2019 당뇨병 치료의 최신 지견 SGLT2-Inhibitor를 중심으로

서울시 개원 내과의사회 학술대회 2019. 6. 23 송영득엔도내과 Introduction

 Diabetes is a complex, chronic illness requiring continuous medical care with multifactorial risk reduction strategies beyond glycemic control, so System of Care (Guideline) was developed

 Guidelines provide an evidence-based and systematic approach to diabetes management for the primary care physician.

 Knowledges are updated as New Research, New Drugs, Technology, Management Approach and Clinical Data emerges Ideal Anti-Diabetic Drugs

 Cure the diabetes  Control blood glucose (continuous)  Less hypoglycemia, less weight gain  Stop or delay progression of diabetes (Preserve β-cell fx)  No harmful effect on comorbidity/complications of DM  Beneficial effects on ~  Less side effects The Rate of Introduction of New Drugs has been accelerated Over The Last 20 years

PATHOPHYSIOLOGY AND TREATMENT OF TYPE 2 DIABETES: PERSPECTIVES ON THE PAST, PRESENT AND FUTURE. Steven E. Kahn, M.B., Ch.B.1, Mark E. Cooper, M.B., B.S, Ph.D.2, and Stefano Del Prato, M.D, 제2형 당뇨병의 병인 - 대응약제 에너지/당대사 - 이용약제

GLP1-RA, DPP4-i Decreased Incretin effects Insulin, Analogues TZD SU Increased Lipolysis

Increased Glucagon secretion GLP1-RA, DPP4-i SGLT2-i

Metformin Metformin TZD Neurotransmitter Anti-Obesity Drugs? dysfunction

Ominous Octet Adapted from: DeFronzo RA. Diabetes 2009;58:773–95. Wolters Kluwer Health Development with selective SGLT-2 Inhibitors

Phlorizin Discovered from the root bark of apple tree 1835 Glucosuric effect 1987 Impractical for pharmaceutical use

Human genetic validation Mutations in the SGLT2 gene in familial renal glucosuria; excreted ;30–200g/1.73 m2/day of glucose in urine in 2003 Mutations in the SGLT1 gene (SLC5A1) exhibit glucose-galactose malabsorption

Medicinal Chemistry Phlorizin  Dapagliflozin, Canagliflozin, Empagliflozin

Both academia and industry to translate Scientific insights into innovative Therapies Phlorizin

Dapagliflozin Canagliflozin Empagliflozin

 SGLT2 selectivity,  Oral bioavailability  Long half-lives Overview of Glucose Transporters within the Human Organism

Transport across cell membranes is depicted by arrows, and specific transporters are shown as symbols: rounded symbols are used for sodium dependent, secondary “active” transporters (SGLTs); angular symbols are used for facilitative, “passive” transporters (GLUTs). Red symbols represent the known defects of SGLT1 (glucose-galactose malabsorption), SGLT2 (familial renal glucosuria), GLUT1 (glucose transporter-1 deficiency), and GLUT2 (Fanconi-Bickel syndrome). GLUT10 ... Physiology Glucose Intake ~ 300g/day Glucose Filtered ~ 180 g/day Reabsorption ~ 100% Glucose in Urine ~ 0 Glucose Intake ~ 300g/day Glucose Filtered ~ 180 g/day Reabsorption ~ 100% Glucose in Urine ~ 0

GFR ~120 ml/min/1.73 m2 TmG : Tubular Maximum Glucose Reabsorptive Capacity ~ 400g/day Ps : Plasma Glucose 80 ~ 150 mg/dl RTG : Renal Threshold for Glucose Excretion, ~ 180 mg /dl

 In Healthy Person SGLT2 Inhibition ~ 50% Compensatory SGLT1 Activation Glucose in Urine ~ 50g/day (30 ~ 90g/day)

 In Diabetes

↑ Plasma Glucose, ↑ RTG , ↑ SGLT2 Expression when SGLT2 Inhibition → Greater Glycosuria ↓ HbA1c 0.4 ~ 0.8% Removing 50g CHO form diet, Triggers Fatty substrate Utilization, Ketogenic At 52 weeks, Forxiga was associated with weight loss of –3.2 kg versus weight gain of +1.4 kg with glipizide (p<0.0001)2

3.0 -

2.0 - +0.73 kg 1.0 - (95% CI, +0.06 Glipizide + metformin to +1.40; n=140) (Mean baseline weight 87.6 kg, n=401) 0.0 - 10

-1.0 - 10 difference 10 -2.0 - 10 10 FORXIGA 10mg + metformin 1010 (Mean baseline weight 88.4 kg, n=400

Adjusted Mean Change Adjusted -3.0 - 10 10 10 10 10 10 10 10 10 10 10 10 10 10 From Baseline body weight (kg) weight body Baseline From 10 10 -3.65 kg -4.0 - (95% CI, -4.30 to -3.01; n=159) -5.0 - l l l l l l l l l l l l l l l l l l l l 0 6 12 18 26 34 42 52 65 78 91 104 117 130 143 156 169 182 195 208 Study week

 During study period, urinary energy loss averaged 206 kcal/day.  Predicted weight loss would be 11.32 kg  Observed weight loss was 3.65 kg  Homeostatic mechanisms triggered a compensatory increase in food intake. apparent after 18 weeks, weight reached a plateau

A Phase III, multicentre, randomised, double-blind, parallel-group, 52-week, glipizide-controlled, non-inferiority study with a double-blind extension to evaluate the efficacy and safety profile of Forxiga 10 mg + metformin (1500–2000 mg/day) versus glipizide + metformin (1500–2000 mg/day) in patients with inadequate glycaemic control (HbA1c >6.5% and ≤10%) on metformin alone. CI, confidence interval. Del Prato S, et al. Diabetes Obes Metab 2015;17:581–90; 2. Nauck MA, et al. Diabetes Care 2011;34:2015–22. Sodium Balance and Reabsorption in Kidney

Na+ 70% 15% 5% 5% / 95% 재흡수

5% 섭취 (식이 Na+)

SGLT2 ~5% SGLT2 - Inhibitor

NaCl 1.0 ~ 1.5 g 5% (소변배설) Na+ Negative Na+ Balance by Dapagliflozin

 Transient, Compensated within 5 days, by Other nephron site by increased Renin-Ang-System  a New steady state N+ with reduced total Body Na+ without activation of Sympathetic N system  Reduction in Plasma volume, sustained BP lowering  Additional effects: reduction in serum Uric acid increase in serum Phosphate Cardiovascular Effects Mg Cardioprotection K+ ( in CKD, ARB) Novel Anti-diabetic Drugs and CV outcomes

Glucose Lowering Drugs Glucose lowering & CV Outcome & CV Outcome DPP4 inhibitor SAVOR EXAMIN TECOS • UKPDS (1998) •No significant Saxagliptin E Sitagliptin cardiovascular risk (2013) (2015) Alogliptin reduction • ACCORD (2008) (2013)

GLP-1 R Agonist ELIXA LEADER SUSTAIN REWIND • ADVANCE (2008) •Different within Lixisenatide Liraglutide Semaglutide Excenatide class (2015) (2016) (2016) (2018) • VADT (2009) SGLT2 inhibitor DECLARE CANVAS VERTIS-CV •Different within EMPA-REG TIMI 58 Empagliflozin Canagliflozin Dapagliflozin Eurtugliflozin class (2017) (2019) (2015) (2018)

2008, New FDA requirements1 New diabetes drugs should demonstrate CV safety with meta-analysis and a CV outcome trial (CVOT)

1. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/%20guidances/ucm071627.pdf; Four SGLT2 inhibitors have been approved by the U.S. FDA for the treatment of type 2 diabetes. Data have been taken from the FDA approved prescribing information for each drug and/or from the cardiovascular (CV) outcome trials (1–3,53). The prescribing information expresses HbA1c as a percent (NGSP units). HbA1c levels in International Federation of Clinical Chemistry (IFFC) units (mmol/mol) were generated using the conversion tool at http://www.ngsp.org/convert1.asp, which uses the following equation for the conversion: NGSP = (0.09148 3 IFCC) + 2.152. Accordingly, it is not straightforward to accomplish the conversion for mean D HbA1c. For purposes of the article, we have estimated D HbA1c (mmol/mol) by assuming that the baseline HbA1c was ;8.0% (64 mmol/mol) and calculating the change in HbA1c if that baseline HbA1c were decreased by reported change in HbA1c. For example, if the prescribing information reports that D HbA1c = 20.6%, this would correspond to an HbA1c of 7.4% (relative to a baseline HbA1c of 8.0%). The website converts an HbA1c of 7.4% to 57 mmol/mol. Thus, we have subtracted 64 mmol/mol from 57 mmol/mol, thereby converting a value of D HbA1c = 20.6% to D HbA1c = 27 mmol/mol. This should be viewed as an approximation. It would be necessary to convert data on individual patients before averaging to accomplish an exact unit conversion. BP, blood pressure; MI, myocardial infarction. *For the CV outcome trials, data are hazard ratio (95% CI). Because the CV outcome study for ertugliflozin is still in progress, data are not yet available. Potential Mechanisms for the Beneficial Effect of Empagliflozin on Cardiovascular Outcomes Renal, metabolic and cardiovascular considerations of SGLT2 inhibition: DeFronzo R.A. Nature Review. 2017

↓ Blood pressure ↔ Heart rate ↓ Insulin ↓ Plasma volume resistance

↓ Glucose ↓ Arterial stiffness

↓ Weight and ↓ SNA activity Visceral fat

↓ Ang1-7 AT receptor ↓ Uric acid 2

↑ Ketones ↓ Inflammation and ↓ Albuminuria Oxidative stress

 Thrifty Substrate Hypothesis (절약기질 가설)  Myocardium Energy: Glc 30%, FFA 70%  Diabetic Myocardium : FFA ~99%  에너지효율↓  Mild Ketosis, β-OH-Butyrate, act as a Superfuel for the Heart  에너지효율↑, Aanti-Oxidative, Anti-Arrhythmic Effect Mechanisms Implicated in Renal Protective Effect of SGLT2 Inhibition Diabetes

Diabetes treated with SGLT2-I Renal outcomes in the EMPA‐REG OUTCOME (EMPA), CANVAS Program (CANVAS), and DERIVE‐TIMI 58 (DERIVE) trials

FIGURE 2 Renal outcomes in the EMPA‐REG OUTCOME (EMPA), CANVAS Program (CANVAS), and DERIVE‐TIMI 58 (DERIVE) trials. Data are expressed as incidence per 1000 patient‐year in SGLT2i‐treated (red bars: composite end‐point; blue bars: progression; brown bars: ESRD) and placebo‐treated patients (white bars). Hazard ratio (95% CI) values are also reported. On the x‐axis, it is specified: end‐point definition, type of variable (post‐hoc, secondary, exploratory) and whether analyses were based on either single or confirmed measurements. Comparison should be taken with caution because of differences in both study design and recruited subjects. ESRD, end‐stage renal disease; dSCr, doubling of serum creatinine; eGFR, estimated glomerular filtration rate (value expressed as mL/min/1.73 m2), RRT, renal replacement therapy Direct Effects Indirect Effects  Renal Hemodynamic effect ↓ Plasma Glc, HbA1c Restored G-T feedback ↓ Serum Uric acid ↓ Intra-Glomerular pressure ↓ Blood pressure ↓ Abuminuria ↓ Insulin level ↓ ANP Level ↓ Body weight ↓ Tubular Na+ reabsorption

 Non Hemodynamic effect ↓ Tubular glucotoxicity ↓ AGE-mediated inflammation ↓ Tubular energy demand ↓ Tubular apoptosis ↓ Inflammatory mediators ↓ Oxidative stress

From Bancha Satirapoj: Sodium-Glucose Cotransporter 2 Inhibitors with Renoprotective Effects. Kidney Dis 2017;3:24–32 Non-Alcoholic Fatty Liver Disease (NFALD), SGLT2-i improved ALT, AST, γ-GT, US-Fibroscan, Visceral Fat Mass, MRI Scan [Proton Density Fat Fraction]

Results are expressed as changes before → after treatment. Open non- controlled studies are not considered in this table. MRI-PDFF, magnetic resonance imaging-proton density fat fraction; NA, not available; NS, not significant; NAFLD, non- alcoholic fatty l

From André J. Scheen: Effect of sodium-glucose cotransporter type 2 inhibitors on liver fat in patients with type 2 diabetes: hepatic beyond Cardiovascular and renal protection? Ann Transl Med 2018;6(Suppl 1):S68 Improvement of histological findings of liver samples after 9 months Ipragliflozin treatment : Fewer fat droplets and inflammatory neutrophil aggregations and less hepatocellular ballooning (H&E, 200×). Interstitial fibrosis (silver staining, 200× --- A Case Report ---

9 months Ipragliflozin

From Akihiko Takeda, et al: The Improvement of the Hepatic Histological Findings in a Patient with Non-alcoholic Steatohepatitis with Type 2 Diabetes after the Administration of the Sodium-glucose Cotransporter 2 Inhibitor Ipragliflozin. Intern Med 56: 2739-2744, 2017 Mechanism of Action of SGLT2-i on NAFLD

SGLT2-i SGLT2-i FGF21 Glycosuia Fasting like State Independent Glucose Lipid Oxidation Ketones Glucagon Weight Loss effect Glucose Control Transcriptional Reprogramming ↑PPARα, ↑PGC1α, ↓ChREBP Inhibition/Modulation of de Novo Lipogenesis FGF21 ↑↑Hepatokine FGF21 Decease Inflammatory Dependent markers Oxidative stress

↓ Fat Mass ↓ Adipocyte size (Fibroblast From Chan-Hee Jung, Ji-Oh Mok: The Effects of Hypoglycemic ↓ Activation of Lipolysis Growth Factor21) Agents on Non-alcoholic Fatty Liver Disease: Focused on Sodium-Glucose Cotransporter 2 Inhibitors and Glucagon-Like From Soravis Osataphan, et al SGLT2 inhibition reprograms systemic Peptide-1 Receptor Agonists. Journal of Obesity & Metabolic metabolism via FGF21-dependent and -independent mechanisms. JCI Insight. Syndrome 2019;28:18-29 2019;4(5):e123130 SGLT2 –I as add-on to Insulin in Type 1 diabetes

1. Henry RR, et al. Efficacy and safety of canagliflozin as add-on to insulin in patients with type 1 diabetes. Diabetes Care 2015;38:2258–2265 2. Buse JB, et al. Sotagliflozin in combination with optimized insulin therapy in adults with type 1 diabetes: the North American in-Tandem1 study. Diabetes Care 2018;41:1970–1980 3. Garg SK, et al. Effects of sotagliflozin added to insulin in type 1 diabetes. N Engl J Med 2018;378:967–968 4. Danne T, et al. HbA1c and hypoglycemia reductions at 24 and 52 weeks with sotagliflozin in combination with insulin in adults with type 1 diabetes: the European inTandem2 study. Diabetes Care 2018;41:1981–1990 5. Rosenstock J, et al. Empagliflozin as adjunctive to insulin therapy in type 1 diabetes: the EASE trials. Diabetes Care 2018;41:2560–2569 6. Dandona P, et al. Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (DEPICT-1): 24 week results from a multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol 2017;5:864–876 7. Dandona P, et al. Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes: the DEPICT-1 52-week study. Diabetes Care 2018;41:2552–2559 8. Mathieu C, et al. Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (the DEPICT-2 study): 24-week results from a randomized controlled trial. Diabetes Care 2018;41:1938–1946 Overall HbA1c Reduction 0.2~0.4% Weight Reduction 3.0 ~ 4.5% Kotoacidosis induced by SGLT2-i

 Type 2 DM Case report ~? % Risk Factor: anti-GAD65 autoantibodies, recent surgery, recent alcohol intake, and markedly decreased food intake Some cases of Euglycemic ketoacidosis

 Type 1 DM (8 Phase 3 Trials) SGLT2 treated 4,076 patients → 3.5% DKA Placebo treated 2,062 patients → 0.6% DKA, ↑ 5.8 HR 100,000 T1DM  4,000 DKA, Mortality 0.4%,  16 death

The European Commission (EC) approved Dapagliflozin, Sotagliflozin as adjunctive therapy in T1DM on 22 March 2019 The US FDA announced not to approve Safety and Side Effects A long list of adverse effects, were not recognized when the drugs were first approved

(Data are %)

Ketoacidosis Acute Kidney Injury Perineal Necrotizing Fasciitis Hyperkalemia

Data are %, unless otherwise indicated. Selected data on various adverse effects are summarized for the four FDA-approved SGLT2 inhibitors and have been taken from the FDA-approved prescribing information for each drug. Impact of canagliflozin on bone health

Figure 2—Impact of canagliflozin on bone health: pharmacodynamic effects on hormones regulating bone and mineral metabolism. SGLT2 inhibitors promote tubular reabsorption of phosphate, thereby increasing serum phosphorus levels. In pharmacodynamic studies of canagliflozin in healthy volunteers (18), the increase in serum phosphorus was followed promptly by an increase in plasma FGF23, which in turn triggered a decrease in plasma levels of 1,25-dihydroxyvitamin D [1,25-(OH)2VitD]. The decrease in 1,25-(OH)2VitD levels was followed by an increase in plasma levels of parathyroid hormone (PTH) presumably triggered by decreased gastrointestinal absorption of ↑ Serum Phosphate calcium. The increased levels of serum phosphorus and FGF23 returned toward baseline levels in this 5-day study conducted in healthy volunteers. However, in studies of canagliflozin in patientswith type 2 diabetes, the increase in serumphosphorus (Pi)was sustained for at least 26 weeks (80).On the lower left side of the diagram, similar to the pathophysiology of bone disease associated with chronic kidney disease, the decrease in 1,25-(OH)2VitD and increase in PTH (18,81,82) may contribute to mediating the adverse effect of canagliflozin on bone health (78,83).

Illustration by T. Phelps, used with permission from the Department of Art as Applied to Medicine, Johns Hopkins University. Summary: Effects, Clinical Efficacy of SGLT2-i • Renal Effect • Direct: Glycosuria, Natriuresis • Indirect: ↑Serum Phosphate, ↓Uric acid • Extrarenal Effect • Pancreatic α-Cell: ↑ Glucagon • Biliary duct and Sweat gland: (↑ )volume of secretion

• Metabolic Effect • ↓ HbA1c, ↓ Body Weight • ↑ Insulin sensitivity, ↑ Glc-stimulated Inulin secretion, ↓ Glucotoxicity • Compensation: ↑ Food intake, ↑ ketosis, ↑ Hepatic glucose production, ↑ Lipid oxidation • Improvement of NAFLD • Cardiovascular Effect • Natriuresis, ↓ BP, ( - ) Sympathetic Activation, ( - ) Heart Rate • Cardioprotection • (↓) MACE Risk, ↓ Cardiac death, ↓ Heart failure ( Hospitalization) • Renoprotection • ↓ Progression of Proteinuria, ↓ to ESRD Summary SGLT2 –i is the most recently approved class of diabetes drugs.

 Act on the kidney to promote urinary glucose excretion, and provide multiple benefits, ↓ HbA1c, ↓ Wt, and ↓ BP. paly as Catabolic diabetes drugs

 Special attention: ↓ CVOT, ↓ Progression of Nephropathy ↓ NAFD, Add on in Type 1 DM

 Long list of side effects: Genitourinary Infections, Ketoacidosis, Bone Fractures, Amputations, Acute Kidney Injury, Perineal Necrotizing Fasciitis, Hyperkalemia. Negative Sodium Balance by Dapagliflozin

Urinary Sodium Excretion Na+ Na+ NaCl (mmol) mEq mg 50 1145 2919

- 1.0 ~ 1.5 g NaCL 33 763 1946

17 382 973

0 0 0

Heerspink HJ, List J, Boulton D, Liu X, Ying L, de Zeeuw D. The SGLT2 inhibitor dapagliflozin, a proximal tubular diuretic with antihypertensive properties? Presented at the World Congress of Nephrology, 8–12 April 2011;Vancouver, Canada. 2011. Abstract SU183. Figure 1—Role of selected solute transporters related to tubular reabsorption of glucose. SGLT2 (encoded by the SLC5A2 gene) is a high-capacity, low-affinity SGLT located in the S1 segment of the renal proximal tubule. Under physiological conditions, SGLT2 mediates reabsorption of 90% of the filtered glucose load. SGLT1(encoded by the SLC5A1 gene) is a low-capacity, high-affinity SGLT located in the S3 segment of the renal proximal tubule, which mediates near-complete reabsorption of the glucose that escapes reabsorption by SGLT2. SGLT family transporters are located on the apical membrane of renal tubular epitelial cells and mediate active transport of glucose into epithelial cells. GLUT2 and/or GLUT1 (encoded by SLC2A2 and SLC2A1, respectively) are located on the basolateral membrane and mediate passive diffusion of glucose out of renal tubular epithelial cells. We have indicated stoichiometries for SGLT family transporters: one Na+ ion for SGLT2 and two Na+ ions per glucose molecule for SGLT1. However, the figure does not indicate stoichiometries for other transporters. Na/K-ATPases are also located on the basolateral membrane and mediate active transport of Na+ out of cells, thereby establishing an electrochemical gradient for Na+ that provides the energy required to drive active transport of glucose. SGLT2 inhibitors block cotransport of glucose and Na+ in the S1 segment of the proximal tubule. Two sodium phosphate cotransporters (NaPi-IIa and NaPi- IIc encoded by SLC34A1 and SLC34A3, respectively) compete with SGLT2 and SGLT1 for energy stored in the Na+ gradient to drive active transport. Potential mechanisms for the beneficial effect of empagliflozin on cardiovascular outcomes

Figure 8. Potential mechanisms for the beneficial effect of empagliflozin on cardiovascular outcomes. The EMPA-REG OUTCOME study was not designed to examine the mechanisms responsible for the cardiovascular benefit achieved with SGLT2 inhibition. However, haemodynamic factors, including reductions in blood pressure (after load), intravascular volume (preload), and aortic stiffness are likely to have contributed. The failure of heart rate to increase despite intravascular volume depletion suggests a potential role for reduced sympathetic nervous system activity. Of considerable interest is the ketone hypothesis, by which a switch from glucose to fat oxidation in the liver increases the plasma concentration of ketones that are preferentially taken up and oxidized as a fuel by the myocardium. Improved glycaemic control is unlikely

to explain the cardioprotective effect of empagliflozin as the reduction in HbA1c was very modest (−0.25%) and as any beneficial cardiovascular effect of improved glycaemic control takes up to 10 years to manifest, whereas the reductions in cardiovascular mortality and hospitalization for heart failure with SGLT2 inhibition were observed within 3 months. Weight loss and reduced visceral fat content could contribute to continued separation of the cardiovascular benefit of empagliflozin and placebo after 6–12 months but are unlikely to explain the cardiovascular benefit observed within the first 3 months. A number of other mechanisms (decreased plasma uric acid level, reduced inflammation and

oxidative stress, activation of the angiotensin II receptor type 2 (AT2) , improved insulin sensitivity, and diminished albuminuria) have been suggested to explain the cardioprotective effective of empagliflozin but hard evidence to support any of these possibilities is lacking. Ang, angiotensin; SNS, sympathetic Nervous System.

Renal, metabolic and cardiovascular considerations of SGLT2 inhibition: DeFronzo R.A. Nature Review. 2017 Effect of Diabetes and SGLT2 inhibition on Afferent and Efferent Arteriolar Tone, GFR, and Na+ excretion

Afferent Efferent Afferent art Efferent art Afferent art Efferent art arteriole arteriole Vasodilatation Vasoconstriction Vasoconstriction Unaffected

Diabetes Normal TGF Diabetes + SGLTG2 -i (Tubulo-Glomerular Feedback)

Renal, metabolic and cardiovascular considerations of SGLT2 inhibition: DeFronzo R.A. Nature Review. 2017 Protective effects of empagliflozin in high-fat diet-induced obese mice

Figure 2. Protective effects of empagliflozin in high-fat diet-induced obese mice. Inhibiting SGLT2 with mpagliflozin directly decreases blood glucose levels, leading to the following: (1) Empagliflozin promotes fat utilization by enhancing AMPKa and ACC phosphorylation in skeletal muscle and increasing hepatic and plasma levels of FGF21. (2) Empagliflozin enhances browning and thermogenesis in WAT and BAT, which results in increased energy expenditure. (3) Empagliflozin improves insulin sensitivity by polarizing M2 macrophages in fat and liver.

From Liang Xua and Tsuguhito Otaa,b Emerging roles of SGLT2 inhibitors in obesity and insulin resistance: Focus on fat browning and macrophage polarization. Adipocyte 2018, VOL. 7, NO. 2, 121–128