WHAT THE DPP-4? #$%&!!!! DIABETES TREATMENT IN 2017

BY DR NANCY BOZEK

OBJECTIVES

• REVIEW THE CANADIAN DIABETES ASSOCIATION (CDA) NOV 2016 UPDATE

• REVIEW THE PHARMACOLOGY OF THE NEWER ORAL AGENTS FOR DIABETES

• COMPARE THE DPP4 VS SGLT2 INHIBITORS

• GIVE YOU A CHART OF CHOICES FOR ORAL MEDICATIONS BASED ON RENAL FUNCTION

• LOOK AT THE RECENT STUDIES SHOWING IMPROVED CARDIAC OUTCOMES

CONFLICT OF INTEREST

• I HAVE NO PERSONAL OR FINANCIAL

INTERESTS TO DISCLOSE

• I HAVE USED THE CDA GUIDELINES AND THE

SLIDE DECKS FROM DR JEREMY GILBERT

WHO PRESENTED AT THE ASA IN DECEMBER

CASE OF MR RC AGE 60

CHARACTERISTICS

• OVERWEIGHT

• NO HX CAD/PANCREATITIS

• CHRONIC BACK PAIN

• RESP INFECTION, WAS VENTED NOW ON O2

• A FIB

• LITTLE EXERCISE , DIET?

• EGFR 57

MEDICATIONS

• PRIOR TO 2016 WAS ON METFORMIN AND

DIAMICRON

• DID NOT WANT TO TAKE INSULIN

• WAS ON JANUVIA (SITAGLIPTIN) WITH

SOME BENEFIT

• STARTED INVOKANA (CANAGLIFLOZIN)

Canagliflozin added

if symptomatic

hyperglycemia

with metabolic

decompensation

initiate insulin

+/- metformin

Lifestyle intervention is always the first priority

CDA guidelines

Add another agent best suited to the individual by prioritizing patient

characteristics:

Degree of hyperglycemia Risk of hypoglycemia Overweight or obesity CV disease or multiple risk factors Comorbidities (renal, CHF, hepatic) Preferences & access to treatment

Consider relative A1C lowering Rare hypoglycemia Weight loss or weight neutral Effect on cardiovascular outcome See therapeutic considerations; consider eGFR See cost column; consider access

PATIENT CHARACTERISTIC CHOICE OF AGENT

Antihyperglycemic agent with

demonstrated CV outcome benefit

(empagliflozin, liraglutide)

PRIORITY

Clinical cardiovascular disease

New in

2016

L

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S

T

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L

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WHAT IS THE INCRETIN EFFECT

Glucagon like peptide 1

(GLP1) has multiple

actions :

insulin secretion

Beta cell mass

satiety

Glucose production

Gastric emptying

Food intake

GLP 1 is broken down by

dipeptidyl peptidase IV (DPP4)

INCRETIN THERAPY MECHANISM OF ACTION

• DPP4 INHIBITORS PREVENT THE BREAKDOWN OF NATURAL GLP-1

• THIS INCREASES INSULIN SECRETION (GLUCOSE DEPENDENT)

• DECREASES GLUCOSE PRODUCTION

• INCREASES GASTRIC EMPTYING

• INCREASES SATIETY AND DECREASES FOOD INTAKE

RENAL FUNCTION AND DPP-4 INHIBITORS

• LINAGLIPTIN IS SAFE WITH EGFR DOWN TO 15

• THE REST MUST BE USED WITH CAUTION OR NOT USED OR HAVE DOSE REDUCTIONS

PROS FOR DPP4 INHIBITORS

• NO HYPOGLYCEMIA

• EFFECTIVE AT LOWERING A1C (AROUND 0.5-0.7% WHICH IS SIMILAR TO SULFONYLUREAS)

• AVAILABLE AT LOWER EGFRS

• WEIGHT NEUTRAL

• COME IN COMBINATIONS WITH METFORMIN

• CV SAFETY

CONS FOR DPP4 INHIBITORS

• HOSPITALIZATIONS FOR CHF WITH SAXA (ONGLYZA)

• NOT AS EFFECTIVE AT HIGHER A1C

• NOT WEIGHT LOSING

• PANCREATITIS, PANCREATIC CANCER

COMMON DPP4 INHIBITORS IN CANADA

DPP4 INHIBITORS Trade name Combination with Metformin

alogliptin Nesina Kazano

linagliptin Trajenta $81/month Jentadueto

saxagliptin Onglyza $75-92/month Komboglyze

sitagliptin Januvia $90/month Janumet/Janumet XR

Metformin 1000 mg bid costs $8/month

All are

covered on

ODB-even

Combo’s

PANCREATITIS AND DIABETES

• DIABETICS HAVE A 2.8 FOLD HIGHER RISK THAN THE GENERAL POPULATION OF DEVELOPING

PANCREATITIS (4.2 VS 1.5 CASES PER 1,000 PATIENT YEARS)

• DPP4 AND GLP1 RECEPTOR AGONISTS HAVE BEEN ASSOCIATED WITH PANCREATITIS

• A CAUSAL RELATIONSHIP HAS NOT BEEN ESTABLISHED

• DO NOT USE IN PATIENTS WITH A HISTORY OF PANCREATITIS (EXCEPTION IS GALLSTONE

PANCREATITIS AFTER TREATMENT)

SAXAGLIPTIN AND CARDIOVASCULAR OUTCOMES IN PATIENTS WITH TYPE 2 DIABETES MELLITUS (SAVOR)

PRIMARY END POINT=CV DEATH, NONFATAL MI OR NONFATAL STROKE

Primary end point

occurred in 7.3% of

the sax group vs 7.2%

of placebo

SECONDARY END POINTS=PRIMARY END POINTS + HOSPITALIZATION FOR HF, CORONARY

REVASCULARIZATION OR UNSTABLE ANGINA

More patients in the

saxagliptin group than in

the placebo group were

hospitalized for heart

failure (3.5% vs 2.8%)

No difference was seen in

rates of pancreatitis

TECOS = SITAGLIPTIN AND CV OUTCOMES

14,671 patients

Follow up 3 yrs

hgbA1c was 0.29%

lower with sita

Noninferior to

placebo for

primary outcome

No signif diff in

rates of

hospitalization for

heart failure

EXAMINE = ALOGLIPTIN CV STUDY

n = 5380 patients

Follow up 18 mo

Dropped hgbA1c

.036%

No difference in

primary end points

A MULTICENTER OBSERVATIONAL STUDY OF INCRETIN-BASED DRUGS AND HEART FAILURE

• ORIGINAL ARTICLE

• A MULTICENTER OBSERVATIONAL STUDY OF INCRETIN-BASED DRUGS AND HEART FAILURE

• KRISTIAN B. FILION, PH.D., LAURENT AZOULAY, PH.D., ROBERT W. PLATT, PH.D., MATTHEW DAHL,

B.SC., COLIN R. DORMUTH, SC.D., KRISTIN K. CLEMENS, M.D., NIANPING HU, M.D., PH.D., J.

MICHAEL PATERSON, M.SC., LAURA TARGOWNIK, M.D., M.S.H.S., TANVIR C. TURIN, M.D., PH.D.,

JACOB A. UDELL, M.D., M.P.H., AND PIERRE ERNST, M.D., FOR THE CNODES INVESTIGATORS*

• N ENGL J MED 2016; 374:1145-1154MARCH 24, 2016DOI: 10.1056/NEJMOA1506115

HOW DO SGLT2 INHIBITORS WORK ON THE KIDNEY

• SGLT = SODIUM GLUCOSE CO-TRANSPORTER

GLUCOSE EXCRETION IS 70-120 G/DAY

WITH SGLT2 INHIBITION

TYPE 2 DIABETICS

• IF GLUCOSE IS >13.8 THEY SPILL GLUCOSE

IN THE URINE

TYPE 2 DM ON SGLT2 INHIBITOR

• IF GLUCOSE IS >5 THEY SPILL GLUCOSE IN

THE URINE

PROS FOR SGLT2 INHIBITORS

• MECHANISM INDEPENDENT OF PANCREAS SO NO HYPOGLYCEMIA

• EFFECTIVE AT HIGHER A1C

• WEIGHT LOSS (2-3 KG)

• REDUCES SBP

• CV BENEFIT WITH 1 AGENT (EMPAGLIFLOZEN)

CONS OF SGLT2 INHIBITORS

• LIMITED AVAILABILITY AT LOWER GFR

• CAN’T USE ANY OF THEM WITH EGFR <45

• INCREASED UTI AND YEAST INFECTIONS

• VOLUME DEPLETION

• LOWER THRESHOLD TO GET DKA

CONSIDERATIONS FOR DOSING SGLT2

• USE LOWER DOSES IF THEY GET UTI’S

• USE HIGHER DOSES FOR HEALTHY PEOPLE NOT ON LASIX

SGLT2 INHIBITOR ASSOCIATED DIABETIC KETOACIDOSIS

• MAY OCCUR IN <0.1% OF SGLT2 INHIBITOR TREATED PATIENTS WITH TYPE 2

• MOST DKA OCCURS IN INSULIN DEFICIENT DIABETES (LONGSTANDING T2D, T1D)

• SOME CASES OF EUGLYCEMIC DKA (GLUCOSE <14

• MOST CASES ASSOCIATED WITH A PRECIPITANT LIKE SURGERY, EXTENSIVE EXERCISE, MI,

SEVERE INFECTION, STROKE, LOW CARB DIETS, ALCOHOL

Add another agent best suited to the individual by prioritizing patient

characteristics:

Degree of hyperglycemia Risk of hypoglycemia Overweight or obesity CV disease or multiple risk factors Comorbidities (renal, CHF, hepatic) Preferences & access to treatment

Consider relative A1C lowering Rare hypoglycemia Weight loss or weight neutral Effect on cardiovascular outcome See therapeutic considerations; consider eGFR See cost column; consider access

PATIENT CHARACTERISTIC CHOICE OF AGENT

Antihyperglycemic agent with

demonstrated CV outcome benefit

(empagliflozin, liraglutide)

PRIORITY

Clinical cardiovascular disease

Empagliflozin =SGLT2

Liraglutide =GLP!

Receptor agonist

EMPA REG TRIAL DESIGN

• 7020 PATIENTS -4687 IN EMPAGLIFLOZIN GROUP AND 2333 IN PLACEBO GROUP

• PRIMARY COMPOSITE OUTCOME WAS DEATH FROM CV CAUSES, NONFATAL MI OR NONFATAL

STROKE

• ADULTS OVER 18 WITH A BMI OF 45 OR LESS AND EGFR OF AT LEAST 30

• ALL HAD CARDIOVASCULAR DISEASE AND HAD NOT RECEIVED GLUCOSE LOWERING AGENTS

FOR 12 WEEKS AND HAD AHGBA1C OF 7-9% OR HAD BEEN ON GLUCOSE LOWERING

AGENTS AND HAD A HGBA1C OF 7-10%

• THEY RECEIVED EITHER 10 MG OR 25 MG OF EMPAGLIFLOZIN OR PLACEBO

HGBA1c

decreased

by .54-.6%

CARDIOVASCULAR OUTCOMES IN EMPA REG

• PRIMARY OUTCOME OCCURRED IN 490/4687 (10.5%) IN EMPAGLIFLOZIN GROUP

• PRIMARY OUTCOME OCCURRED IN 282/2333 (12.1%) IN THE PLACEBO GROUP

• EMPAGLIFLOZIN RESULTED IN LOWER RISK OF DEATH FROM CV CAUSES, DEATH FROM ANY

CAUSE AND HOSPITALIZATION FOR HEART FAILURE

RENAL BENEFITS IN EMPAREG OUTCOME TRIAL

• FEWER MICROVASCULAR COMPLICATIONS

• LESS MACROALBUMINURIA

• LOWER CREATNINE

• LESS DIALYSIS

• RELATIVE RISK REDUCTION FROM 38-55%

EMPA REG outcome is a relevant success also with respect to

trials comparing conventional vs intensive strategies of

glucose control on CV endpoints

Since the UKPDS study has been published [12], the international

community is still debating whether or not optimizing glucose

control could reduce CV risk. To address this question, three main

large randomized clinical trials were completed, aimed at

verifying whether or not an improved metabolic control

(irrespective of how this was obtained) could be associated with

a better CV outcome: ACCORD [13], ADVANCE [14] and VADT

[15]. It is well known that these studies have generated negative

results and frustration, even if they resulted to be very useful in

inducing a change in the vision of how we have to treat our

patients, emphasizing the need for a “tailored therapy” able to

address the individual needs of each single patient, especially

with respect to the targets to pursue.

IS THIS A CLASS EFFECT?

• DECLARE IS A TRIAL WITH DAPIGLIFLOXIN

• CANVAS IS A TRIAL WITH CANAGLIFLOZIN

• THESE FUTURE TRIALS IN THE NEXT FEW YEARS WILL ANSWER THAT QUESTION

SGLT2 INHIBITORS IN CANADA

dapigliflozin Forxiga $83 / month

canagliflozin Invokana $83/ month

empagliflozin Jardiance $83/ month

All are covered

by ODB

GLP1 RECEPTOR AGONISTS INCREASE GLP1 LEVELS

GLP1 has multiple

actions

insulin sectetion

Beta cell mass

satiety

Glucose production

Gastric emptying

Food intake

GLP 1 is broken down by DPP4

LEADER TRIAL DESIGN

• DOUBLE BLIND PLACEBO CONTROLLED TRIAL – LIRAGLUTIDE OR PLACEBO- MEDIAN 3.5 YRS

• HGBA1C LEVEL >7.0%

• AGE >50, WITH AT LEAST ONE CV COEXISTING CONDITION (CORONARY HEART DISEASE,

CEREBROVASCULAR DISEASE, PVD, CHRONIC KIDNEY DISEASE OR CHF)

• AGE >60 WITH AT LEAST ONE CARDIOVASCULAR RISK FACTOR (MICROALBUMINURIA OR

PROTEINURIA, HYPERTENSION, LV HYPERTROPHY)

• OUTCOMES: DEATH FROM CV CAUSES, NON FATAL MI OR NONFATAL STROKE

• 9340 PATIENTS WERE RANDOMIZED

NNT =66 to prevent 1 event in

3 yrs

A number of

patients stopped

the med due to

side effects –

mainly GI

SADMANS (SICK DAY MEDICATION LIST)