diabetes: GLP1 and SGLT2 decrease hyperkalemia risk

 An article was just published showing that SGLT-2 inhibitors and GLP-1 receptor agonists decreased the likelihood of hyperkalemia in patients with type II diabetes: see GLP1 and SGLT2 dec hyperkalemia risk BMJ2024 in dropbox, or  https://doi.org/10.1136/bmj-2023-078483

 

Details:

-- a population-based study using claims data from Medicare and two large commercial insurance databases (Optum and Clinformatics Data Mart Database) in the US, with data from 2013-2022

-- adults were matched (by propensity score) who were newly started on SGLT-2 inhibitors versus DPP-4 inhibitors (n=778,908), GLP-1 receptor agonists versus DPP-4 inhibitors (n= 729,820) and SGLT-2 inhibitors versus GLP-1 receptor agonists (n= 873,460)

-- patients with CKD stage 5 or ESRD were excluded from the analysis

-- mean age 63, 50% female, 71% white/11% Black/10% Asian

-- comorbidities: hypertension 79%, hyperlipidemia 78%, cardiovascular disease 30%, heart failure 8%, atrial fibrillation 7%, ischemic stroke 7%, peripheral arterial disease 8%, acute kidney injury 3%, chronic kidney disease stage III or IV 7% (though was 11% in a comparison of GLP-1 versus DPP-4), diabetic nephropathy 12%

-- hyperkalemia 1%, hypokalemia 2%

-- number of drugs taken=13; number of diabetes meds=2;  metformin 80%, sulfonylureas 38%, insulin 20%

-- other meds: ACEi or ARB 72%, mineralocorticoid receptor antagonists 4%, beta blockers 35%, calcium blockers 27%, loop diuretics 13%, statins 71%, antiplatelet drugs 10%, anticoagulants 7%, potassium supplements 8%

-- eGFR 80 by creatinine, serum potassium 4.4 mmol/L

-- GLP-1’s: liraglutide 37%, dulaglutide 32%, exenatide 16%, semaglutide 13%

-- SGLT-2’s: empagliflozin 41%, canagliflozin 39%, dapagliflozin 20%

 

-- Main outcome: hyperkalemia diagnosed in the inpatient or outpatient setting, as determined by diagnosis code

-- secondary analysis: hyperkalemia diagnosed in the inpatient or emergency department setting, with hyperkalemia defined as serum potassium level >5.5 mmol/L (the secondary outcome only included those from the Clinformatics Data Mart Database, since Medicare and Optum had too few lab test results recorded)

 

-- mean on treatment follow-up range from 8.1-8.8 months (there was a large rate of discontinuation in routine clinical practice)

 

Results:

-- SGLT-2 versus DPP-4: 25% decrease, HR 0.75 (0.73-0.78)

    -- incidence rates were 25.3 versus 18.5 events per 1000 person-years

    -- three-year absolute risk was 2.4% lower with SGLT-2 (4.6% versus 7.0%)

-- SGLT-2 versus GLP-1: 8% decreased risk, HR 0.92 (0.89-0.95)

    -- incidence rates were 22.1 versus 19.8 events per 1000 person-years

    -- three-year absolute risk was 1.8% lower with GLP-1 (5.7% versus 7.5%)

-- GLP-1 versus DPP-4: 21% decreased risk, HR 0.79 (0.77-0.82)

    -- incidence rates were 28.5 versus 22.1 events per 1000 person-years

    -- three-year absolute risk was 1.2% lower with SGLT-2 (4.7% versus 6.0%)

 

 

-- The differences in hyperkalemia incidence was apparent within six months of follow-up

-- the benefits for similar for the individual SGLT-2 inhibitors (canagliflozin, dapagliflozin, and empagliflozin) and GLP-1 receptor antagonists (dulaglutide, exenatide, liraglutide, semaglutide)

    -- this suggests that the benefits were a class effect and not derived from specific individual meds

 

-- secondary analysis, using a serum potassium of at least 5.5 mmol/L as a definition of hyperkalemia:

    -- SGLT-2 versus DPP-4: 14% difference, HR 0.86 (0.78-0.95)

    -- GLP-1 versus DPP-4: 18% difference, HR 0.82 (0.73-0.91)

    -- SGLT-2 versus GLP-1: insignificant difference, HR 1.01 (0.91-1.12)

 

-- secondary analysis assessing hyperkalemia diagnosis in the inpatient or emergency department setting:

    -- SGLT-2 versus DPP-4: 23% difference, HR 0.77 (0.69-0.85)

    -- GLP-1 versus DPP-4: 35% difference, HR 0.65 (0.59-0.72)

    -- SGLT-2 versus GLP-1: insignificant difference, HR 0.96 (0.86-1.06)

 

-- subgroup analysis: the benefits of the SGLT-2 and GLP-1 were especially profound for those who had heart failure, chronic kidney disease, and those on mineralocorticoid receptor antagonists

-- no difference by subgroups defined by age, sex, race, medical conditions, other drug use, and hemoglobin A1c to levels

 

Commentary:

-- this huge study clearly found that patients on either SGLT-2 inhibitors or on GLP-1 receptor agonists had a lower rate of developing hyperkalemia through several definitions and across different subgroups and different sensitivity analyses

-- this study extends the results found in a meta-analysis of six randomized controlled trials with almost 50,000 patients, finding that SGLT-2 antagonists are associated with less hyperkalemia

    -- the current study extends these results to include GLP-1 receptor agonists, with a similar rate of hyperkalemia reduction to the SGLT-2’s

 

-- Patients with diabetes are at a higher risk for hyperkalemia, especially those with heart failure and chronic kidney disease.

-- and the hyperkalemia is exacerbated by many of the drugs used in patients with diabetes, including renin-angiotensin-aldosterone system inhibitors

-- evidence also suggests that stopping these drugs may lead to adverse cardiovascular outcomes

-- the results of this study is consistent with a few studies finding that, in secondary analysis, SGLT-2 inhibitors lowered the risk of developing hyperkalemia in the setting of RCTs

    -- this study extends these results to a very large database of people not in an RCT setting. And suggests that DPP-4 inhibitors are significantly less effective

    -- there are fewer prior studies on GLP-1 receptor agonists, so hyperkalemia benefit was less clear

-- potential mechanisms:

    -- GLP-1 receptor agonists and SGLT-2 inhibitors could increase sodium delivery to the cortical collecting duct and alter tubular electronegativity, therefore increasing potassium excretion (confirmed in a small study of 35 participants)

    -- both meds slow progression of renal decline and albuminuria, and this could also decrease hyperkalemia over time

 

A few comments about DPP-4 inhibitors:

-- there are several of these inhibitors on the market, including sitagpliptin, saxagliptin, linagliptin, alogliptin.

-- I was unable to find the number of prescriptions for these medications in the US or internationally for diabetes control, but likely lots of these meds are prescribed regularly

-- these meds provide only a modest effect on diabetes control, lowering the hemoglobin A1c by 0.5%-0.8%

-- Their suspected mechanism of action for diabetes control is by increasing incretin hormone levels, mostly GLP-1 but also GIP (gastric inhibitory peptide). this is accomplished by decreasing the incretin degradation by the DPP-4 enzyme systems

-- BUT:

    -- DPP-4 (Dipeptidyl peptidase-4, also known as adenosine deaminase complexing protein 2 or CD26 ) is a ubiquitous enzyme present on the surfaces of most cells in the body and is associated with immune regulation, signal transduction, and apoptosis

    -- it is present in blood plasma and various body fluids; it is known to cleave a broad range of substrates, including growth factors, chemokines, neuropeptides, and vasoactive peptides

    -- it bonds with adenosine deaminase specifically and with high affinity

    -- DPP-4 may well of a role in tumor biology, with its level in some cancers being increased and in others decreased

    -- the Middle East Respiratory Syndrome coronavirus (MERS) binds to DPP-4

    -- its homologue MtDPP may well play a role in the pathogenesis of tuberculosis

    -- earlier analyses suggested that DPP-4 inhibitors were associated with an increased risk of:

        -- heart failure: diabetes DPP-4 inhibitors and the risk of heart failure (gmodestmedblogs.blogspot.com

        -- inflammatory bowel disease: DPP-4 inhibitors increasing IBD (gmodestmedblogs.blogspot.com)

        -- severe joint pain, leading to an FDA warning: DPP-4 inhibitors in diabetics and severe joint pain (gmodestmedblogs.blogspot.com)

    -- disclaimer: I got most of this information directly from the Wikipedia page of DPP-4 (Dipeptidyl peptidase-4 - Wikipedia), which is well-referenced and, on my review, seems to be quite accurate

    -- for a recent review of the many adverse effects of DPP-4 inhibitors, see Dipeptidyl Peptidase IV (DPP IV) Inhibitors - StatPearls - NCBI Bookshelf (nih.gov)

-- as a perspective on the above rationale against using DPP-4 inhibitors, one of my criteria for being open to new meds is how much they are complements to the normal physiology vs potentially distorting important normal physiologic processes. In this light, i was much more open to GLP-1 receptor agonists than SGLT-2 inhibitors. The former augmented a normal physiologic process (incretin effect) that is diminished in those with diabetes.  By contrast, SGLT-2 inhibitors distort normal renal function to excrete large amounts of glucose and were found early on to be associated with the expected  adverse effects (severe urinary tract infections and urosepsis, fungal genital-area infections, and a bit later to Fourier's gangrene) and some less expected adverse effects (fractures/amputations, severe ketoacidosis even at not-so-high blood sugar levels in patients with diabetes): https://gmodestmedblogs.blogspot.com/2019/05/sglt-2-inhibitors-and-fourniers-gangrene.html 

    -- DPP-4 inhibitors poison a extensive group of proteins that seem to be physiologically important, so these inhibitors are on the surface much more disruptive to normal physiology

    -- and, given their wide-spread effects on so many targets, there may well be collateral damage to growth factors, chemokines, etc that could then lead to increased cancer incidence, for example. or ?susceptibility to Covid (since they seem to bind to MERS coronavirus, though with unclear effect. And this may take years to manifest itself for some of these potential adverse effects (eg cancer) and not be evident in short-term surveillance

Limitations:

-- the study had a relatively short follow-up time period of 8 to 9 months, attributable to the high rates of treatment discontinuation in the patients in these databases. The fact that the curves above are increasingly divergent over time is reassuring that the hyperkalemia protection may be long-standing

    -- however, one advantage of this database study is it likely reflects community practice more than rigorous randomized controlled trials might

-- the patients involved in the study are not truly representative of the US population, since these databases include patients who have healthcare insurance

-- since the comparison of GLP-1's and SGLT-2's is to DPP-4's and not placebos, it does raise the question as to whether the SGLT-2/GLP-1 meds are protective of hyperkalemia or the DPP-4s just make it worse (a possibility given their widespread targets)

 

so,

-- the big issue here is that hyperkalemia is common in patients with diabetes, especially those with underlying CKD; the beneficial medications often used in diabetes treatments (ACEi/ARBs and mineralocorticoid receptor antagonists, the latter often used in the rather frequent comorbidities of diabetes and heart failure) may well increase the likelihood of hyperkalemia (and stopping these medications may lead to adverse cardiovascular and renal outcomes); and therefore the use of these newer agents (GLP-1’s and SGLT2’s) that are both renoprotective and cardioprotective and that seem to  decrease the incidence of hyperkalemia is a reassuring big step forward

-- the side issue here is that I would argue that there seems to be a very limited role for DPP-4 inhibitors in the treatment of diabetes, and probably none to minimal in the prevention of hyperkalemia

 

geoff

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