Oral Agents in Management ofType 2 Diabetes

Nemanja Stojanović

Consultant Endocrinologist

Queen’s Hospital, Romford

We will talk about

• T2DM in general…• Metformin• Sulphonylureas + PPG regulators• α-Glucosidase Inhibitors• Statistics• Glitazones and meta- analysis• DPP-4 inhibitors and meta- analysis• GLP-1 analogues

Definition

– Fasting plasma glucose 7mmol/l- 2 occasions

– 2 h plasma glucose or random glucose of 11.1 mmol/l

BM’s

Fasting Beforelunch

Beforedinner

Beforebed

Normal 3.9 4.4 4.9 5.0

Type 2 DM 8.2 13.4 13.1 10.7

Type 2 DM 6.8 8.7 6.8 6.2

Type 1 DM 3.1 4.1 4.2 10.2

Normal 24h profile

T1DM: Relationship between HbA1c and Mean Glucose

HbA1c Mean Glucose (mmol/l)

6% 7.5

7% 9.5

8% 11.5

9% 13.5

10% 15.5

11% 17.5

12% 19.5 Dia Care2002: 25: 275-8

“Drug therapies are

replacing a lot of medicines

as we used to

know it…”

George W Bush

Treatment

Diet, Exercise

Medications:Metformin

SulphonylureasPPGs

Acarbose

Metformin

NH

NH2 C NH2

Guanidine

Galega officinalis

CH3

CH3

N C NH

NH

C

NH

NH2

Metformin

Metformin : Non- Glycaemic Effects

• Abdominal obesity- stabilizes body weight; reduces weight gain and can facilitate weight loss

• Reduces progression of IGT to type 2 diabetes

• Dyslipidaemia: VLDL-TG, LDL-C, HDL-C

• Procoagulant state: PAI-1,fibrinogen and platelet aggregation

Metformin : contraindications

• Cr> 150 umol/l• Hypoxic states

- CCF/acute heart failure- sepsis- Severe COPD

• Severe liver disease • Alcoholism• History of lactic acidosis• Radiological contrast

Insulin Secretaguoges

• SU

• Repeglanide

• Nateglinide

• Glibenclamide

Insulin Secretaguoges: Concerns

• Hypoglycemia

• Weight gain

• Cardiovascular disease risk

α-Glucosidase Inhibitors

• Take within 15' of a major meal

• Increase the dose gradually

• SE/benefit dose 50mg tds

α-Glucosidase Inhibitors: Side effects

• Deranged LFT’s high doses

• Ileus Japanese.

• Contraindications:- IBD- Malabsorption- Bowel obstruction- Liver failure- Cr clearance<25 ml/min

Thiazolidinediones

Pharmacokinetics of TZD’s

Pioglitazone

Rosiglitazone

Thiazolidinedions (Glitazones)

• Reduce HbA1c by

1-2%

• Peripheral vascular resistance : 4mmHg in 24-h mean systolic and diastolic blood pressure

• Lipids

- Convert small, dense LDL particles to large, buoyant LDL particles

- Increase plasma HDL cholesterol

- Decrease plasma triglycerides if they are elevated (>200 mg/dl)

Pioglitazone vs Rosiglitazone

Pioglitazone Rosiglitazone p

HbA1c - 0.7% - 0.6% NS

Cholesterol 5.7± 0.1% 15.9± 1% <0.001

LDL 15.7±1.9% 23.3± 1.9% <0.02

HDL 14.9± 1.2% 7.8± 1.3% <0.001

Non HDL 3.8±1.3% 18.6± 1.3% <0.001

Trigs -12±3 % 14.9±3.1% <0.001

Dia Care 2005: 1547-54

Rosiglitazone

Before We Start

• Rofecoxib

• Muraglitazar

• Rosiglitazone

• Rofecoxib= Vioxx

• SE Nissen

Odds Ratio

• Odds of an event occurring in a patient in the experimental group relative to that of a patient in the control group

Confidence Interval and Odds Ratio

• Odds ratio, for the result to be statistically significant, the 95% confidence interval should not overlap 1 (i.e. the odds ratios within the confidence interval should all be >1 or <1, the no difference point)

Nissen SE, Wolski K. N Engl J Med 2007;356:2457-2471

• Analysed 42 out of 48 trials • 6 trials without CVS events ruled out of analysis• Trial duration ≥ 24 weeks • No time to event analysis• Mean age 57 years

n MI CVS Death

p

Avandia 15560 Odds Ratio 1.43

Odds Ratio 1.64

0.03

No Avandia 12283 95%CI

1.03-1.98

95%CI

0.98- 2.740.06

Nissen SE, Wolski K. N Engl J Med 2007;356:2457-2471

Caution about use…Limitations of the study acknowledgedMay increase CVS risk

RECORD TrialInterim analysis at 3.9 yrs

• Non- inferiority Study !!• 4447 patients- 40- 75 years- A1c 7.1-9%- BMI> 25

• 2220 Rosi + Met or SU • 2227 Met + SU

Primary Outcomes

- Myocardial infarction- Congestive heart failure- Stroke- TIA- Unstable angina- Unplanned CVS

revascularization- Amputation of extremities- Death from CVS cause

RECORD Study : Problems

• Expected event rate 11% p.a.

• Actual event rate 2% p.a.

• Expected study dropout rate 2% p.a.

• Actual study dropout rate 3% p.a.

• As a result the study is underpowered

RECORD: Conclusion

• Rosiglitazone association with an increased risk of heart failure acknowledged

• As the study was underpowered, it is nit possible to determine whether the drug was associated with an increase in the risk of myocardial infarction

Pioglitazone

PROactive

• 5238 patients• HbA1c above 6.5%• At least one of the following - Previous MI- Previous CVA- PTCA- ACS> 3months prior to the study entry- History of intermittent claudication

Lancet; 366: 1279-89

PROactive

• Primary Endpoints

- Composite of all cause mortality, MI, CVA, unstable angina,

PTCA, Revascularisation procedures, amputations

• Secondary Endpoints

• Time to death of any of the disease endpoints

- MI- CVA- Unstable angina etc

Lancet; 366: 1279-89

PROactive

• NNT 49 over 3 years to prevent an event

• 21 first MI would be saved in 1000 patients started on pioglitazone

• Heart failure was increased in pioglitazone group( Odds ratio 1.38), but LVF mortality was equal

Pioglitazone Meta-analysis

• 16390 Patients

• Pioglitazone n= 8554; Control n= 7836

• Primary Endpoint: Composite of Death, Non-fatal MI and Non-fatal CVA

• Secondary Endpoint Heart Failure

Pioglitazone did well…

• Primary endpoint Pioglitazone 4.4% vs Control 5.5% p=0.05

• HR= 0.82; CI 0.72- 0.94

• Time to event apparent after 1 year

• Heart Failure: Pioglitazone 2.3% vs Control 1.8% p=0.02 HR 1.4

• No difference in fatal

HF!!!

The PERISCOPE Trial

• 547 patients randomised: pioglitazone vs glimepiride

• Age 35- 85

• HbA1C 6-9%

• Angiographic Coronary a stenosis 20-50%

• Target vessel stenosis had to be less than 50% throughout 4cm segment

JAMA 2008; 299: 1561- 73

The PERISCOPE Trial

JAMA 2008; 299: 1561- 73

Glimepiride n=273

Pioglitazone n= 270

p

Smokers 53 (19.4%) 31 (11.5%) 0.01

Ex Smokers 119 (43.6%) 147 (54.5%) nsNever smoked 99 (36.4%) 89 (33%) ns

Prior MI 70 (25.6%) 83 (30.7%) ns

BP 250 (91.6%) 225 (83.3%) 0.02

Insulin 63 (23.1%) 49 (18.1%) ns

Glimepiride Pioglitazone

LS mean (CI)

P valueΔ from baseline

LS mean (CI)

P valueΔ from baseline

p

% atheroma Volume

0.73

(0.33- 1.12)

< 0.001 -0.16 (-0.57-0.25)

0.44 0.002

Max atheroma thickness

0.011 0.054 -0.011 0.06 0.006

Normalized atheroma Volume

-1.5

(-4.5 to 1.54)

0.34 -5.5

(-8.7 to -2.4)

<0.01 0.06

Ath Vol in 10mm most diseased segment

-2.1

(-3.3 to -0.84

0.01 -2

(3.3 to -0.67)

0.003 0.93

Glimepiride Group End

Glimepiride Group Baseline Pioglitazone Group Baseline

Pioglitazone Group End

Pioglitazone Group EndGlimepiride Group End

Glimepiride Group Baseline Pioglitazone Group Baseline

ACCORD Trial

• Intensive glycaemic management

• Target HbA1c 6.4%

• Stopped a month ago…

• Increased mortality in active treatment group

• Analysis is awaited

New Kids on the Block

DPP-4 inhibitors

GLP-1 mimetics

Of Men and Mice

• Dipeptidyl Peptidase – 4 (DPP-4)

degrades

- Glucose-dependent Insulinotropic Peptide (GIP):improves glycaemic control in mice

- Glucagon Like Peptide 1 ( GLP-1): improves glycaemic control in mice and men

DDP-4 Knock Out Mice

• Improved glucose tolerance

• Elevated GLP-1 and GIP levels

• Resistance to diet induced obesity and hyperglycaemia

DDP-4 Knock Out Mice

• Increased pain threshold

• Reduced stress like responses

• Reduced number of CD4 cells in spleen

• Immune and inflammatory responses increased in experimental arthritis

DPP-4 other Biological Activities

• Loss of DPP-4 in tumours: > aggressive behaviour

• Implicated in control of immune and lymphocyte function

• Cell migration

Sitagliptin Studies

Added to Duration nStarting

A1c Δ A1c placebo

Metformin 6 months 701 8.00% -0.65% yes

Metformin 1 year 1172 7.50% -0.70% yes

vs Metformin+ Glipizide Less hypos Weight loss

Pioglitazone 6 months 353 8.00% -0.70% yes

Vildagliptin Studies

Added to Duration nStarting

A1c Δ A1c placebo

Metformin 12+40 wk 107(72) 7.80% -0.70% yes

Metformin 24wks 544 8.40% (50mg) -0.7% yes

(100mg) -1.1%

Pioglitazone 26 weeks 592 8.70% -1.90% yes

Insulin 24 weeks 296 8.90% -0.50% yes

Indications

• Sitagliptin

• In addition to - TZD OR- Metformin OR- SU ± Metformin

- Dose 100mg OD

• Vildagliptin

• In combination with

- TZD OR- Metformin

- SU: 50mg OD

50 mg BD

Exenatide

• GLP-1 analogue

• 5-10 ug BD

• Injection

• Licensed with SU/Metformin or in combination

• Induces ~2kg weight loss

Exenatide

• HbA1c reduction ~ 1%

• FPG reduction of 1.5mmol/l

• Reduction in postprandial hyperglycaemia

• Rare hypos

• Nausea and vomiting

• ? pancreatitis

Meta- analysis

• DPP-4 inhibitors

• A1c by mean 0.74%• Weight neutral• Risk of infection• Not inferior to other

oral hypoglycaemic agents

• GLP-1 Analogues

• A1c by mean 0.97%• Induce weight Loss• More GI side effects

JAMA 2007; 289: 194- 206

In Conclusion

• Several classes of drugs are available

• Metformin, SU’s and Acarbose … tried, tested and do not suit every patient

• Glitazones…

• DPP-4 inhibitors / GLP- 1…we need to get the feel for them

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