new therapies in type 2 diabetes: focus on sglt-2...

New Therapies in Type 2 Diabetes: Focus on SGLT-2 Inhibitors

NACE – Emerging Challenges in Primary Care: Update 2013 Diabetes - 1


Emerging Challenges in Primary Care: Update 2013 1

Faculty

•  Robert S. Busch, MD, FACE Managing Partner of The Endocrine Group, LLP, Albany, NY

•  Luigi F. Meneghini, MD, MBA Professor of Clinical Medicine, Division of Endocrinology, Diabetes & Metabolism Director, Kosow Diabetes Treatment Center, Diabetes Research Institute University of Miami Miller School of Medicine, Miami, FL

•  Mark Stolar, MD Associate Professor of Clinical Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL

2



Faculty Disclosure

•  Robert S. Busch, MD, FACE –  Speakers Bureau - Merck, Janssen, Bristol Myers Squibb and Novo

Nordisk

•  Luigi F. Meneghini, MD, MBA –  Advisory Board - Novo Nordisk and Halozyme –  Consultant - Novo Nordisk and Sanofi –  Researcher - MannKind, Pfizer, Boehringer Ingelheim, Biodel and

Sanofi Aventis (pending)

•  Mark Stolar, MD –  Advisory Board – Takeda –  Speaker - Vivus 3

Learning Objectives for Discussion:

•  Discuss the role of the kidney in the pathophysiology of diabetes in health and disease

•  Discuss the role of glycemic control in the pathogenesis of microvascular complications

•  Discuss the physiology of SGLT-2 in glucose metabolism •  Discuss the role of SGLT-2 inhibitor therapy in management of

diabetes and possible impact on other metabolic risk factors

4



ON A SCALE OF 1 TO 5, PLEASE RATE HOW CONFIDENT YOU ARE IN RECOGNIZING THE ROLE OF SGLT2-INHIBITORS IN THE MANAGEMENT OF DIABETES

1.  Not at all confident 2.  Slightly confident 3.  Moderately confident 4.  Pretty much confident 5.  Very confident

Pre-Test Question 1

5

Which of the following is incorrect about the kidney in diabetes? 1.  Serum creatinine and eGFR are equally predictive of renal

function in diabetes 2.  The kidney contributes 20-25% of all glucose output in the

fasting state and 40% of all gluconeogenesis 3.  Renal glucose production is increased in the diabetic

postprandial state contributing to hyperglycemia 4.  The risk of hypoglycemia is significantly increased in renal

impairment

Pre-Test Question 2

6



Which of the following is incorrect regarding metabolic memory and the legacy effect? 1.  It is likely mediated by oxidative stress induced changes in the

mitochondria 2.  May be mediated by advanced glycosylated end products

(AGE’s) 3.  Both the EDIC and UKPDS trials demonstrated the presence of

an enduring legacy effect. 4.  Clinical trials have consistently shown that early aggressive

treatment of diabetes will reduce long term risk of complications 5.  VADT trial did not show significant benefit of intensive control on

complication risk

Pre-Test Question 3

7

Which of the following is incorrect about SGLT-2 physiology in the kidney?

1.  10% of all glucose filtered by the kidney are reabsorbed by

these receptors 2.  SGLT-2 activity is upregulated in diabetes 3.  SGLT-2 inhibition causes natriuresis and a drop in systolic and

diastolic blood pressure 4.  SGLT-2 inhibition of glucose uptake by renal cells may reduce

progression of diabetic kidney disease

Pre-Test Question 4

8



Which of the following does not occur with use of SGLT-2 Inhibitors?

1.  lowering of A-1c by 0.5-0.7% 2.  lowering of LDL-cholesterol 3.  lowering of blood pressure 4.  increased glucose excretion in urine 5.  decreased body weight

Pre-Test Question 5

9

Challenges in Type 2 Diabetes

•  Progressive worsening of insulin secretory deficit requiring

increased number of antihyperglycemic medications over time •  Treatment models do not match disease state understanding •  Risk for hypoglycemia, weight gain and ? CV risk with some

therapies •  Preventing and managing complications and co-morbidities of

renal dysfunction and cvd •  Difficulty attaining and sustaining optimal long-term glycemic

control

CDC 2010. Na*onal Diabetes Fact Sheet. US Department of Health and Human Services. Cefalu, WT. Am J Med. 2012;343(1):21-‐26. 10



UKPDS: Correlation Between A1C and Microvascular Endpoints

0.5

1

10 P<0.0001

Microvascular endpoints*

5 6 7 8 9 10 11

Haza

rd r

ati

o

(lo

g s

cale

)

Updated mean A1C (%)

*Estimated hazard ratios (95% CI) between updated mean A1C and microvascular endpoints. Data are adjusted for age at diagnosis of diabetes, sex, ethnic group, smoking, presence of albuminuria, systolic BP, HDL-C, LDL-C, and TG. UKPDS=United Kingdom Prospective Diabetes Study Reprinted with permission from Stratton IM et al. BMJ. 2000;321(7258):405-412.

Type 2

37% ↓ per 1% ↓ in A1C

11

FPG and Prevalence of Albuminuria: The AusDiab Study

AusDiab=Australian Diabetes, Obesity, and Lifestyle Study; IFG=Impaired Fasting Glucose; IGT=Impaired Glucose Tolerance; KDM=Known Diabetes Mellitus; NDM=Newly Diagnosed Diabetes Mellitus; NGT=Normal Glucose Tolerance Note: Data expressed as numbers of percentages. *Adjusted to the Australian population. †Excludes type 1 diabetes mellitus

Reprinted with permission from Tapp RJ, et al. Am J Kidney Dis. 2004;44(5):792-798.

Unadjusted (%) Adjusted for Age and Sex* (%)

Glucose Tolerance Status

No. of Patients

Micro- albuminuria

Macro- albuminuria

Micro- albuminuria

Macro- albuminuria

NGT 7,615 4.3 0.8 4.7 0.9

IFG level 625 8.3 1.0 8.8 0.7

IGT 1,319 9.9 1.1 7.6 0.7

NDM 456 15.4 2.4 10.6 2.0

KDM† 423 26.5 6.1 23.2 5.8

Type 2

12



10

9

8

7

1983

Conventional A

1C

(%

)

1989 1993 2004

Intensive 9.1±1.6 9.1±1.5a

7.8±1.3

7.9±1.3

7.4±1.1

DCCT at baseline End of DCCT Year 11 of EDIC Year

Nathan DM, et al. N Engl J Med. 2005;353(25):2643-2653.

DCCT/EDIC Cohort: Intensive vs Conventional Treatment Effect on A1C

aP<0.01 comparing two treatments. DCCT=Diabetes Control and Complications Trial; EDIC=Epidemiology of Diabetes Interventions and Complications

Type 1

13

Long-Term Benefits of Glycemic Control for Microvascular Complications

•  Long-term benefits persist after intervention –  Type 1 (EDIC): intensive treatment reduces risk of microvascular

complications for at least 8 years beyond therapy –  Type 2 (UKPDS): tight glycemic control reduces risk of microvascular

effects—even 10 years after treatment •  Long-term benefits not seen consistently

–  No reduction of microvascular complications* in Veterans Affairs Diabetes Trial (VADT) intensive arm

•  Results suggest a “metabolic memory” (“legacy”) effect

*Except for conversion from normo- to micro- or macroalbuminuria EDIC=Epidemiology of Diabetes Interventions and Complications; UKPDS=United Kingdom Prospective Diabetes Study Martin CL, et al. Diabetes Care. 2006;29(2):340-344. Holman RR, et al. N Engl J Med. 2008;359(15):1577-1589. Writing Team for DCCT/EDIC Research Group. JAMA. 2003;290(16):2159-2167. Del Prato S, et al. Diabetologia. 2009;52(7):1219–1226

Type 2

14



Proposed Role of Duration of Diabetes on Glucose Effects

Reprinted with permission from Del Prato S, et al. Diabetologia. 2009;52(7):1219–1226. aDuckworth W, et al. N Engl J Med. 2009;360(2):129–139. bUK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):837–853.

After entering VADT intensive treatment arm

9.5

9.0

8.5

8.0

7.5

7.0

6.5

6.0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Time Since Diagnosis (Years)

A1

C (

%)

Generation of ‘bad glycemic legacy’

Drives risk of complications

Before entering VADT intensive treatment arm

A1C in the VADTa

Average UKPDS profileb

Ideal control

UKPDS=United Kingdom Prospective Diabetes Study; VADT=Veterans Affairs Diabetes Trial

Type 2

15

A Proposed Microbiological Vicious Cycle of Metabolic Memory

Reprinted with permission from Ceriello A, et al. J Clin Endocrinol Metab. 2009;94(2):410-415.

ROS

Mitochondria Epigenetic changes

Vascular stress signaling

Endothelial dysfunction

Diabetic Complications Cardiovascular disorders

Retinopathy Nephropathy Loss of limb

Respiratory chain activity

Respiratory chain protein

(glycated)

Respiratory protein alteration

ROS

mtDNA

Deleterious cycle leading to the

“metabolic memory”

AGE inhibitors

AGE formation

Glucose

RAGE

RAGE inhibitors

Antioxidants

Respiratory chain activity

16



AGE Evidence from DCCT/EDIC

•  DCCT: Intensive treatment associated with significantly lower levels of AGEsa

•  EDIC: 10-yr incidence of retinopathy and nephropathy significantly associated with levels of AGEs as measured by skin collagensb

•  AGEs are a marker for retinopathy and nephropathy but is not known if they are causative

aMonnier VM, et al. Diabetes. 1999;48(4):870-880. bGenuth S, et al. Diabetes. 2005;54(11):3103-3111.

AGE=advanced glycation end-product

Type 1

b 17

Ominous Octet

DeFronzo RA. Diabetes. 2009;58:773-‐795. 18



Making Choices When Metformin Is Not An Option: Do SGLT-2 Inhibitors Have a Role?

•  Mary is a 58 y.o woman with a 5 yr history of type 2 diabetes. Although overweight with a BMI of 30.7, she has been more adherent to a diet and exercise program recently. She had been treated with metformin which was discontinued due to gastrointestinal side effects. She was then placed on a sulfonylurea which was recently stopped by the patient due to frequent hypoglycemia. She is hypertensive for which she takes lisinopril 30mg and HCTZ 12.5mg. She is also on atorvastatin 40mg. Current BP is 136/82 and A-1-c is 7.4%

19

Which would be an appropriate therapy to initiate for this patient?

1.  Pioglitazone 2.  SGLT-2 inhibitor 3.  DPP-4 inhibitor 4.  Glp-1 analogue 5.  Reinforce diet and exercise

20



•  Normal Renal Glucose Physiology

•  180 g of glucose is filtered each day

•  Virtually all glucose reabsorbed in the proximal tubules & reenters the circulation with virtually no glucose in the urine

•  SGLT2 reabsorbs about 90% of the glucose/SGLT-1 10%

The Kidneys Play an Important Role in Glucose Control

Mather, A & Pollock, C. Kidney Interna4onal. 2011;79:S1-‐S6. 21

Altered Renal Glucose Control in Diabetes

•  Gluconeogenesis is increased in postprandial and postabsorptive states in patients with Type 2 DM –  Renal contribution to hyperglycemia postprandially is significant –  3-fold increase in glucose output relative to patients without diabetes –  In renal insufficiency renal glucose output is decreased increasing

risk of hypoglycemia

•  Glucose reabsorption –  Increased SGLT-2 expression and activity in renal epithelial cells

from patients with diabetes vs. normoglycemic individuals

Marsenic O. Am J Kidney Dis. 2009;53:875-‐883. Bakris GL, et al. Kidney Int. 2009;75(12):1272-‐1277. Rahmoune H, et al. Diabetes. 2005;54(12):3427-‐3434.

22



Dysregulated Renal Glucose Handling in T2DM Exacerbates Hyperglycemia and Leads to Glucotoxicity

23

Plasma glucose concentration1

Filtered glucose load1,2

Expression/function of SGLTs1,2

Tubular glucose reabsorption2

Renal threshold for glucose excretion2

Adapted with permission from Chao EC, Henry RR. Nat Rev Drug Discov. 2010;9(7):551-559. T2DM = type 2 diabetes mellitus; SGLT = sodium-glucose cotransporter. 1. Chao EC, Henry RR. Nat Rev Drug Discov. 2010;9(7):551-559. 2. DeFronzo RA et al. Diabetes Obes Metab. 2012;14(1):5-14.

23

Rationale for SGLT2 Inhibitors

•  SGLT2 is a low-‐affinity, high capacity glucose transporter located in the proximal tubule and is responsible for 90% of glucose reabsorp*on

•  Selec*ve SGLT2 inhibitors have a novel & unique mechanism of ac*on reducing blood glucose levels by increasing renal excre*on of glucose

•  Insulin independent glucose lowering poses lible risk of hypoglycemia

•  Selec*ve SGLT2 inhibi*on, would also cause urine loss of the calories from glucose, poten*ally leading to weight loss

Brooks AM, Thacker SM. Ann Pharmacother. 2009;42(7):1286-‐1293. 24



Reabsorption of Filtered Glucose in the Normal Kidney

Adapted with permission from Chao EC, Henry RR. Nat Rev Drug Discov. 2010;9(7):551-559. SGLT = sodium-glucose cotransporter. 1. Gerich JE. Diabet Med. 2010;27(2):136-142. 2. Neumiller JJ et al. Drugs. 2010;70(4):377-385.

Proximal convoluted tubule

Distal convoluted tubule Glomerulus

25

Collecting duct

Glucose

Late segment of proximal tubule

Early segment of proximal tubule

~90% reabsorption

~10% reabsorption

SGLT1

SGLT2

No glucose in urine2

~180 g of glucose filtered by the kidneys/day1,2

SGLT2: High capacity, low affinity1

SGLT1: Low capacity, high affinity1

25

Potential Benefits and Risks of SGLT-2 Inhibition

•  Glycemic control without risks of hypoglycemia •  Modest Weight Loss: possible reduction in visceral fat •  Statistically Significant Drop in Blood Pressure •  Potential but yet unproven reduction in progression of diabetic

kidney disease/microalbuminuria •  Risks:

•  Increased risk of genitourinary infection •  Modest efficacy in A-1c reduction especially in setting of low GFR •  Non-disease state mechanism of action: neither insulin sensitizer

nor beta cell active

26



Changes from Baseline in A1C in Phase 3 Dapagliflozin Studies

Wilding JPH, et al. Abstract 78-‐OR. ADA 2010; Strojek K, et al. Abstract 870. EASD 2010; Ferrannini E, et al. Diabetes Care. 2010;33(10):2217-‐2224; Bailey CJ, et al. Lancet. 2010;375(9733):2223-‐2233.

Placebo Dapa 2.5mg Dapa 5mg Dapa 10mg

27

Changes from Baseline in Body Weight in Phase 3 Dapagliflozin Studies

Placebo Dapa 2.5mg Dapa 5mg Dapa 10mg

Wilding JPH, et al. Abstract 78-‐OR. ADA 2010; Strojek K, et al. Abstract 870. EASD 2010; Ferrannini E, et al. Diabetes Care. 2010;33(10):2217-‐2224; Bailey CJ, et al. Lancet. 2010;375(9733):2223-‐2233. 28



Change in HbA1c (%) during the 52 week double-blind treatment period

Study Week

Cha

nge

in H

bA1c

, (%

)

Nauck, M. et al., Diabetes Care 2011;34:2015-22.

0 3 6 9 12 15 18 26 34 42 52

Titration Period Maintenance Period

29

Change in TBW (kg) during the 52 week double-blind treatment period

Study Week

Cha

nge

in T

BW

(kg)

Nauck, M. et al., Diabetes Care 2011;34:2015-22.

0 3 6 9 12 15 18 26 34 42 52

Titration Period Maintenance Period

30



Effect of treatments of DAPA and GLIP with MET on hypoglycemia at 52 weeks

≥1 hypoglycemic episode during 52 weeks

Prop

ortio

n of

Pat

ient

s (%

)

Nauck, M. et al., Diabetes Care 2011;34:2015-22. 31

Effect of treatments of DAPA and GLIP with MET on reduction in body weight at 52 weeks

Weight reduction ≥5% at 52 weeks

Prop

ortio

n of

Pat

ient

s (%

)

Nauck, M. et al., Diabetes Care 2011;34:2015-22. 32



Making Choices When Metformin Is Not An Option: Do SGLT-2 Inhibitors Have a Role?

•  Mary is a 58 y.o woman with a 5 yr history of type 2 diabetes. Although overweight with a BMI of 30.7, she has been more adherent to a diet and exercise program recently. She had been treated with metformin which was discontinued due to gastrointestinal side effects. She was then placed on a sulfonylurea which was recently stopped by the patient due to frequent hypoglycemia. She is hypertensive for which she takes lisinopril 30mg and HCTZ 12.5mg. She is also on atorvastatin 40mg. Current BP is 136/82 and A-1-c is 7.4%

33

Questions to discuss:

§  What is your determinant in choosing a next therapy in this patient?

§  How important are effects on weight in choosing therapy? §  How important are effects of SGLT-2 on blood pressure in

choosing this class vs another §  Is treating insulin resistance still important in this patient? §  How important is avoiding hypoglycemia in treating diabetes?

34



Asymptomatic Episodes of Hypoglycemia May Go Unreported

§  In a cohort of patients with Type 2 diabetes, more than 45% had asymptomatic (unrecognized) hypoglycemia, as identified by continuous glucose monitoring1

§  Other researchers have reported similar findings2,3

1. Copyright © 2003 American Diabetes Association. Chico A et al. Diabetes Care. 2003;26(4):1153–1157. Reprinted with permission from the American Diabetes Association. 2. Weber KK et al. Exp Clin Endocrinol Diabetes. 2007;115(8):491–494. 3. Zick R et al. Diab Technol Ther. 2007;9(6):483–492.

0

25

50

75

100

All patients with

diabetes

Type 1 diabetes

Patie

nts, %

Type 2 diabetes

55.7 62.5

46.6

Patients With ≥1 Unrecognized Hypoglycemic Event, %

n=70 n=40 n=30

35

Managing Diabetes in the patient with renal insufficiency: Risks of hypoglycemia/therapeutic challenges

§  Ellen is a 68 y.o retired school teacher with a 12 year history of diabetes, well controlled until recently on metformin 850 twice daily and glimepiride 2mg qam. She has recently joined a walking club but is unable to fully participate due to feeling weak and tired after a mile walk as well as occasionally while doing laundry in the afternoon. She attributes the weakness to the new diuretic recently begun to control a rise in blood pressure.

§  She currently also takes lisinopril 20mg daily, metoprolol SR 50 mg and simvastatin 20mg.

–  Past medical history is significant for an LAD stent placed in 2009 post episode of ACS.

–  She fractured a wrist in 2010 after a fainting spell in the middle of the night. –  A review of her HGM logbook shows glucoses ranging from 74 to 210 mg/dl in

the AM to 90-130 pre-dinner. –  She blames the high AM readings on a piece of cake or pie at dinner.

36



Physical Examination and Labs:

§  Height 66in,weight 138 lbs BMI 22.3 BP 118/74mm/hg sitting, 120/74 standing .pulse 64/68

§  Random glucose 118 mg/dl §  Hgb-A1c 7.5% §  BUN 21mg/dl Creatinine 1.9mg/dl §  eGFR 27 §  Potassium 4.5 §  Microalbumin 45mg/gram creatinine

37

Which of the Following Therapies Require Dosage Adjustment in Renal Impairment?

1.  Pioglitazone 2.  All DPP-4 inhibitors 3.  All GLP-1 analogues 4.  Sulfonylureas 5.  All of the above

38



Diabetes Therapy in the Setting of Impaired Renal Function: Where to go with our patient

•  Metformin not indicated based on eGFR •  Sulfonylureas should be used cautiously if at all due to

hypoglycemic risk •  TZD drugs are safe but risk of edema increased with low gfr •  DPP-4 therapies may require dosage adjustment •  GLP-1 analogues may require dosage adjustment •  Insulin clearance is decreased and risk of hypoglycemia is

increased. •  SGLT-2 safe but efficacy may be decreased

39

Metabolism/Clearance and Dosing Adjustments of Incretin-Based Therapies in the Presence of Renal Impairment

Drug Metabolism/ Clearance Dose Adjustment in CKD

Sitagliptin Renal 50 mg/d if GFR 30-60 mL/min 25 mg/d if GFR < 30 mL/min

Saxagliptin Hepatic/renal 2.5 mg/d if GFR < 30 mL/min

Linagliptin Hepatic No dose adjustment necessary

Exenatide Renal Usual doses may not be well tolerated in patients with moderate to severe renal impairment

Liraglutide In vivo No dose adjustment necessary

Adapted from Fonseca, Am J Med. 2011;124:(1 Suppl):S54-61.

CKD = chronic kidney disease; GFR = glomerular filtration rate.

40



Investigational therapies for Type 2 Diabetes: Reducing Hypoglycemia

SGLT-2 Inhibitors • Dapagliflozin (phase three) • Canaglifozin ( recently approved) • Empagliflozin (phase three)

Insulin • Degludec insulin (ultra-basal)

GLP-1 Analogue • Albiglutide • Semaglutide • Dulaglutide

Summary:

•  Type 2 Diabetes is a chronic progressive disease which results in microvascular complications over time

•  Early intensive management of hyperglycemia may have enduring benefit on the incidence of microvascular disease long term. (metabolic memory)

•  The kidney plays an important role in glucose metabolism in health and disease. Preservation of function and careful changes in therapy over time based on eGFR are essential in diabetes management

•  SGLT-2 inhibitors can be a useful adjunct therapy in management of diabetes, especially in patients with hypoglycemic risk or concomitant hypertension

42



Which of the following is incorrect about the kidney in diabetes? 1.  Serum creatinine and eGFR are equally predictive of renal

function in diabetes 2.  The kidney contributes 20-25% of all glucose output in the

fasting state and 40% of all gluconeogenesis 3.  Renal glucose production is increased in the diabetic

postprandial state contributing to hyperglycemia 4.  The risk of hypoglycemia is significantly increased in renal

impairment

Post-Test Question 1

43

Which of the following is incorrect regarding metabolic memory and the legacy effect? 1.  It is likely mediated by oxidative stress induced changes in the

mitochondria 2.  May be mediated by advanced glycosylated end products

(AGE’s) 3.  Both the EDIC and UKPDS trials demonstrated the presence of

an enduring legacy effect. 4.  Clinical trials have consistently shown that early aggressive

treatment of diabetes will reduce long term risk of complications 5.  VADT trial did not show significant benefit of intensive control on

complication risk


44



Which of the following is incorrect about SGLT-2 physiology in the kidney?

1.  10% of all glucose filtered by the kidney are reabsorbed by

these receptors 2.  SGLT-2 activity is upregulated in diabetes 3.  SGLT-2 inhibition causes natriuresis and a drop in systolic and

diastolic blood pressure 4.  SGLT-2 inhibition of glucose uptake by renal cells may reduce

progression of diabetic kidney disease


45

Which of the following does not occur with use of SGLT-2 Inhibitors?

1.  lowering of A-1c by 0.5-0.7% 2.  lowering of LDL-cholesterol 3.  lowering of blood pressure 4.  increased glucose excretion in urine 5.  decreased body weight


46



ON A SCALE OF 1 TO 5, PLEASE RATE HOW CONFIDENT YOU ARE IN RECOGNIZING THE ROLE OF SGLT2-INHIBITORS IN THE MANAGEMENT OF DIABETES

1.  Not at all confident 2.  Slightly confident 3.  Moderately confident 4.  Pretty much confident 5.  Very confident


47

WHICH OF THE STATEMENTS BELOW DESCRIBES YOUR APPROACH TO DIAGNOSING AND TREATING PATIENTS WITH DIABETES?

1.  I do not manage diabetes, nor do I plan to this year.

2.  I did not manage diabetes before this course, but as a result of attending this course I’m thinking of managing it now.

3.  I do manage patients with diabetes and this course helped me change my treatment methods.

4.  I do manage patients with diabetes and this course confirmed that I don’t need to change my treatment methods.


48

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