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Late-Stage T2D Care

CME

Patients With Late-Stage Type 2 Diabetes and Adjusting Current Regimens

Physicians: Maximum of 0.25 AMA PRA Category 1 Credit™

ABIM MOC: maximum of 0.25 Medical Knowledge MOC point

Released: November 28, 2023

Expiration: November 27, 2024

Vivian A. Fonseca
Vivian A. Fonseca, MD, FRCP
CME/CE Information

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Key Takeaways
  • SGLT2 inhibitors slow chronic kidney disease progression and can be used in worsening kidney disease up to and possibly including dialysis.
  • GLP-1 RAs can cause dehydration because of gastrointestinal adverse events, increasing the risk of acute renal failure in patients with chronic kidney disease. 
  • Patients with type 2 diabetes may have multiple comorbidities and compelling indications for treatment with different agents, so healthcare professionals should carefully consider current data when weighing treatment options.

When you consider patients who have had type 2 diabetes for many years and those who have additional comorbidities—so-called “late-stage diabetes”—they present particular challenges. Often, many of those years have been with poor blood glucose control, leading to complications of diabetes. In this commentary, I will try to address these complications and put into context some of the newer medications for patients who have one or more of these complications.

Chronic Kidney Disease
Chronic kidney disease (CKD) is very common in patients with late-stage type 2 diabetes, and we now have specific recommendations for treatment of these patients. Sodium-glucose cotransporter 2 (SGLT2) inhibitors slowed the progression of CKD in multiple clinical trials in patients with and without diabetes. SGLT2 inhibitors slowed the decline in glomerular filtration rate (GFR), reduced microalbuminuria onset, and slowed or reversed the progression of proteinuria. In fact, because the glucose-lowering ability of SGLT2 inhibitors declines as GFR declines, the focus on the use of these agents should be on renal benefits rather than on glycemic benefits, particularly as a patient’s GFR falls below 30-45 mL/min/1.73 m2. The previous recommendation was not to use SGLT2 inhibitors in this situation because of decreased improvement in glucose levels. However, SGLT2 inhibitors continue to slow CKD progression down to the point where the patient is ready for dialysis, so it can be useful in patients who are seeing progression of the disease.

SGLT2 inhibitors previously were not recommended for patients on dialysis, but some experts now recommend continuing them even once dialysis is started. Although the results of many large-scale trials show the renoprotective and cardiovascular benefits of SGLT2 inhibitors in patients with CKD and heart failure, we do not yet know if they benefit heart failure in dialysis. Therefore, I use them mainly in people with advancing CKD who are not on dialysis.

Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) have been shown to be safe in CKD, but some people do experience nausea and vomiting because of the common gastrointestinal adverse events. This can cause dehydration, which makes CKD worse and can result in acute renal failure. It is important that we warn patients that if they get dehydrated from vomiting, they should stop the medications and rehydrate themselves. There is some evidence that GLP-1 RAs slow the decline in GFR in patients with CKD, but this has not yet been proven in specific clinical trials with renal benefit as the primary endpoint. Ongoing trials are addressing this issue, so we will wait for the outcome of those.

The impact on type 2 diabetes (glycemic control and body weight loss) can be very good with GLP-1 RAs and the glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 coagonist. However, nausea and vomiting may be a problem at higher doses, so I tend to use them cautiously in lower doses and with slower titration to avoid dehydration. The effect of GLP-1 RAs on glucose control is very good at a time when many people in that category can no longer use metformin or sulfonylureas, get less glycemic benefit from SGLT2 inhibitors, and may be treated with insulin. Although these drugs themselves do not typically cause hypoglycemia, these patients can get hypoglycemia when GLP-1 RAs are used with insulin because insulin action gets prolonged. GLP-1 RAs also have some blood pressure‒lowering properties.

People who live with type 2 diabetes for many years become insulin deficient over time. This is recognized by their very high A1Cs, and they often will need insulin in addition to a GLP-1 RA. Basal insulin plus a weekly GLP-1 RA has become a commonly used regimen. For people with even more advanced type 2 diabetes who are using basal-bolus regimens—because there is some benefit of GLP-1 RA on prandial control—we may decrease or even stop the prandial insulin altogether when adding a GLP-1 RA. This benefits patients by avoiding the weight gain and hypoglycemia associated with prandial insulin in type 2 diabetes.

It is important to remember that some people will still need prandial insulin for glucose control despite use of GLP-1 RAs because in the very late stages of type 2 diabetes and in older people, the insulin response after a meal becomes subdued, and the GLP-1 RA may not be enough to overcome it. In addition, some people with type 2 diabetes use insulin pumps, and taking a GLP-1 RA might help decrease their insulin requirement and make their glycemic variability a little better. It is important to remember that there still may be situations where the combination of these agents is warranted.

Heart Failure
In patients with heart failure, SGLT2 inhibitors have been shown to reduce hospitalization for heart failure, which is an important outcome. GLP-1 RAs do not currently have data on reducing hospitalization for heart failure. There is some controversy that some people might not have any benefit at all. However, a recent study showed that people who lost a lot of weight with GLP-1 RAs became more mobile and therefore had fewer heart failure symptoms. Patients’ walking distance improved, and they were less breathless. Therefore, from a practical standpoint, patients taking GLP-1 RAs may experience some heart failure benefit regarding quality-of-life improvements despite not having the robust data we have with SGLT2 inhibitors.

Neuropathy
Currently, no significant effect on neuropathy by GLP-1 RAs has been reported, but studies on the impact of GLP-1 RAs on the neurologic system are underway. We should not use GLP-1 RAs or GIP/GLP-1 coagonists in people who have significant gastroparesis due to autonomic neuropathy because this can be exacerbated by the gastrointestinal symptoms associated with these agents.

Retinopathy
There have been reports of worsening retinopathy due to use of GLP-1 RAs in people with type 2 diabetes and active retinopathy but no reports of de novo retinopathy with these agents. For people with mild retinopathy, it is typically quite safe to use a GLP-1 RA. However, when people are having active intra-ocular injections or laser treatment, I ask them to defer starting a GLP-1 RA until their treatment is completed.

Final Thoughts
We should remember that all of these complications can occur together in the same patient. One complication may be more compelling than the others, and deciding on priority of treatment with these agents may be complex. There is an opportunity for improving patient outcomes if we choose correctly, so keeping in mind the benefits of these agents and what we do not yet know about them can help guide treatment for our patients.

If you would like to learn more about these medications, click here to watch a short video describing the mechanisms of action of SGLT2 inhibitors, GLP-1 receptor agonists, and GIP/GLP-1 coagonists in type 2 diabetes and obesity.

Your Thoughts
In your practice, how often do you see patients with complications of late-stage diabetes? Do you consider initiating treatment with SGLT2 inhibitors or GLP1 RAs in these patients?

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In your practice, how often are you initiating SGLT2 inhibitors, GLP-1 RAs, and GIP/GLP-1 coagonists in patients with complications of late-stage type 2 diabetes?

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