Diabetes is emerging as the dominant healthcare epidemic

Source: Diabetes Atlas 3rd Edition. www.eatlas.idf.org. Last accessed 25 January 2007

The Tale of Two Epidemics• SA prevalence Diabetes

= 5.5% • Direct cause of death =

4.3%• Contributory to 14% IHD,

12% hypertensive, 12% renal + 10% stroke deaths

• Glycemic Control: 37% of patients have HbA levels < 7.0%

• Metabolic Control: 20% achieve HbA + BP + Lipid targets

AIDS RELATED DEATHS 1990 - 2009

(UNAIDS 2010) (SAMJ 2007)

HIV vs DM in SA

• Absolute No (m)• Mortality Rank• Mortality Growth Rate• ARV vs OHA/Ins (%)• VL vs HbA control (%)• Medication vintage• Advocacy 1• Advocacy 2

• 6 vs 4 • 1 vs 6 • 1 vs 3 • 37 vs 66 • 90 vs 30• 2010 vs 1947• TAC vs SA Diabetes• Guidelines HIV vs DM

Cost of DM Care

• US 2006: $1 in $7 / $ 200 billion • OPD: 15% / consultations / laboratory /

medications• In-Patients: 85% / complications /

investigations / procedures / medications

Poor Glucose Control in SA

• Many patients• Many undiagnosed• Few health personnel• Poorly skilled personnel • Poorly resourced clinics

• Reduced patient contact time (40 min per year)

• Poor uptake / application of lab testing (30 % have regular tests)

• Delay in treatment change / up-titration

• Sub-optimal medication

Diabetes

“Re-thinking the Failure”

Defining Mental Retardation

“ achieve no result, persist in doing the same and expect and different outcome”

(Albert Einstein)

UKPDS 35: Higher HbA1c is associated with increased micro- and macrovascular

complications in T2DM• Each 1% rise in mean HbA1c was

associated with

– 21% risk increase for any diabetes endpoint (p<0.0001)

– 21% risk increase for diabetes-related mortality (p<0.0001)

– 14% risk increase for myocardial infarction (MI) (p<0.0001)

– 37% risk increase for microvascular complications (p<0.0001)

Stratton IM, et al. BMJ 2000;321:405–12

Any diabetes endpoint

Diabetes-related morbidity

MI

<6% 67% 78% 89% 910% ≥10%

140

120

100

80

60

40

20

0

Mean HbA1c concentration (%)

Adju

sted

eve

nt ra

te /

1,0

00 p

erso

n ye

ars

Microvascularcomplications

Diagnosis – Fasting Glucose

• Insulin Resistance

• Pre-Diabetes

• Diabetes

• > 5.6 mmol/l

• > 6.0 mmol/l

• > 7.0 mmol/l

T2 DM and Primary Prevention

Parameter

• Weight Loss

• Exercise

Success Rate

• < 5 %

• < 5 %

ADA CONCENSUS 2007

TREAT PRE-DIABETES (IFG / IGT)

LIFESTYLE LIFESTYLE + METFORMIN

Age < 60 y

Risk Factors (BP, Lipids, BMI)

HbAic > 6 %

Type 2 Diabetes and Primary Prevention

Cost Analysis DPP 10 y FU:

Lifestyle vs Metformin:: +$1500 vs -$30 [ADA 71st 2011]

Years

HbA

1c (%

)

0

9.0

0

8.5

8.0

6.5

6.0

1 2 43

7.5

7.0

5 6

Standard therapyIntensive therapy

8.1%

7.5%

6.4%

Effects of intensive glucose lowering in T2DM

ACCORDACCORD

Gerstein et al. N Engl J Med 2008;358:2545–59

Years Years

Pati

ents

wit

h e

vents

(%

)

0 1 2 43 5 60

25

20

15

10

5

First occurrence of non-fatal MI, non-fatal stroke or CV death

HR (CI) 0.90 (0.78, 1.04)p=0.16

HR (CI) 1.22 (1.01, 1.46)p=0.04

0

25

20

15

10

5

0 1 2 43 5 6

Death from any cause

Effects of intensive glucose lowering in T2DM

ACCORDACCORD

Gerstein et al. N Engl J Med 2008;358:2545–59

Standard therapyIntensive therapy

Side-effects of intensive glucose lowering

Hypoglycaemia*

N (%)

Drug interaction

Weight gain >10kg

N (%)

Standard therapy

Intensive therapy

p-valueHypothesis:

*hypoglycaemia defined as requiring any assistance

261 (5.1) <0.001

713 (14.1) <0.001

70% of non-insulin-treated and 60% of insulin-treated patients were taking three or more

oral antidiabetic drugs at study end

830 (16.2)

1399 (27.8)

ACCORDACCORD

Gerstein et al. N Engl J Med 2008;358:2545–59

Potential mechanisms of hypoglycaemia-induced mortality

Cardiac arrhythmias due to abnormal cardiac repolarisation in high-risk patients (IHD, cardiac autonomic neuropathy)

Increased thrombotic tendency/decreased thrombolysis

Cardiovascular changes induced by catecholamines• Increased heart rate• Silent myocardial ischaemia• Angina and myocardial infarction

GLP 1 Mimetics The Virtuous Therapeutic Cycle

GLUCOSE CONTROL

WEIGHT LOSS NO HYPOGLYCEMIA

HbA = 7 %

Diabetes Therapy - Safety

• Hypoglycemia

• Weight gain

• CVS mortality • Cancer

Strategic Rx

AE / PE Wt Gain Hypo’s Wt Loss BPLipidsetc

Met (3) no no yes=no yes=no

SU (0) yes yes no no

Pio (2) yes no no yes

DPP (3) no no yes>no yes>no

GLP1 (4) no no yes yes

ADVERSE POSITIVE

OHA and CV Protection

• Metformin (UKPDS)

• Rosi / TZD (RECORD)

• Tolbu / SU (UGDP)

• MI reduction 39% (vs insulin / chlor / gliben

• MI increased (OR 1.43)

• CV mortality increased by 30%

SU vs Met (Schramm T et al, Eur Heart J, April 2011)

SU Increase All-Cause Mortality

Increase MI, All CVD, Stroke

Glimiperide 32 % 21 %

Glibenclamide 19 % 12 %

Glipizide 27 % 17 %

Tolbutamide 28 % 27 %

[Conclusion: Metformin = protective? vs some SU bad?]

DM and Cancer

• Medications for DM can affect cancer risk and outcome - ? Insulin ? Pioglitazone

• Metformin reduces cancer risk• Sulfonylurea: probably no effect• GLP-1 agonists: currently unknown but

seemingly safe

GLP-1 and DPP-41

CL=clearance rate; DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; IV=intravenously.1. Vilsbøll T et al. J Clin Endocrinol Metab. 2003;88(1):220–224

Plasma t½ = 1–2 min (IV)

CL = 5–10 L/min

His Ala Glu Gly Thr Phe Thr Ser Asp

Val

Ser

SerTyrLeuGluGlyGlnAlaAlaLys

Glu

Phe

Ile Ala Trp Leu Val Lys Gly Ala NH2

36

7 9

DPP-4

Incretin Therapy

DPP 4

• Sitagliptin ^• Vildagliptin*• Alogliptin • Saxagliptin

GLP1

• Exenatide*• Liraglutide ^• Exenatide LAR• Albuglutide• Taspoglutide

[*Available / ^ Imminent in SA]

Incretin - GLP 1 Therapy

• Stimulates insulin secretion

• Insulin secretion is glucose dependent

• Inhibits glucagon secretion

• Increases beta cell mass

• Delays gastric emptying• Inhibits appetite

• Secretogogue

• No hypoglycemia

• Reduces meal-related glucose peaks

• Maintains beta cell reserve

• Reduces meal-related peaks; reduces weight

• Reduces weight

Liraglutide in combination with metformin presents a low risk of hypoglycaemia

• Minor hypoglycaemic events are at the placebo level (LEAD 2, above)

• There is a small but increased risk of minor hypoglycaemia when combined with SUs (1.0 events per subject every second year; LEAD 1)

Min

or h

ypos

/pat

ient

/yea

r

Liraglutide1.2 mg

Placebo Glimepiride0

0.2

0.4

0.6

0.8

1

1.2

1.4

Liraglutide1.8 mg

Nauck et al, Diabetes Care, published online 10.23 37/dc08-1355 (LEAD 2) and Marre et al. Diabetes 2008;57(Suppl. 1):A4 (LEAD 1).

A quarter of patients lose an average of 7.7 kg with liraglutide

Weig

ht

chan

ge (

kg)

0–Q1: mean weight change for the 25% of subjects who had the largest weight loss Q1–Q2: mean weight change for the 25–50% weight loss quartile Q2–Q3: mean weight change for the 50–75% weight loss quartile Q3–Q4: mean weight change for the 75–100% weight loss quartile, that is, the 25% who had the smallest weight loss

Liraglutide 1.8 mg + met

Q3-Q4

Nauck et al, Diabetes Care, published online 10.23 37/dc08-1355 (LEAD 2).

Sustained weight reduction over

52 weeks with liraglutide

Liraglutide 1.8 mg/day

Liraglutide 1.2 mg/day

Glimepiride 8 mg/day

• Waist circumference was reduced from baseline by 3.0 cm with liraglutide 1.8 mg

• Waist circumference increased by 0.4 cm with glimepiride (p<0.0001)*** ***

***p<0.0001 for change from baseline

52

Garber et al, The Lancet, early online publication, 25 Sept 2008 (LEAD 3).

Liraglutide reduces visceral body fat

Change in body fatDEXA scan

-4

-3

-2

-1

0

1

2

3

Chang

e in b

ody f

at,

kg (

%)

• Two thirds of weight lost was fat tissue (liraglutide 1.8 mg)

Liraglutide 1.2 mg + met Glimepiride + met

-1.6*(-1.1%*) -2.4*

(-1.2%*)

+1.1 kg(+0.4%)

Liraglutide 1.8 mg + met

Visceral vs. subcutaneous fatCT scan

-25

-20

-15

5

0

5

10

-10

Visceral Subcutaneous

Chang

e in p

erc

enta

ge f

at

(%)

-17.1 -16.4

-4.8 -7.8* -8.5*

+3.4

Data are mean±SEM; *p<0.05 vs. glim+met; n=160.LEAD 2 substudy, originally presented as Jendle et al. Diabetes 2008;57(Suppl. 1):A32.

Liraglutide improves beta-cell function as measured by HOMA-B and

proinsulin:insulin ratio56.4% 70.6% 56.3%45.5%Baseline

p=0.0313

p=0.0033

HO

MA

(%

)

0.48 0.45 0.420.45

Chang

e in p

roin

sulin

:insu

lin

Liraglutide1.8 mg

Liraglutide1.2 mg

Rosi-glitazone

PlaceboLiraglutide1.8 mg

Liraglutide1.2 mg

Rosi-glitazone

Placebo

Marre et al. Diabetes 2008;57(Suppl. 1):A4 (LEAD 1). Data are mean±2SE.

Diabetes Care – Future?

1) Pre-Diabetes

2) CVD Protection

3) Cancer

4) Hypoglycemia

5) Weight

6) Disease Modifying

• Metformin• Metformin, TZD, GLP1 • Metformin• Metformin, TZD, GLP1 • Metformin, GLP1• GLP1