Effects of SGLT2 Inhibitors and GLP-1 Receptor Agonists on Renin-Angiotensin-Aldosterone System

Sodium-glucose cotransporters inhibitors (SGLT2-i) and GLP-1 receptor agonists (GLP1-RA) are glucose-lowering drugs that are proved to reduce the cardiovascular (CV) risk in type 2 diabetes mellitus (T2DM). In this process, the renin-angiotensin-aldosterone system (RAAS) is assumed to play a role. The inhibition of SGLT2 improves hyperglycemia hampering urinary reabsorption of glucose and inducing glycosuria. This “hybrid” diuretic effect, which couples natriuresis with osmotic diuresis, potentially leads to systemic RAAS activation. However, the association between SGLT2-i and systemic RAAS activation is not straightforward. Available data indicate that SGLT2-i cause plasma renin activity (PRA) increase in the early phase of treatment, while PRA and aldosterone levels remain unchanged in chronic treated patients. Furthermore, emerging studies provide evidence that SGLT2-i might have an interfering effect on aldosterone/renin ratio (ARR) in patients with T2DM, due to their diuretic and sympathoinhibition effects. The cardio- and reno-protective effects of GLP-1-RA are at least in part related to the interaction with RAAS. In particular, GLP1-RA counteract the action of angiotensin II (ANG II) inhibiting its synthesis, increasing the inactivation of its circulating form and contrasting its action on target tissue like glomerular endothelial cells and cardiomyocytes. Furthermore, GLP1-RA stimulate natriuresis inhibiting Na+/H+ exchanger NHE-3, which is conversely activated by ANG II. Moreover, GLP1 infusion acutely reduces circulating aldosterone, but this effect does not seem to be chronically maintained in patients treated with GLP1-RA. In conclusion, both SGLT2-i and GLP1-RA seem to have several effects on RAAS, though additional studies are needed to clarify this relationship.

Risk of volume reduction associated with sodium-glucose cotransporter-2 inhibitors treatment: a meta-analysis of randomized controlled trials

Introduction Sodium-glucose cotransporter-2 (SGLT2) inhibitors is a newly class of drug which improving glycemia by enhancing glycosuria, subsequently reducing blood pressure by osmotic diuresis and natriuresis. There are multiple large-scale randomized control trials demonstrating that SGLT2 inhibitors had salutary effect on cardiovascular-renal outcome, especially on heart failure. Although SGLT2 inhibitors exhibited promising potential value on treatment for type 2 diabetes mellitus (T2DM) with cardiovascular-renal comorbidities, the potential adverse events (AEs) related to osmotic diuresis such as volume reduction should not be neglected. Moreover, older individuals, those with moderate renal impairment, and those receiving antihypertensive therapies are susceptible to adverse events related to volume reduction. Purpose To assess the association between sodium-glucose cotransporter-2 inhibitors and risk of volume reduction in patients with type 2 diabetes mellitus. Methods A systematic literature retrieval was performed in PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception up to 10 December 2019, Data for study characteristics and outcomes of interest were extracted from each eligible study. Pooled risk ratios (RRs) with 95% confidence interval (CI) for volume reduction was calculated using random-effects model. Result A total of 51 studies (n=56,866) were included in our meta-analysis, with a result of 1,337 incident volume reduction cases (814 in the SGLT2 inhibitors group, 523 in the control group). The pooled RR was 1.15 (95% CI: 1.03–1.28). It is evident that receiving SGLT2 inhibitors had increased the risk of volume reduction, when stratified by placebo-control or active-control the result was consistent. Conclusion Our meta-analysis has demonstrated that SGLT2 inhibitors increase the risk of volume reduction in patients with T2DM. It is necessary to attention for the risk of volume reduction associated with SGLT2 inhibitors, especially in older individuals, those with moderate renal impairment, and those receiving antihypertensive therapies. SGLT2 inhibitors vs control Funding Acknowledgement Type of funding source: None

ICU-Acquired Hypernatremia Is Associated with Persistent Inflammation, Immunosuppression and Catabolism Syndrome

Developing hypernatremia while on intensive care unit (ICU) is a common problem with various undesirable effects. A link to persistent inflammation, immunosuppression and catabolism syndrome (PICS) can be established in two ways. On the one hand, hypernatremia can lead to inflammation and catabolism via hyperosmolar cell stress, and on the other, profound catabolism can lead to hypernatremia via urea-induced osmotic diuresis. In this retrospective single-center study, we examined 115 patients with prolonged ICU stays (≥14 days) and sufficient renal function. Depending on their serum sodium concentrations between ICU day 7 and 21, allocation to a hypernatremic (high) and a nonhypernatremic group (low) took place. Distinct signs of PICS were detectable within the complete cohort. Thirty-three of them (28.7%) suffered from ICU-acquired hypernatremia, which was associated with explicitly higher signs of inflammation and ongoing catabolism as well as a prolonged ICU length of stay. Catabolism was discriminated better by the urea generation rate and the urea-to-creatinine ratio than by serum albumin concentration. An assignable cause for hypernatremia was the urea-induced osmotic diuresis. When dealing with ICU patients requiring prolonged treatment, hypernatremia should at least trigger thoughts on PICS as a contributing factor. In this regard, the urea-to-creatinine ratio is an easily accessible biomarker for catabolism.

SAT-682 Unusual Presentation of Diabetic Ketoacidosis Associated with Hypernatremia in Adult Patient

Diabetic ketoacidosis (DKA) is an acute, life threatening complication of diabetes characterized by hyperglycemia, ketonemia and acidosis. It is known to commonly present with hyponatremia and rarely with hypernatremia. DKA can present with hypernatremia in pediatric population which carries poor prognosis when present. We present a 27 year- old Ethiopian lady, previously healthy who was brought to emergency department (ED) with decreased level of consciousness. She had polyuria and polydipsia associated with weight loss for 1 month and flu like symptoms for 3 days prior to admission. On day of presentation, she was found to be confused, sleepy and not able to recognize people around her. In ED, patient was confused, GCS 8 severely dehydrated with poor skin turgor and marked delay in capillary refill >3s. Patient was afebrile, with HR 115 bpm, BP 95/60mmHg, and BMI 20kg/m2. Initial labs revealed; severe acidosis pH 6.8, blood glucose (BG) >38 mmol/l and corrected Na 155 mmol/l. Calculated serum osmolality 357mOsm/kg, lactic acid 5 mmol/l and HCO3 3 mmol/l. Further labs revealed K 4.4 mmol/l, Urea 10 mmol/l, Cr 150 micromole/l, WBC 26 and Ketones 3+ in urine. DKA was diagnosed and treated in ED with 4L IVF (2L bolus NaCl and other 2L of 0.23% NaCl given at 15 ml/hr) and NaHCO3 150 mmol. Continuous insulin regular infusion at rate of 0.1U/Kg/hr as per protocol was initiated. Patient was admitted to ICU for close monitoring of BG, GCS and electrolytes. After 9 hours of management, patient GCS improved to 13-14. Repeated labs revealed; improvement in PH 7.17, BG 22mmol/l, HCO3 5 mmol/l and lactic acid 1 mmol/l. There was worsening of Na 159 mmol/l and K dropped to 2.6 mmol/l. IV KCL bolus 20mmol followed by 40mmol IV continuous in IVF was initiated. IVF was changed from NaCl to D5W at 125ml/hr. Electrolytes were repeated after 7 hours and showed improvement in and Na and k levels. During her stay in ICU, patient recovered to baseline GCS 15 with no residual symptoms. IV insulin infusion was stopped on 3rd day and commenced on Insulin glargine and insulin Aspart boluses. Further investigations confirmed DM type 1; HbA1c 15%, C-peptide 0.08 nmol/l, IA2Ab of >400 and GAD Ab >250. Patient had an uneventful hospital course, she stayed in ICU for 3 days and then shifted to medical floor. She was discharged on basal bolus insulin regimen. In patients with uncontrolled DM/DKA, serum Na level is variable, reflecting the balance between the hyperglycaemia induced water movement out of the cells that lowers serum Na level, and the glycosuria induced osmotic diuresis, which tends to raise serum Na. When there is marked osmotic diuresis, DKA may present with a normal or even elevated serum Na concentration, despite a markedly elevated serum BG. To best of our knowledge, this is the second case to report an unusual DKA presenting with hypernatremia in adult patient.

SUN-699 Canagliflozin Induced Severe Hyponatremia- a Rare Life Threatening and Poorly Understood Complication- a Case Report

Background: Sodium-glucose cotransporter-2 (SGLT2) inhibitors induce osmotic diuresis by inhibiting the proximal renal tubular reabsorption of the filtered glucose load. This can occasionally lead to severe dehydration, hypotension and in some cases, severe hyponatremia. The effects of SGLT2 inhibitors on sodium and water handling by the renal tubules is not well studied. Clinical Case: A 49-year-old male with history of type 2 diabetes mellitus on canagliflozin, an SGLT2 inhibitor, who was brought to the Emergency Room following a motor vehicle accident from acute onset of confusion and altered mental status. Initial trauma workup was negative. He was found to have severe hyponatremia to 118 mEq/ L (n 135–145 mEq/ L) and was also noted to be in euglycemic ketoacidosis with positive serum ketones (qualitative assessment) along with acute onset urinary retention. Urine toxicology was negative including negative blood alcohol level. Thyroid function was normal 1.080 mIU/ L (n 0.47- 6.90mIU/L). His total urine osmolar excretion was ~ 2400 mOsm in 12h (n 500–800 mOsm/kg of water/ 24 hours), confirming the diagnosis of his ongoing massive osmotic diuresis. On admission, his antidiuretic hormone (ADH) level was noted to be elevated to 9.1 pg/mL (n <4.3pg/ mL). This severe degree of hyponatremia was postulated to be secondary to canagliflozin causing massive osmotic diuresis resulting in severe intravascular volume depletion with reflex increase in antidiuretic hormone (ADH) compounded by increased free water intake by the patient. Conclusion: With more widespread use of this relatively new hypoglycemic medication with protective metabolic and cardiovascular benefits that include weight loss and reduction of BP in T2DM patients, it is equally important to understand the physiology of potentially life-threatening adverse effects associated with severe volume depletion by massive osmotic diuresis and electrolyte abnormalities that include hypernatremia (even hyponatremia), and the timely recognition of euglycemic ketoacidosis.

The role of urea-induced osmotic diuresis and hypernatremia in a critically ill patient: case report and literature review

Hypernatremia is a common electrolyte problem at the intensive care setting, with a prevalence that can reach up to 25%. It is associated with a longer hospital stay and is an independent risk factor for mortality. We report a case of hypernatremia of multifactorial origin in the intensive care setting, emphasizing the role of osmotic diuresis due to excessive urea generation, an underdiagnosed and a not well-known cause of hypernatremia. This scenario may occur in patients using high doses of corticosteroids, with gastrointestinal bleeding, under diets and hyperprotein supplements, and with hypercatabolism, especially during the recovery phase of renal injury. Through the present teaching case, we discuss a clinical approach to the diagnosis of urea-induced osmotic diuresis and hypernatremia, highlighting the utility of the electrolyte-free water clearance concept in understanding the development of hypernatremia.

701 Outcome Evaluation of High Dose Ascorbic Acid Infusion in Adult Burn Patients

Introduction High dose ascorbic acid (HDAA) infusion has been associated with lower resuscitation volumes following severe burn injuries. Recent data has linked the use of HDAA to an increased risk of renal failure. HDAA infusion causes an osmotic diuresis which confounds fluid titration. For these two reasons, HDAA has become controversial. The objective of this study is to examine the outcomes of adult burn patients who received HDAA infusion during acute burn resuscitation. Methods This study is an IRB approved retrospective chart review of all adult burn patients admitted from January 2016 through December 2018 who received HDAA for resuscitation. Patients were excluded if age < 18 years, had pre-existing hemodialysis-dependent chronic kidney disease, received < 16 hours of HDAA, or expired/withdrew from care within 48 hours of admission. The primary outcome was the incidence of patients receiving HDAA infusion who required renal replacement therapy (RRT) within 7 days of admission. Secondary outcomes included the incidence of abdominal compartment syndrome (ACS), duration of mechanical ventilation, actual crystalloid volume administered in the first 24 hours compared to estimated volume, ICU length of stay (LOS), and mortality. Results Twenty-four patients were included with a mean age of 48 (+/-16) and a mean TBSA of 49.1% (+/-17.8). The estimated fluid requirements in the 1st 24 hours were calculated using 4mL/kg/TBSA. Four patients required RRT (16.7%) and 12 patients were diagnosed with ACS (50%). The mean volume of crystalloid administered in the 1st 24 hours was 4.7 mL/kg/TBSA (+/-1.9), and the ratio of actual to estimated crystalloid in the 1st 24 hours was 1.2 (+/-0.5). Seventeen patients received albumin therapy in the 1st 24 hours. The mean urine output in 1st 24 hours was 1.7 mL/kg/hr. Mean duration of mechanical ventilation and ICU LOS was 15 and 16 days respectively. Thirteen patients died (54.2%). Conclusions The incidence of patients requiring RRT, along with the crystalloid volume administered and the observed to expected ratio of crystalloids in the 1st 24 hours were comparable to recent literature. The known effect of osmotic diuresis from HDAA potentially impacted fluid titration practice, increasing the risk of complications from over-resuscitation such as ACS, and mortality. Additionally, the estimation of 24-hour fluid requirements using 4mL/kg/TBSA may have contributed to the rates of ACS. Further studies comparing fluid management strategies are necessary. Applicability of Research to Practice This study describes the outcomes associated with HDAA during acute burn resuscitation at an adult burn center. Given the current controversy surrounding HDAA infusion, this study provides further data to help burn centers make a decision regarding their opinion of HDAA during acute burn resuscitation.