SGLT2 Inhibitors: Town Hall
Benefits vs Concerns:
A renal perspective
Matthew R. Weir, MD
Professor and Chief
Division of Nephrology
University of Maryland School of Medicine
Disclosure Slide
Scientific Advisor: Janssen, Astra, BI, MSD, Akebia,
Relypsa, Boston Scientific, Lexicon
Grant Funding: NIDDK: R01DK 066013 and
U01DK106102, NHLBI: R01HL127422
Concerns:
•Ketoacidosis
•Reduction in eGFR
Case Presentation: History
• 54-year-old African American female
– Type 2 diabetes mellitus x 8 years
– Hypertension x 12 years
– Nonsmoker
• Past history
– Obesity
– OA of the knees
• Current medications
– Insulin, pioglitazone
– Atorvastatin 20 mg once daily
– HCTZ 25 mg QD, metoprolol 25 mg BID
Case Presentation: Physical Exam
•
•
•
•
•
•
BP 154/92 mm Hg PR 68
Weight 106 kg
BMI 36.6 kg/m2
Retinopathy, S4, 1+ edema
Diminished peripheral pulses
Peripheral neuropathy
eGFR = estimated glomerular filtration rate; FBG = fasting blood glucose; FLP = fasting lipid profile; HbA1c = glycosylated
hemoglobin; UAE = urinary albumin excretion; WNL = within normal limits.
Case Presentation: Lab Findings
• Scr 1.3 mg/dL, K 5.1 mEq/L, A1 c 8.8%
• Estimated GFR = 56 ml/min/1.73 m2
• TG 220 mg/dL, HDL 33 mg/dL, LDL 98 mg/dL
• Urine Analysis: 1+ glucose, 3+ protein, no cells, casts, crystals
• 24 hour urine
– total protein 1,752 mg
– alb/cr ratio 1,550 mg/g
– sodium 287 mEq
• Renal Sono: 11 cm kidneys, mild echogenicity
54-year-old African American Female with
Hypertension, Type 2 Diabetes, Macroalbuminuria
• What is working diagnosis and differential?
• What additional laboratory data?
• What are the Treatment Options?
What are optimal treatment considerations?
1.
2.
3.
4.
5.
BP below 130/80 mmHg
RAS inhibition
Tight control of hemoglobin A1C
Anti-platelet therapy
Full dose statin
Concerns:
•Ketoacidosis
•Reduction in eGFR
Ketogenic Pathways
• The 2 principal ketone bodies, acetoacetate and beta-hydroxy
butyrate are derived from the metabolism of FFA released from
adipocytes and delivered to the liver
• FFA are activated to their acetyl CoA derivative
• The primary determinates as to whether acetyl CoA is directed
toward a ketogenic or non-ketogenic pathway are the
concentrations of insulin and glucagon
Malonyl CoA
• Increased production with high insulin, and low glucagon
• Increased malonyl CoA inhibits fatty acyl CoA entry into
mitochondria
• Fatty acids are directed to TG Synthesis
• Under conditions of low insulin and high glucogon, malonyl CoA
levels are reduced, facilitating entry of fatty acyl CoA into the
mitochondria to form ketoacids
Starvation Ketosis
• More efficient renal conservation of ketone bodies through
saturable and non-saturable pathways
• Increased production of ketone bodies suppresses protein
catabolism by reducing the need for gluconeogenesis
• Ultimately, the rate of ketone body synthesis matches the rate of
ketone body utilization
• There is usually a sufficient amount of insulin to prevent
excessive mobilization of fatty acids, because ketone bodies
stimulate insulin production
Starvation Ketosis
• Adaptive response
• Minimize loss of metabolic fuels
• Spares sodium and potassium losses
• Minimize loss of ammonium nitrogen
• Minimizes protein break down
• No net consumption of bicarbonate
Diabetic Ketoacidosis
• Negative feedback loop on insulin secretion does not occur
• Greater fatty acid mobilization
• Unrestrained hepatic ketone body production
• Production of ketones exceeds utilization
• Increase in gluconeogenesis
• Increased muscle breakdown and release of aminoacids
• Loss of urinary ketone bodies as sodium or potassium salts
represents indirect loss of bicarbonate
SGLT 2 Inhibitor Ketoacidosis
• Reduction in glucose leads to a reduction in insulin (glucose is
the chief stimulus for insulin release)
• Increase in plasma glucagon via 1) diminished inhibitory effect of
insulin on glucagon release and 2) inhibition of the SGLT2
transporter in the pancreatic alpha cells (triggering glucagon
release)
• Glucagon may directly suppress insulin release
• Degree of insulin deficiency and resistance induced by SGLT 2
inhibitors is much less than in DKA, so that glucose over
production and underutilization is quantitively less, and often
results in euglycemic ketoacidosis
SGLT2 Inhibitor Ketoacidosis
• ↑ delivery of FFA to the kidney
• ↑ oxidation of FFA leads to ↑ ATP
• ↓ consumption of ATP byNa+ K+ -ATPase because of ↓ sodium
cellular entry
• ↓ consumption and ↑production of ATP causes a decrease of
other ATP generating pathways
• This change causes a secondary reduction in other cellular
pathways to generate ATP, such as renal ammoniagenesis from
the metabolism of glutamine and the uptake and metabolism of
filtered ketone bodies
SGLT2 Inhibitor Ketoacidosis
• The excretion of ketone bodies in the urine as either a Na+ or
K+ salt represents a net bicarbonate loss
• However, if ketone bodies are excreted with NH4+, there is no
net change in the H+ or HCO3 concentration
• Ketonuria may increase and exceed the NH4+ excretion rate,
resulting in the development of metabolic acidosis, especially in
the setting of ATP excess and reduced ammoniagenesis
SGLT2 Inhibitor Ketoacidosis
• Since urinary excretion of ketoacid salts coupled to NH4+ is
neutral with regard to acid-base balance it is critical to
understand predisposing factors: CKD, diabetes, RAAS
blockade, Type IV RTA, etc; since hyperkalemia suppresses
renal ammoniagenesis
• Thus, decreased renal ATP consumption in the proximal tubule
by SGLT2 inhibitors may lead to bicarbonate loss (with Na+ or K+
resulting in ketoacidosis
The role of the kidney in SGLT2-induced
ketoacidosis.
Palmer B. Journal of Diabetes and Its Complications 30 (2016) 1162-1166.
Renal Handling of Ketones in Response to SGLT2
Inhibition in Patients with T2DM
• n=66 patients with T2DM, eGFR >60ml/min
• 4 weeks of empaglifozin 25 mg daily
– Fractional excretion of glucose rose from 38 to 46% (fasting, postmeal)
– Excretion of beta-hydroxybutyrate, lactate, and sodium increased
positively related to glycosuria
• Similar observations of lesser magnitude were seen in non-diabetic
controls (n=25)
• It appears that SGLT2 – inhibitor mediated ketoacidosis is due to
increased production, rather than reduced renal clearance, as might
be seen in starvation ketosis.
Fernannini E, et al. Diabetes Care (In Press)
Ketone Bodies and Renal Function
• Ketone bodies enhance GFR and RPF which may counter the
effect of TGF in reducing GFR via pre-glomerular
vasoconstriction
• Stabilization of urinary Na+ losses may be helpful to limit ketone
body excretion as a sodium salt which could worsen acidosis
Ferraninni, E. et al. Diabetes Care (In Press)
Relationship between glucose excretion and urinary excretion of βhydroxybutyrate during chronic treatment with empagliflozin
Fernannini E, et al. Diabetes Care (In Press)
Relationship between glucose excretion and urinary excretion of lactate during
chronic treatment with empagliflozin
Fernannini E, et al. Diabetes Care (In Press)
Relationship between glucose excretion and urinary excretion of sodium during
chronic treatment with empagliflozin
Fernannini E, et al. Diabetes Care (In Press)
Urinary β–hydroxybutyrate (β-HB and lactate excretion rate during fasting and
following meal ingestion at baseline, after acute and chronic empagliflozin
administration in patients with type 2 diabetes
Fernannini E, et al. Diabetes Care (In Press)
Factors Which Could Predispose to Ketoacidosis
• Reduced eGFR
• Hyperkalemia which reduces renal ammoniagenesis
• RAAS blockers
• Type 4 RTA
• Conditions which increase fatty acid delivery to the kidney
• NSAIDs
Case Presentation
• Empagliflozin 10 mg and Lisinopril 20 mg started
• Labs assessed 3 weeks later:
136
101 Anion Gap 18 HgbA1C 7.6%
5.3 17 Creat
1.6
UACR 892 mg/g, urine ketostix positive
• BP 136/82 mmHg
Case Presentation
• What would you do?
↑ ANION GAP
↑ CREATININE
BP ↓
UACR ↓
Case Presentation: 6 months later
• HgbA1C 7.1% with intensified insulin, pioglitazone and
empalifozin
• BP 128/78 mmHg with increase in HCTZ 50 mg daily
• Creat stable at 1.6, and anion gap 12
• Potassium 4.2
Are SGLT2 inhibitors Renal
and Cardio protective?
Possible Mechanisms of Benefit
• Glomerular Hyperfiltration
– Lower systemic blood pressure
– Lower glomerular capillary BP
• Pro-inflammatory Processes
– Lower BP, glucose, cholesterol
– Anti-inflammatory therapies?
• Enhance cellular energy via increased production of ATP
Glomerular Structure
Mesangial
Cell
Capillary Loop
Endothelial
Cell
Efferent
Arteriole
Afferent
Arteriole
Juxtaglomerular Apparatus
Renal glucose re-absorption under
healthy conditions1,2
Filtered glucose
load 180 g/day
SGLT2
~ 90%
SGLT1
~ 10%
SGLT, sodium glucose cotransporter.
Adapted from: 1. Gerich JE. Diabet Med. 2010;27:136–142; 2. Bakris GL, et al. Kidney Int. 2009;75;1272–1277.
Virtually all of the
filtered glucose is
re-absorbed in the
In healthy
proximal
tubules
individuals,
through SGLT2 and
thewith
renal
SGLT1
SGLT2
accountingfilter
for
glomeruli
~ 90%~180
in the gS1 and
S2
and
of segments
glucose per
SGLT1 accounting
day
for
~ 10% in the
S3 segment
Renal glucose re-absorption in
patients with diabetes1,2
Filtered glucose
load > 180 g/day
SGLT2
~ 90%
SGLT1
~ 10%
SGLT, sodium glucose cotransporter.
Adapted from: 1. Gerich JE. Diabet Med. 2010;27:136–142; 2. Bakris GL, et al. Kidney Int. 2009;75;1272–1277..
When blood
glucose
increases above
the
renal threshold
(~ 11 mmol/L or
190 mg/dL), the
capacity of the
transporters is
exceeded,
resulting in
urinary glucose
excretion
Postulated tubuloglomerular feedback (TGF) mechanisms in normal physiology, early
stages of diabetic nephropathy, and after sodium-glucose cotransporter (SGLT) 2
inhibition.
David Z.I. Cherney et al. Circulation. 2014;129:587-597
Postulated tubuloglomerular feedback (TGF) mechanisms in normal physiology, early
stages of diabetic nephropathy, and after sodium-glucose co-transporter (SGLT) 2
inhibition.
David Z.I. Cherney et al. Circulation. 2014;129:587-597
Renal Hemodynamic Studies in T1DM
• 8 weeks of therapy with empagliflozin
• n=27 hyperfilterers (GFR >135 mL/min) and n=13 normal
GFR
• Studied during euglycemic (4–6 mmol/L) and
hyperglycemic (9–11 mmol/L) clamps at the beginning and
end of 8 weeks treatment
Cherney DZ et al. Circulation. 2014;129:587-97.
Glomerular filtration rate (GFR) responses to empagliflozin during
clamped euglycemia (A) and hyperglycemia (B; mean±SD)
*P<0.01 for baseline GFR in type 1
diabetes mellitus subjects without
(T1D-N) vs with (T1D-H) renal
hyperfiltration
†P<0.01
for the within-group change
in GFR in T1D-H
‡P<0.01
for the between-group effect
of empagliflozin on change in GFR
Cherney DZ et al. Circulation. 2014;129:587-97.
EMPA-REG Outcome Study
• 7020 patients with T2DM at high risk for CV events were
randomized to receive placebo, empaglifozin 10 gm, or
empaglifozin 25 mg once daily
• Median observation time 3.1 years
• Primary composite outcome measure: death from CV
causes, nonfatal MI, or nonfatal stroke
Zinman B, et al. NEJM 2015; 373:2117-2128.
Glycated Hemoglobin Levels
Zinman B et al. N Engl J Med 2015;373:2117-2128.
Cardiovascular Outcomes and Death from Any Cause
Zinman B et al. N Engl J Med 2015;373:2117-2128.
LEADER Study
• Patients with type 2 diabetes and high
cardiovascular risk were assigned to receive either
the glucagon-like peptide 1 analogue liraglutide or
placebo.
• The rate of first occurrence of cardiovascular death,
nonfatal MI, or nonfatal stroke was lower with
liraglutide.
Primary and Exploratory Outcomes
Marso SP et al. N Engl J Med 2016;375:311-322
Conclusions
• In the time-to-event analysis, the rate of the first
occurrence of death from cardiovascular causes,
nonfatal myocardial infarction, or nonfatal stroke
among patients with type 2 diabetes mellitus was
lower with liraglutide than with placebo.
Considerations about Newer Therapies Besides Safety
and Efficacy
• Complementary with RAAS blockers?
• Would you see the effect if SBP is 110 mmHg, 120 mmHg,
130 mmHg, or only at higher SBP?
• Persistency of effect after drug cessation?
• Is change in albuminuria an adequate surrogate measure,
or do we need observable stabilization of estimated GFR?
• Low salt diet and thiazide diuretics have anti-proteinuric
effects.
•Multiple theories about renal and
CV benefits with SGLT2 Inhibitors
•Is it more than simply
pressure/volume reduction?
Physiologic mechanisms implicated in the cardiovascular
and renal protection with SGLT2 inhibition
Hiddo J.L. Heerspink et al. Circulation. 2016;134:752-772
Raised circulating FFAs are taken up by the liver and
metabolized via β-oxidation.
Ele Ferrannini et al. Dia Care 2016;39:1108-1114
However, if there is a
reduction of GFR with the
SGLT2 inhibitors; is this a
good or adverse
prognostic sign?
Relationship between 2-and 8-week changes in glomerular filtration rate (GFR) and subsequent renal
and cardiovascular outcomes in 9340 patients new to RAS Blockade in ONTARGET/TRANSCEND
Clase, et al. Kidney International (2017) 91,683-690.
Relationship between 2-and 8-week changes in glomerular filtration rate (GFR) and subsequent renal
and cardiovascular outcomes in 9340 patients new to RAS Blockade in ONTARGET/TRANSCEND
Clase, et al. Kidney International (2017) 91,683-690.
Association between percent decline in renal function in AASK and MDRD participants from time of
randomization until month 3-4 and risk of ESRD
Ku, Elaine (In Press)
Association between percent decline in renal function in AASK and MDRD participants from time of
randomization until month 3-4 and risk of ESRD
Ku, Elaine (In Press)
Which balance is required for CV and Renal Risk
Reduction?
↓ EGFR
↓ PROTEINUIRA
↓ PRESSURE
↓ VOLUME