Typ 2 Diabetes

Marc Donath USB

N Engl J Med 2012 Oct 18;367(16):1562-4

Recent CV outcome studies in Diabetes

•  N Engl J Med. 2015 373:2117-28 (Empa-Reg outcome study)

•  N Engl J Med. 2016 June 13 (LEADER trial)

Urinary glucose excretion via SGLT2 inhibition

SGLT2SGLT2 inhibitor

SGLT1

SGLT2 inhibitors reduce glucose re-absorption

in the proximal tubule, leading to urinary glucose excretion and

osmotic diuresis

Filtered glucose load > 180 g/day

SGLT2 Inhibitors

•  HbA1c↓ •  Body weight ↓( 80-100 gr. glucose = ~ 300-400 cal/day) •  Blood pressure ↓ •  No hypoglyceamia •  All combination possible (incretin limits)

BUT: •  Genital infections •  Ketoacidosis •  New drug (Glucagon secretion ↑, Osteoporosis ?)

SGLT2 Inhibitors

1.  Canagliflozin (Invokana) 2.  Dapagliflozin (Forxiga) 3.  Empagliflozin (Jardiance)

GLP-1 analoga

Twice-daily •  Exenatide (Byetta) Daily •  Liraglutide (Victoza) and

Liraglutide & Degludec (Xultophy) Once�weekly •  Exenatide Once Weekly Sustained-release

(Bydureon) •  Dulaglutide (Trulicity)

EMPA-REG®

•  Randomised, double-blind, placebo-controlled CV outcomes trial

•  Objective

To examine the long-term effects of empagliflozin (Empa-reg) or Liraglutide (Leader) versus placebo, in addition to standard of care, on CV morbidity and mortality in patients with type 2 diabetes and high risk of CV events

CV, Cardiovascular

Primary outcome: 3-point MACE CV death, non-fatal MI, or non-fatal stroke

EMPA-REG®

CV death

EMPA-REG®

Hospitalisation for heart failure

EMPA-REG®

Number needed to treat (NNT) to prevent one death

1. 4S investigator. Lancet 1994; 344: 1383-89 2. HOPE investigator N Engl J Med 2000;342:145-53

Simvastatin1

for 5.4 years

High CV risk 5% diabetes, 26% hypertension

1994 2000 2015

Pre-statin era

High CV risk 38% diabetes, 46% hypertension

Ramipril2

for 5 years

Pre-ACEi/ARB era

<29% statin

Empagliflozin for 3 years

T2DM with high CV risk 92% hypertension

>80% ACEi/ARB

>75% statin

EMPA-REG®

Number needed to treat to prevent one…

CV: cardiovascular; MACE: major adverse cardiovascular event.

C.J. Nolan N.B. Ruderman2, S. E. Kahn, O. Pedersen, M. Prentki. Diabetes 2015;64:673-686

IL-1β

Metformin

Sport SGLT2i Bariatric surgery

Insulin sulfonylureas

UCP-1

Anti-IL-1β

GLP-1

Treatment of Typ 2 Diabetes

Pioglitazone

KEY POINTS •  Targets and therapies must be individualized. •  Life-style intervention foundation of treatment. •  Metformin first-line drug. •  (After metformin limited data to guide us.) .

Guidelines

Diabetes Care. 2012 Jun;35(6):1364-79

Therapie targets

•  Microvascular: HbA1c

•  Macrovasular: Multifactorial: –  Nutrient

à Life Style (+/- GLP1a), SGLT2i, Bariatric surgery –  Lipid

à Statin, PCSK9i –  Blood pressure –  Inflammation ?

à Metormin, Statin, Pioglitazone, (anti-IL-1)

Glycemic targets

•  HbA1c < 7.0% Individualization is key: •  Tighter targets (6.0 - 6.5%) - younger, healthier •  Looser targets (7.5 - 8.0%) - older, comorbidities, hypoglycemia prone, etc. •  Avoidance of hypoglycemia

Healthy eating, weight control, increased physical activity & diabetes education

Metformin high low risk neutral/loss GI / lactic acidosis low

If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote any specific preference � choice dependent on a variety of patient- & disease-specific factors):

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

high low risk gain edema, HF, fxs low

Thiazolidine- dione

intermediate low risk neutral rare

high

DPP-4 inhibitor

highest high risk gain hypoglycemia variable

Insulin (basal)

Metformin +

Metformin +

Metformin +

Metformin +

Metformin +

Basal Insulin +

Sulfonylurea +

TZD

DPP-4-i

GLP-1-RA

Insulin§

or

or

or

or

Thiazolidine-dione +

SU

DPP-4-i

GLP-1-RA

Insulin§

TZD

DPP-4-i

or

or

or

GLP-1-RA

high low risk loss GI high

GLP-1 receptor agonist

Sulfonylurea

high moderate risk gain hypoglycemia low

SGLT2 inhibitor intermediate low risk loss GU, dehydration high

SU

TZD

Insulin§

GLP-1 receptor agonist +

SGLT-2 Inhibitor +

SU

TZD

Insulin§

Metformin +

Metformin +

or

or

or

or

SGLT2-i

or

or

or

SGLT2-i

Mono- therapy

Efficacy* Hypo risk Weight Side effects Costs

Dual therapy†!

Efficacy* Hypo risk Weight Side effects Costs

Triple therapy

or

or

DPP-4 Inhibitor +

SU

TZD

Insulin§

SGLT2-i

or

or

or

SGLT2-i

or

DPP-4-i

If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any specific preference � choice dependent on a variety of patient- & disease-specific factors):

If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGLT2-i:

Metformin +

Combination injectable therapy‡!

GLP-1-RA Mealtime Insulin

Insulin (basal) +

ADA & EASD 2016 Richtlinen

Silvio E. Inzucchi et al. Dia Care 2015;38:140-149

Therapeutic schema

1.  Lifestyle 2.  Metformin 3.  Individualization :

A.  Early case: Gliptin or GLP-1analog (BMI>28) B.  Established cardiovascular disease: SGLT2i or GLP-1analog C.  Uncontrolled diabetes or GFR < 30 : Basal insulin (& GLP-1analog)

1. Lifestyle