New treatments for type 2 diabetes: current status of development

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New treatments for type 2 diabetes:

current status of development

Bruce H.R. Wolffenbuttel, internist‐endocrinologist University Medical Center Groningen Dept. of Endocrinology: www.umcg.net

Blog: www.gmed.nl Twitter: @bhrw

Disclosure statement

Relevant relationships (last 5 years)

(Company) names

• Bv. Sponsorship or research support

• Bv. Honorarium or other (financial) compensation.

• Eur. Committee: KP7 EU grant (Meerdere)

• DiabetesFonds NL

• Juvenile Diabetes Research Foundation

• NWO

• Min VWS, AZ, Econ Affairs

• Provinces Groningen, Friesland, Drenthe

• Nierstichting (Kidney Foundation)

• Zon MW

• MENZIS

• EASD / EFSD

• AstraZeneca

• Becton Dickinson

• Eli Lilly

• Thermo‐Fisher

• Novo Nordisk

• Roche

• Sanofi Aventis

• Boehringer Ingelheim

• Bayer

The complete presentation can be downloaded from

http://www.gmed.nl/lezingen

(2)

Treatment of type 2 diabetes:

a stairway to heaven ?

Lifestyle

Metformin

Triple medication R/

Complex insulin Simple insulin Dual medication R/

Several drug choices:

Sulphonylurea Thiazolidinediones DPP‐4 inhibitors GLP1 receptor agonists SGLT2 inhibitors

Do not forget, T2DM integrative approach includes:

BP lowering Cholesterol lowering Weight reduction Secondary prevention

NHG standaard

Individualize!! Current treatment algorithms are of limited help

in caring for INDIVIDUALS with T2DM

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1. Hypoglycaemia 2. Weight gain

3. Interference with normal life 4.

5. 6. Injections 7.

..

21. Brussels sprouts

What patients don't like

1

(4)

1. Current therapy is not perfect

What if the UKPDS had stopped after 3‐4 years …

0.6

0.4

0.2

0.0

3 6 9 12 15

Proportion of patients with events

Conventional (411) Intensive (951) Metformin (342)

0

Years from randomisation

Mv I P=0.0034

Remember:

These data apply ONLY to recently diagnosed diabetes w. obesity!

Mv C P=0.0023

(5)

Metformin in type 2 diabetes

Editor of Plos ONE

(6)

Measurement of carotid intima‐media thickness (IMT)

IMT='surrogate endpoint':

* Is vascular disease

* Predicts c.v. events

The CIMT‐study: insulin+metformin vs.

insulin+placebo

(7)

Meta‐analysis of hypoglycaemia with sulphonylurea

Schopman et al, DMRR2014

Meta‐analysis of cardiovascular side‐effects of

sulphonylurea

(8)

sneller dood langer leven

Meta‐analysis of cardiovascular side‐effects of sulphonylurea

In many studies no separate analysis of which

SU was used (for instance gliclazide vs. others) !

(9)

Metformin is a cheap BG‐lowering without promoting weight gain, but also without (significant) effect on CVD

If you want to prescribe an SU, probably gliclazide is associated with lowest incidence of hypoglycaemia

SU lower BG, but stimulate appetite, increase body weight, may provoke nasty hypoglycaemia, and higher CVD incidence (RR 1.26)

Boussageon et al, PlosONE 2012; Phung et al, Diab Med 2014; Schopman et al, DMRR2014

Metformin and SU in T2DMSummary:

Insulin treatment in type 2 diabetes is associated with:

• Better glycaemic control

• Small improvements in dyslipidaemia

• Increase in body weight

• Hypoglycaemia but also:

• Heart rhythm disturbances ¹  related to hypoglycaemia

• Increase in BP ^2,3  sodium retention

• Inflammation of the vascular wall ^4,5  obesity & insulin resistance

• Mitogenic effects ^6,7  insulin growth‐factor

• Inflammation of adipose tissue ⁸  influx macrophages

Insulin: the best there is ??

1. Chow E, et al. Diabetes 2014; 63: 1738‐47; 2. Kanoun F, et al. Diabetes Metab. 2001; 27:695‐700 3. Sarafidis PA, Am J Nephrol 2007; 27: 44‐54; 4. Andersson CX, et al. Diabetes Metab Res Rev 2008; 24: 595‐603 5. Barrett EJ, Liu Z. Rev Endocr Metab Disord 2013; 14: 21‐7; 6. Lundby A, et al. J Appl Toxicol. 2014. doi: 10.1002/jat.3082 7. Rostoker R, et al. Endocr Relat Cancer 2015; 22: 145‐57; 8. Jansen HJ, et al, Diabetologia 2013; 56: 2573‐81

(10)

Higher insulin dose is associated with more atherosclerosis

Muis MJ et al. Atherosclerosis 2005; 181: 185‐192

Insulin use and dose is associated with increased risk of CVD and mortality

Currie CJ, et al. J Clin Endocrinol Metab 2013;98:668‐677 120

80

60

40

20

0

Insulin + metformin

Event rate (per 1,000 person‐years)

Low dose Mid dose High dose

Insulin only and insulin+metformin

Insulin only 18.0 19.320.1

34.6 42.7

54.0 56.6

63.4 78.4

Insulin only 43.0 44.3

54.9 60.9

71.6 81.4 80.6

95.3

All‐cause mortality Combined endpoint

39.6

“In T2DM, exogenous insulin may be associated with increased risk of diabetes‐related complications”

100

(11)

Insulin use and dose is associated with increased risk of CVD and mortality

Currie CJ, et al. J Clin Endocrinol Metab 2013;98:668‐677 120

80

60

40

20

0

Event rate (per 1,000 person‐years)

Low dose Mid dose High dose

Insulin only 18.0 19.320.1

34.6 42.7

54.0 56.6

63.4 78.4

Insulin only 43.0 44.3

54.9 60.9

71.6 81.4 80.6

95.3

All‐cause mortality Combined endpoint

39.6

“In T2DM, exogenous insulin may be associated with increased risk of diabetes‐related complications”

100

Pro and contra of insulin therapy in T2DM

• PRO

• Best reduction of HbA1c

• Individual adaptation of insulin dosage

• Long‐term experience for decades

• Long‐term UKPDS data suggest benefits and slightly better prognosis after 20 years

• CONTRA

• Most patients already obese before start insulin therapy

• Inadvertent weight increases of 5‐

15 kg are common, not exception

• High risk for hypoglycaemia, which is associated with more c.v. events

• No data showing superiority in preventing CVD vs other therapies

• Uncertainty between potential relation between insulin therapy and cancer risk

www.diabetesincontrol.com

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Food for thought

ALS INSULINE ZO VEILIG IS WAAROM MOGEN PILOTEN

DIE INSULINE SPUITEN NIET VLIEGEN ?

2

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2. New drugs for type 2 diabetes

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GLP1‐RA/DPP4i SGLT2i GLP1‐RA/DPP4i

Long‐acting insulins

Biological activities of GLP‐1

Baggio & Drucker. Gastroenterol 2007;132; 2131‐57

↓ glucose production

↑ insulin release

↓ glucagon release

↑ insulin synthesis

↑ β-cell proliferation

↓ β-cell apoptosis

↓ stomach emptying

↑ glucose uptake and storage

↑ heartprotection

↑ heartfunction

↓ bloodpressure

↓ appetite

Food preferences (in animals)

↑ insulin sensitivity

}

GLP-1 made by L-cells in jejunum & ileum

animals

(15)

Metabolism of GLP‐1

Intestinal GLP‐1 release

GLP‐1 inactive Meal

Active GLP‐1

DPP‐4

Adapted from Rothenberg P, et al. Diabetes. 2000;49(suppl 1):A39.

Metabolism of GLP‐1

Intestinal GLP‐1 release

GLP‐1 inactive Meal

Active GLP‐1

DPP‐4 inhibitor

DPP‐4

Adapted from Rothenberg P, et al. Diabetes. 2000;49(suppl 1):A39.

GLP‐1 agonist

Sitagliptine, vildagliptine, saxagliptine, linagliptine (tablets)

Exenatide, liraglutide,

lixisenatide, dulaglutide

(injections)

(16)

Glipizide + metformin Sitagliptin + metformin

P<0.001

32%

5%

0 10 20 30 40 50

Week 52

Incidence (%)

A typical comparison of DPP4i (sitagliptin) vs. SU

Nauck M, et al. Diabetes, Obesity and Metabolism 2007;9:194–205

hypoglycaemia

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DPP‐4 inhibitors & cardiovascular risk: interim analysis

Monami M, et al. Diab Obes Metabol 2012 (online)

Saxagliptin: cv outcome

16.492 DM2, 2^oprev/high risk, saxagliptin vs placebo, FU 2,1 y

Primary End Point = cardiovascular death, myocardial infarction, or ischemic stroke

SAVOR‐TMI 53 study. Scirica B, et al. New Engl J Med 2013

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Saxagliptin: cv outcome

SAVOR‐TMI 53 study. Scirica B, et al. New Engl J Med 2013

Alogliptin: cv outcome study (EXAMINE)

5380 DM2, 2^oprev recent AMI/unstable angina, linagliptin vs placebo, FU 1,5 y Primary End Point = cardiovascular death, myocardial infarction, or ischemic stroke

EXAMINE study. White B, et al. New Engl J Med 2013

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Primary composite cardiovascular outcome*

ITT analysis for superiority

* CV death, nonfatal MI, nonfatal stroke, hospitalization for unstable angina

Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

Patients Events

Sitagliptin (n=7332)

Placebo (n=7339)

Sitagliptin Placebo

Acute pancreatitis 23 (0.3%) 12 (0.2%) 25 17

Severe 4 0 4 0

Mild 19 11 21 16

Unknown severity 0 1 0 1

Confirmed acute pancreatitis & pancreatic cancer ITT HR 1.93 (0.96, 3.88), p=0.065

Sitagliptin n=7332

Placebo n=7339

Pancreatic cancer ^9 (0.1%) ^14 (0.2%)

ITT HR 0.66 (0.28, 1.51), p=0.32

(20)

Confirmed charter defined malignancy*

Event

Sitagliptin n=7332

Placebo n=7339

Total number of malignancies 278 308

Number of patients with malignancy 268 (3.7%) 290 (4.0%) 5 most common types of malignancy

Prostate Lung (bronchus)

Colon (large intestine, cecum, appendix) Bladder

Melanoma

41 (0.6%) 43 (0.6%) 21 (0.3%) 28 (0.4%) 15 (0.2%)

49 (0.7%) 35 (0.5%) 34 (0.5%) 25 (0.3%) 11 (0.1%)

Pancreatic cancer 9 (0.1%) 14 (0.2%)

*Newly diagnosed malignancy or 1st recurrence of previously diagnosed malignancy during the study period

ITT HR 0.91 (0.77, 1.08), p=0.27

Demagogia ‐ no increased HF with alo & sita

EXAMINE, alogliptin, pat's w. history of HF TECOS, sitagliptin, all pat's SAVOR‐TIMI: Saxagliptin, n=8280, placebo, n=8212

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• Patiënt op metformine die:

• geen hypoglycemie mag hebben (bv. piloot, taxichauffeur)

• niet wil aankomen in gewicht

• Nadeel: kosten

Wanneer DPP4‐remmer gebruiken ?

Classification of GLP‐1 receptor agonists acc. to chemical structure

Gorgojo‐Martinez JJ. Hipertens Riesgo Vasc 2014;31:45‐57

(22)

GLP‐1 therapy with insulin

proof of concept:

exenatide (5–10 µg 2x/d) or sitagliptin (100mg/d) in DM2 treated with insulin glargine and metformin

Arnolds S, et al. Diabetes Care 2010;33:1509 Response to standardized breakfast at 4 wks of treatment

glargine + MF + sitagliptin

glargine + MF + exenatide glargine + MF

(23)

Glargine + exenatide vs. basal‐bolus insulin regimen:

4B study

Participants:

• T2DM HbA1c 7.0‐10% op Glargine + metformin 108 clinics, 17 countries (EU, S.Korea, Mex, Arg, Russia)

Week

Optimization of Insulin Glargine

12‐wk BIO Phase

0 30

30‐wk Intervention phase GLP1 receptor agonist 2dd10mcg

Insulin analogue 3x daags Glargine + MF continued

‐12

‐14

Diamant M et al, Diabetes Care 2014

(24)

Diamant M et al, Diabetes Care 2014

INS

EXE

better HRQOL

Glargine + exenatide vs. basal‐bolus insulin regimen:

4B study

• Patiënt met T2DM en:

• Falen van orale medicatie, in plaats van insuline

• Onvoldoende regulatie met basale insuline, in plaats van maaltijd‐gerelateerd insuline

• Nadeel: kosten

• Voordeel: combinatie preparaat van GLP1 en basale insuline in één pen is ‘onderweg’

Wanneer GLP‐1 receptor agonist gebruiken ?

(25)

Incretin based therapy: c.v. outcome studies

No studies have been terminated for safety concerns

Can GLP1 receptor agonists modify the natural

course of T2DM ?

(26)

Woman, 59 years, type 2 diabetes

Type 2 diabetes, since 6 yrs Weight 90 kg

BMI 30kg/m²

intolerant for metformin;

R/ gliclazide + sitagliptin simvastatin

normal bloodpressure

stop sitagliptin;

start GLP1 rec. agonist, is paying this HERSELF 100 Euro per month

Goal: glycaemic improvement but wants to loose weight

Does not consider insulin to be an option

Weight 75 kg (BMI 25) No hypo’s No side‐effects

Obesity – a risk factor for many chronic disorders

‘Metabolic consequences’

Diabetes

Cardiovascular disease

‘Dynamic consequences’

Arthrosis/arthritis/gout Pulmonary complaints Sleep apnoea Esophageal reflux

‘Cancer’

Various types of cancer

‘Other’

Gall stones Alzheimer’s disease Cognitive disturbances Outcome of car accidents Postoperative complications

‐5 ‐ ‐15 kg during GLP1 RA therapy = fewer long‐term sequelae ??

(27)

Possible scenarios regarding body weight benefit of GLP1 agonists

105

100

95

90

85

0 10 30

Body weight (kg)

20 Time (years)

Insulin therapy (weight ) Scenario 1

Scenario 2 (best one) Scenario 3

Possible benefits of long‐term reduction of excess body weight:

 'Metabolic' / 'Dynamic' / 'Cancer' / 'Other' ?

Treatment with DPP4‐inhibitor sitagliptin will postpone the transition to insulin therapy

Blonde L, et al. Diabetes 2014

Metformin + SU vs. Metformin + sitagliptin

but costs are high

(28)

Long‐term and real‐world data are needed to really really really judge the merit of GLP1 treatment

'Real World' experiences

Thong KY, et al. Br J Diab Vasc Dis 2014;14:52‐59

(29)

Patients in the ABCD Nationwide Exenatide and Liraglutide Audit

n=12,955

Exenatide n=6,717 n=2,487

n=1,882

Non‐insulin n=1,027

Insulin n=400 n=1,427

BMI 25‐50 kg/m² n=559

Liraglutide n=6,238 n=1,221

n=1,023

Non‐insulin n=495

Insulin n=353 n=848

BMI 25‐50 kg/m² n=478

Total exenatide and liraglutide patients

Patients with 20‐32 week HbA1c and excluding exenatide switching to liragutide and liraglutide 1.8 mg Patients with 20‐32 week HbA1c and 20‐32 week weight

Patients using exenatide or liraglutide as add‐on therapy

HbA1c reduction with GLP1 agonists:

also beneficial effect when BMI <35 kg/m

²

‐0.0

‐0.2

Mean HbA1c change (%) ‐0.4

‐0.6

‐0.8

‐1.0

‐1.3

‐1.4

‐1.6

Exenatide Liraglutide

(n=20)

‐1.15 (n=123)

‐1.17 (n=185)

‐1.12 (n=157)

‐0.95 (n=74)

‐1.25 (n=31)

‐1.25 (n=129)

‐1.36 (n=146)

‐1.11 (n=110)

‐0.67 (n=62)

‐0.75

Data analysed by ANCOVA using BMI group and number of OAD as fixed effects, and baseline HbA1c, age, gender, ethnicity as covariates.

Exenatide; P=0.67 for effect of BMI group, liraglutide; P=0.024 for effect of BMI group BMI (kg/m²)

(30)

Body weight reduction with GLP1 Agonist:

also beneficial effect when BMI <35 kg/m

²

0

‐8

Mean weight change (kg)

‐4

‐6

‐8

‐10

Exenatide Liraglutide

(n=22)

‐3.6 (n=117)

‐4.6 (n=193)

‐5.5 (n=157)

‐7.3 (n=76)

‐8.0 (n=31)

‐1.8 (n=130)

‐1.4 (n=146)

‐2.8 (n=101)

‐3.1 (n=62)

‐4.1

Data analysed by ANCOVA using BMI group and number of OAD as fixed effects, and age, gender, ethnicity as covariates.

Exenatide; P<0.001 for effect of BMI group, liraglutide; P=0.021 for effect of BMI group BMI (kg/m²)

Retrospective analysis of U.S. health insurance claims data from the IHCIS IMPACT database, which contains medical and pharmacy claims, eligibility data, and laboratory results from 86.4 million covered patients.

Of these, 63.7 million (74%) have pharmacy benefits and 12.6 million (15%) have laboratory results; the database includes all data for individuals in all U.S. census regions and represents 46 health plans.

Dalal MR, et al. Endocr Pract 2015

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Dalal MR, et al. Endocr Pract 2015

(32)

• Patiënt met T2DM en:

• Falen van orale medicatie, in plaats van insuline

• Onvoldoende regulatie met basale insuline, in plaats van maaltijd‐gerelateerd insuline

• Nadeel: kosten

• Geen verhoogd c.v. risico (lixisenatide)

• Voordeel: combinatie preparaat van GLP1 en basale insuline in één pen is ‘onderweg’

Wanneer GLP‐1 receptor agonist gebruiken ?

3

(33)

SGLT2 inhibitors

Dapagliflozin (Farxiga^R) Empagliflozin (Jardiance^R) Canagliflozin (Invokana^R)

(34)

Nauck M, et al. Diabetes Care 2011;34:2015 814 DM2, metformin ≥ 1500 mg/d, HbA1c 7,7 ± 0,9%, rct dapagliflozin vs glipizide

Dapagliflozin vs glipizide

Nauck M, et al. Diabetes Care 2011;34:2015 Nauck M, et al. Diabetes 2011;60(Suppl.1):Poster 40‐LB 814 DM2, metformin ≥ 1500 mg/d, HbA1c 7,7 ± 0,9%, rct dapagliflozin vs glipizide

Dapagliflozin vs glipizide

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814 DM2, metformin ≥ 1500 mg/d, HbA1c 7,7 ± 0,9%, rct dapagliflozin vs glipizide

Dapagliflozin vs glipizide

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

Dapagliflozin: effects on bloodpressure

Heerspink H, et al. Diabetes, Obesity and Metabolism 2013;15:853

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Dapagliflozin: genital and urinary tract infections

GTI

UTI

Johnsson K, et al. J Diab Complic 2013 dx.doi.org/10.1016/j.jdiacomp.2013.04.012 & dx.doi.org/10.1016/j.jdiacomp.2013.05.004

Exciting news ahead ??

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Results of the EMPA‐REG OUTCOME studie

Zinman B, et al. NEJM 2015

7020 patients with type 2 diabetes at high risk for cardiovascular events

• 14 % reduction of primary outcome:

combination of CV death, non‐fatal AMI, and non‐fatal stroke

• 38 % reduction of CV death

• 35 % reduction of hospitalization for heart failure

• 32 % reduction of overall mortality

Ketoacidosis in type 1 diabetes

Ketoacidosis with slightly elevated BG values, as SGLT2 inhibitor causes glucosuria and therefore keeps BG low

(38)

SGLT2 inhibitors: summary of (side‐)effects

• bloodglucose , HbA1c 

• limited hypoglycaemia

• bloodpressure  (natriuresis, osmotic diuresis)

• weight  (glucosuria, diuresis)

• genital infections (glucosuria)

• CARDIOVASCULAR BENEFIT WITH EMPAGLIFLOZIN

Misra M. J Pharmacy Pharmacol 2013;65:317, Zinman B, NEJM 2015

SGLT2‐remmers; verwachte effecten

• Daling van bloedglucose, HbA1c, bloeddruk, gewicht

• Weinig tot geen hypoglycemie

• Nadeel: meer genitale infecties (door glucosurie)

• Gebruik:

• Als 3e medicament als niet op insuline kunnen/durven/willen

• Mensen T2DM hoog risico HVZ (boven op bestaande

behandeling)  EVIDENCE !

(39)

4

(40)

New long‐acting insulins

Insulin glargine ‐300 (Toujeo)

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1. Ritzel R et al. Diabetes Obes Metab. 2015 Apr 30.

2. 2. Data on file, Meta‐analysis T2DM_pack_2014‐05‐28.doc, pg 10;

3. 3. Adapted from Yki‐Järvinen H et al. Diabetes Care. 2014;37:3235‐43 Pooled analysis in T2DM^1,2

Reduces proportion of patients who experience nocturnal hypoglycemia

Lantus Toujeo

Better compromise between HbA_1Cand hypoglycemia:

Lower risk of nocturnal hypoglycemia at all levels of HbA1C

–33%

Toujeo compared to Lantus in T2DM

Relative risk (95% CI) 0.67 (0.53‐0.86)

81 Confirmed (≤70 mg/dL

[≤3.9 mmol/L]) or severe Nocturnal documented

(≤54 mg/dL [<3.0 mmol/L])

Nocturnal confirmed (≤70 mg/dL [≤3.9 mmol/L]) or severe

EDITION 2 in T2DM³

Lantus Toujeo

Relative risk (95% CI) 0.75 (0.68‐0.83)

–25% 25

0

4 6 8 12

HbA_1Cat Month 6 (%) Estimated number of events per participant‐year from Week 9 to Month 6

5 7 9 10 11

5 10 15 20

p=0.159

p=0.010 Toujeo Lantus

Patients with ≥1event from baseline to Month 6, %

Any time (24 h)

Nocturnal

10%

higher dose

Insulin degludec

(42)

5

Some final thoughts on costs of

type 2 diabetes treatment

(43)

New drugs are more expensive than old drugs

• Price per month:

• SU: € 3‐4 Euro, Metformin: € 3‐4

• DPP4‐i & SGLT2 remmer: € 40

• Insulin: € 50 ‐ 75

• GLP1‐RA: € 100

Short term costs vs long term benefits

Miele LG

Obesity – a risk factor for many chronic disorders

‘Metabolic consequences’

Diabetes

Cardiovascular disease

‘Dynamic consequences’

Arthrosis/arthritis/gout Pulmonary complaints Sleep apnoea Esophageal reflux

‘Cancer’

Various types of cancer

‘Other’

Gall stones Alzheimer’s disease Cognitive disturbances Outcome of car accidents Postoperative complications Can a 5 ‐ 15 kg reduction

of body weight reduce weight‐related morbidities?

(44)

Long‐term costs of diabetes treatment

Quality‐adjusted life‐year (QALY):

1. measure of disease burden, including both the quality and the quantity of life lived 2. the number of years of life that would be added by an intervention

• Retrospective administrative claims including medical claims, pharmacy claims, laboratory data, from large, US health plan

• Probability of diabetes complications using the UKPDS outcomes model

• age, sex, ethnicity, smoking, BMI, HbA1c, SBP, lipids, PVD, atrial fibrillation, ischemic heart disease, and congestive heart failure; and blindness at diagnosis

• Probability of death from other cause estimated based on the US 2007 mortality tables

Methodology

Zhang Y, et al. Diabetes Care 2014;37:1338‐1345

(45)

QALY vs. Costs

Δ

met+sulf+insulin met+DPP‐IV+insulin

Expected QALYs prior to the first event

64.34 64.36 64.40

2100 2300 2500 2700 2900

Expected medication cost per QALY (USD/QALY) 64.38 7%

64.32

64.28 64.30

64.26 64.24

6.5%

8%

A B

68.38 68.40 68.44

2100 2300 2500 2700 2900

Expected medication cost per QALY (USD/QALY) 68.42 7%

68.36 68.32 68.34 68.30 68.26

6.5%

8%

met+GLP‐1+insulin met+insulin

QALYs vs. cost incurred by the four different treatment regimens as a function of glycemic control goal. Comparison of the expected QALYs vs. the expected medication cost per QALY incurred from diagnosis to first event (diabetes‐related complication or death) for men (A) and women (B). Each of the four treatments is compared as the glycemic control goal is varied from 6.5% (48 mmol/mol) to 8% (64 mmol/mol). Results are presented using HbA1c of 6.5% (48 mmol/mol) ( ),

7% (53 mmol/mol) ( ), and 8% (64 mmol/mol) ( ) as the glycemic control goal

Men Women

68.28

Zhang Y, et al. Diabetes Care 2014;37:1338‐1345

• Only predicts 1st event of any diabetes‐related complications

• Does not allow series of events

• Does not incorporate morbidities, like neuropathy or foot ulceration

• Hypoglycaemia and hyperglycaemia also excluded

• No single allowance for other co‐morbid conditions, like COPD, osteo‐arthritis, depression ……. & those associated with obesity, which are predicted to be less with GLP1 RA therapy

Drawbacks of the UKPDS Model

(46)

saxa?

Empa

Glycaemic effects BMI>35 kg/m²GLP1RA restriction notevidence‐based

Health‐related quality of life

• incl. daily activities & work Patients prefer GLP1RA vs insulin Effects on diabetic complications Longer term studies needed Time to insulin dependence Will postpone insulin

Side‐effects Risk of pancreatitis in real world

• weight increase & hypoglycaemia experience not substantiated

• pancreatic and other organ safety

Long‐term costs of: Inclusive models needed to assess

• other med's, other co‐morbidities & benefit on obesity‐assoc. disorders

their complications

• absent from work, unemployment, social support