Though helping your patients avoid diabetes by promoting a healthy and active lifestyle is always preferable, I must admit there’s never been a better time in history to be a type 2 diabetic. Clinicians have a rapidly expanding array of new medications and evidence for diabetic treatment; treatment guidance is updated annually by the American Diabetes Association, and the FDA now requires evidence of cardiovascular safety for new diabetes treatments.
Metformin remains the gold-standard treatment of choice for type 2 diabetics, but once a patient needs additional pharmacotherapy, things get interesting.
‘New-ish’ classes of drugs to mitigate CVD risk: SGLT2i and GLP1
Increasingly, we’re adding agents such as Sodium-Glucose Cotransporter-2 inhibitors (SGLT2i) and Glucagon-like peptide 1 agonists (GLP1) early on in treatment to mitigate risks for cardiovascular disease (CVD). A recent meta analysis published by the medical journal BMJ helped parse out the differences in effectiveness between these two “new-ish” classes of drugs.
This analysis looked at about 50 trials including over 11,000 patients. It showed that semaglutide dosed once weekly showed a greater reduction in A1c than the SGLT2i, and a 2- to 4-fold increased likelihood of achieving an a1c < 7% with semaglutide. Patients taking semaglutide 1mg weekly also achieved greater weight loss than patients taking SGLT2i. And at lower doses of semaglutide, weight loss was comparable to the best results seen with SGLT2i.
Meta analyses have shown that SGLT2 inhibitors reduce the risk of major adverse cardiovascular events such as MI by about 10% They also reduce the risk of a composite outcome of CV death or CHF hospitalization by about 20%.
Semaglutide has shown similar favorable effects on CV outcomes. A composite endpoint of CV death, nonfatal MI or nonfatal stroke occurred in fewer patients treated with semaglutide than with placebo (HR 0.74, 95% CI 0.58-0.95).
Both drug classes have similarly shown substantial CV benefit, but of course there are many important factors to consider when choosing between a GLP1 and an SGLT2. Some of the most salient are detailed below.
1. Considerations within the GLP1 class
Choose an agent such as semaglutide or liraglutide with demonstrated CVD benefit, semaglutide requires a 4-8 week titration period, so may not be the most appropriate addition when patients need urgent blood glucose reduction. An important tidbit within this class is that almost all of these agents are >90% structurally similar to human GLP1. The exception to this is the only agent made from the saliva of a Gila monster — good old exenatide is only about 55% structurally similar to endogenous GLP1. Given lack of evidence for CVD benefit, think of this agent when you need the blood-sugar effects of this class but when your patient can’t tolerate other agents in the class.
2. Considerations within the SGLT2i class
Again, the most important issue within this class is choosing an agent with demonstrated CVD benefit and avoiding some of the notable risks such as increased risk of amputations with canagliflozin. A tip here is the relative lack of efficacy difference between the two different doses of Jardiance, perhaps you can save your patients a little money by prescribing the 25mg tablets and having them take one-half tablet daily. Normoglycemic diabetic ketoacidosis is a rare but serious and somewhat unique side effect of the SGLT2i, and patients taking these drugs should be aware of its symptoms.
3. How to choose between classes
The presence of renal disease is one important differentiating factor here. Jardiance shouldn’t be started with a creatinine clearance (CrCl) < 45mL/min and is contraindicated with an estimated glomerula filtration rate (eGFR) < 30 mL/min/1.73 (PDF). This is because the risks of adverse effects can increase drastically at this level.
It’s also important to consider unique and mechanism-based common side effects with these agents. Problems with GLP1 tend to be related to GI upset, nausea and vomiting, whereas the most common side effects in my clinical experience with Jardiance tend to be related to glucosuria such as fungal skin rashes. In the case of recurrent fungal rashes of the groin, daily antifungal powder use seems to be an effective prophylactic measure.
Rare but very scary-sounding side effects exist for both of these classes as well, GLP1 have risks reported for possible pancreatitis and pancreatic and thyroid cancer, given their effects on immune function. The SGLT2i have some case reports of Fournier’s gangrene associated with them. From personal experience, I’d encourage you to discuss that with your patient when prescribing an agent in this class versus them finding out later by Googling it or through late-night attorney ads.
Case study:
KL is a 48-year-old female patient who drives a semi for a living. Her A1c at diagnosis of diabetes was 9.3%. She started metformin at that time; at her 3-month follow-up visit, her a1c was 8.4%, so a good start. She’s working with a nutritionist, but given her profession she’s finding nutritional and exercise recommendations difficult to implement and sustain. Her BMI is 38 and her eGFR is 75mL/min; all other labs are unremarkable. In our discussion, she became open to talking more about add-on pharmacotherapy for her diabetes.
Medications
- Metformin 1000mg twice daily with meals
- Lisinopril 10mg every morning
Discussion and decisions
It would be good to prioritize weight loss in this otherwise-healthy diabetic patient and, per the algorithm above, SGLT2i or GLP1 are both reasonable options at this stage. But after we discussed the pros and cons of both agents, considering her profession and its tight schedule she didn’t want to take anything that can increase her frequency of urination.
She agreed to a trial of weekly semaglutide 0.25mg subcutaneously x 4 weeks, then 0.5mg weekly with a 2-month follow up for review of SMBG and possible A1c and fructosamine draw. Our RxLive clinical pharmacy specialist talked her through medication storage, administration and proper disposal of used pen needles in her somewhat-challenging situation.
Balancing benefits and risks
As we’ve seen, the SGLT2i and GLP1 agonists are two drug classes that provide meaningful benefit in terms of glycemic control and CV risk reduction. These agents potentially represent an exciting new era of diabetes treatment, so we encourage you to consider them when appropriate in your patients.
As always, we’re glad to talk with you and/or your patients regarding situations like these, as an extended part of your collaborative care team.
