflozin 10mg/day, and the potential benefits and adverse effects are discussed (Panels 1 and 2).
Helen’s HbA1c level indicates she will be at risk of hypoglycaemia with the addition of empagliflozin. Fortunately, she is reasonably reliable with her blood glucose monitoring, checking her morning blood glucose level about five days a week, but less often in the evenings – her blood glucose level is usually 6–7mmol/L in the morning but rises over the day to 8–10mmol/L before dinner.
Owing to Helen’s HbA1c level and risk of hypoglycaemia, her gliclazide dose is reduced to 80mg in the morning. She is encouraged to monitor her blood glucose more consistently for the next two weeks, including before dinner and at bedtime, and to send the results via the patient portal, especially if any readings are <6mmol/L.
Helen’s metformin dose is not reduced as this is the preferred oral therapy over a sulphonylurea or dipeptidyl peptidase-4 inhibitor, such as vildagliptin.
Panel 1 | Potential benefits and adverse effects of empagliflozin
The Norwegian website magicevidence.org (https://bit.ly/3jHaUZR) can help quantify the benefits and harms of SGLT2 inhibitors (and glucagon-like peptide-1 receptor agonists). You begin by selecting the baseline risk of diabetes, such as those with high cardiovascular risk (with or without chronic renal disease). Data is then provided on all-cause mortality, cardiovascular mortality, non-fatal myocardial infarction, non-fatal stroke, ESRD, heart failure, diabetic ketoacidosis, genital infection, severe gastrointestinal events, body weight, quality of life and “practical issues”.1
Expected benefits:2
- Reduced risk of progressing to ESRD by approximately one-third
- Reduced risk of fatal heart attack (one person in 45 over three years)
- Potential weight loss of 2kg
- Potential blood pressure reduction of 4–5mmHg
- HbA1c reduction of about 8mmol/mol (more or less depending on baseline HbA1c).
Potential adverse effects:
- Genital fungal infections – usually minor, but patient should immediately report any genital or perianal tenderness or swelling, fever or feeling unwell
- Urinary tract infections – uncommon and usually mild
- Nausea in approximately two in 100 people
- Increased thirst
- Increased urination in about one in 45 people
- Euglycaemic ketoacidosis – patient should report any nausea/vomiting, abdominal pain, generalised malaise and/or shortness of breath.
Panel 2 | Patient advice
- Don’t be surprised if there is a need to change doses of other medicines that reduce blood glucose during the next four weeks. It is important to monitor your blood glucose level (for those on gliclazide with or without insulin).
- Keep well hydrated, particularly in summer.
- Do not overindulge with alcohol.
- Stop the empagliflozin if you get stomach pains, nausea, vomiting, shortness of breath or feel generally very tired – contact your general practice.
- Let the practice know if you want to make a dramatic change in diet (eg, large changes in carbohydrates), and avoid the keto diet.
- Check your feet and maintain good foot care.
- Good personal hygiene may reduce the occurrence of genital infections.
- Contact your practice if you notice any infections or rashes.
- Ensure all health professionals know you are taking empagliflozin, especially before surgery.
Monitoring once on empagliflozin
Had Helen’s HbA1c level been closer to 64mmol/mol, the reduction in gliclazide dose could have been less. If it had been over 65mmol/mol, dose reduction would have been considered based on the stability of her HbA1c level over 12 months.
A dose reduction may not be appropriate if the person monitors their blood glucose level well, although increased blood glucose monitoring is encouraged in all situations. Ideally, 24-hour, continuous blood glucose monitoring for two weeks would be a good safeguard, if affordable.
After four weeks, Helen reports that her blood glucose level has increased to 7–8mmol/L in the morning and is still approximately 9mmol/L in the evening. Her empagliflozin is increased to 25mg/day.
After a further four weeks, Helen’s blood glucose level has returned to 6–7mmol/L in the morning, and it has reduced to 6–8mmol/L before dinner. Three months after starting empagliflozin, her HbA1c level is 51mmol/mol, albumin:creatinine ratio is reduced to 6.7mg/mmol, and she reports 1kg in weight loss.
Penny Clark is a pharmacist prescriber at NorthCare in Hamilton and chair of the Clinical Advisory Pharmacists Association; Linda Bryant is a clinical advisor and pharmacist prescriber at Newtown Union Health Service and Porirua Union and Community Health Service, Wellington.
Professional college endorsements
This activity has been endorsed by The Royal New Zealand College of General Practitioners (RNZCGP) and has been approved for up to 0.25 CME credits for continuing professional development purposes (1 credit per learning hour). To claim your CPD credits, log in to your Te Whanake dashboard and record these activities under the appropriate learning category.
References
- 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. BMJ 2012;372:m4573.
- Zinman B, Wanner C, Lachin J, et al. Empagliflozin, cardiovascular outcomes and mortality in type 2 diabetes. N Engl J Med 2015;373(22):2117–28.
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