Topic Discussion: SGLT-2 Inhibitors: An update

The glucoretics SGLT-2 inhibitors have really come with a wave to improve the outcomes in diabetic patients, especially cardio-vascular and renal outcomes. I had the pleasure to listen to Inzucchi SE recently on this topic and the science has really taken off.

Here is a summary of what is happening in the world of SGLT-2 inhibitors and what we need to know as nephrologists.

SLGT-2 inhibitors overall(  all of them) only have a minor to modest effect on A1C reduction. For anything, it might even stay the same after 12 weeks on the drug. This doesn’t translate into the benefits we see in trials. Regardless of the A1C being only modestly decreased, the cardiac benefits are amazing.

Even though they have a weight loss effect( usually just 2kg total no matter what), they are not approved for weight loss

Even though they have a significant bp effect, not approved for BP management

Obviously, they are not going to work if you have no URINE, so unclear benefit in ESRD patients

All trials, from CANVAS to EMPA-REG(empagliflozin), the cardiovascular benefits have been astounding- decreased number of MACE events( MI, stroke, cardiac event).

What the cardiologist world is excited about is also the decreased CHF admissions and readmissions ( perhaps due to the naturetic effect of the agent acting as a proximal tubule diuretic without really increasing renin-aldo axis)—making it an amazing drug for volume management. Recent studies have also shown increase in HCT with the drug use showing it’s effect on plasma volume.  Ongoing trials might shed light on CHF management in diabetics and non-diabetics with this agent. A recent review summarizes this.

Renal outcomes in EMPA-REG, initial decrease in GFR was reversible – related to the hyperfiltration decrease( similar to ACEI/ARB). But hard renal outcomes, 46% decrease in  doubling of crt, RRT or renal death. In addition, decrease in macro and micro-albuminuria as well.

CANVAS study- with a different drug- also similar MACE outcomes as EMPA-REG, but component of MACE individual were less pronounced. Comparable CHF benefits. Canaglifozin related CANVAS had more amputations and fractures as a major side effect that EMPA-REG(empagliflozin) data didn’t show that when re done to look for it; unclear why one drug does it and other doesn’t.  Visual abstract from NephJC

CANVAS Renal outcomes…40% reduction with agent with change in EGFR, dialysis and death-almost similar.

Should we start using this drug in diabetic patients with CKD? Or even CKD patients without DMII given significant cardio-vascular and renal benefit. When cost analysis was done, empagliflozin use resulted in higher total lifetime treatment costs ($371,450 versus $272,966) but yielded greater QALYs (10.712 vs. 9.419) compared to standard treatment. This corresponded to an ICER of $76,167 per QALY gained. This suggested that empagliflozin would be cost-effective in 96% of 10,000 iterations assuming a willingness-to-pay threshold of $100,000 per QALY gained.

Here is a nice review on both drugs and effects.

If we start prescribing as nephrologists, likely will be empagliflozin and dose of 10mg given similar effect and monitor for what effects? As might not change A1C anyway—more long term benefits such as cardio-vascular and renal effects.

We truly have entered a new era!!

Topic Discussion: Euglycemic Diabetic Ketoacidosis

The first time the term Euglycemic DKA(eDKA) was mentioned was in 1973- in British Medical Journal in patients who were diabetic but didn't have the full blown hyperglyecmic part.  Compared to classic DKA, eDKA presents with mild to moderate hyperglycemia typically <300mg/dl blood glucose levels.  

Why is this more important now?

In 2013, many SGLT2 inhibitors got approved for DM management( the glucoretics).  The FDA performed a FAERS search of adverse effects with these agents and 73 cases were identified of ketoacidosis linked to SGLT-2 inhibitors.  All patients required hospitalization, and 60% had DMII. Blood glucose levels ranged from 90mg/dl - 1300mg/dl( median 211).  Timing of onset was around 43 days or starting or dose change of the agent.  Majority of the cases also had dehydration, infection or change in insulin doses.   No mortality has been reported with this effect.  All patients respond quickly with intravenous hydration and insulin once recognized. The FDA did acknowledge that some of the cases occurred in DMI, where it's an off label use. More detail here. 



Is it a class effect? 
Yes. The initial FDA reporting was done with canagliflozin(invokana). A more recent study found an incidence rate of 0.07% with this agent.  In a large study with dapagliflozin( Farxiga), 0.1% of patients got eDKA.  Empagliflozin(Jardiance) also has been found to cause eDKA. 

What are the risk factors for development of eDKA with SGLT2 inhibitors?

Dehydration
Alcohol use
decrease in insulin use
Infection
Low carbohydrate diet
Reduction in caloric intake
Advance age

Mechanism of action

Ketosis results from restriction of carbohydrate usage with increased reliance on fat oxidation for energy production. The pathogenesis of hyperglyemic DKA is well established. Since SGLT2 are glucoretics as described before, they can lead to volume depletion- like a diuretic and perhaps leading to a "starvation" like ketoacidosis with normal glucose levels. SGLT2 induced glycosuria can happen over 24 hours and this artificial low plasma glucose do not stimulate insulin. In eDKA, insulin deficiency and insulin resistance are milder; therefore, glucose overproduction and under-utilization are quantitatively lesser than in DKA. More importantly, renal glucose clearance (i.e., the ratio of glycosuria to prevailing glycemia) is twice as large with eDKA than with DKA. Ketoacidosis follows with the same sequence of events in eDKA as in DKA. Insufficient insulin levels will then decrease glucose utilization and promote lipolysis and ketogenesis. In addition, these drugs can increase glucagon levels leading to increase ketone production.

In summary, eDKA is pathophysiologically similar to DKA except for the circumstance—SGLT2-induced glycosuria—that “artificially” lowers plasma glucose levels and predisposes to increased ketogenesis.

Prevention and treatment
Blood and urine monitoring of ketones is essential especially when patients get ill or are experiencing one of the risk factors.  Adequate hydration and carbohydrate intake will help and holding the offending agent is indicated.  No data exists on a safe time to restart the agent. 

Here is a nice review on this topic
http://onlinelibrary.wiley.com/doi/10.1111/jdi.12401/pdf