NEW DRUGS FOR DIABETES

Dr Helen Gray Consultant Physician CGH

Objectives

To describe the incretin system To describe new treatment options in diabetes To discuss some practical patient examples

Medications
Medications Insulin Inhaled insulin Introduction 1921 2006

Sulfonylureas
Biguanides

1946
1957

Glycosidase inhibitors
TZDs GLP analogues

1995
1999 2007

DPP-IV inhibitors

2007

New Drugs

Incretins

GLP1 analogues: Exenatide (Byetta) DPP4 Inhibitors: Sitagliptin (Januvia)

Role of Incretin in Glucose Homeostasis

IN-CRET-IN
INtestine seCRETion INsulin
Definition: gut derived factors that increase glucose stimulated insulin secretion

Two hormones: (1) glucagon-like peptide-1 (GLP-1)

(2) glucose-dependent insulinotropic polypeptide (GIP)

Creutzfeldt Diabetologia 28: 5645 1985

GLP-1 and GIP Are Incretin Hormones

GLP-1

GIP

Released from L cells in ileum and colon1,2 Stimulates insulin from beta cells in a glucosedependent manner1 Inhibits gastric emptying1,2 Reduces food intake and body weight2 Inhibits glucagon secretion from alpha cells in a glucosedependent manner1 Deficient in type 2 diabetes

1. Meier JJ et al. Best Pract Res Clin Endocrinol Metab. 2004;18:587606. 2. Drucker DJ. Diabetes Care. 2003;26:29292940.

Released from K cells in duodenum1,2 Stimulates insulin from beta cells in a glucosedependent manner1 Minimal effects on gastric emptying2 No significant effects on satiety or body weight2 Does not appear to inhibit glucagon secretion from alpha cells1,2 Normal levels but decreased responsiveness in type 2 diabetes

The Incretin Effect in Healthy Subjects Oral Glucose

Intravenous (IV) Glucose 200 Plasma Glucose (mg/dL) * 2.0 *

C-peptide (nmol/L)

1.5

* * Incretin Effect * *

100

1.0 * 0.5

0 0 60 Time (min)
N = 6; Mean SE; *P0.05 Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-498.

0.0 120 180

60 120 Time (min)

180

Loss of Incretin Effect

Nauck M,et al. Diabetologia 1986;29:46-52.

Incretins: The medications

GLP1 analogues:Exenatide (Byetta)
DPP4 Inhibitors:Sitagliptin (Januvia)

New Therapies: Incretin System

Ingestion of food Release of active incretins GLP-1 and GIP Pancreas Glucose dependent Insulin (GLP-1and GIP)
Glucose uptake by peripheral tissue

Beta cells Alpha cells

Glucosedependent Glucagon (GLP-1)
Hepatic glucose production

GI tract

Blood glucose in fasting and postprandial states

Exenatide Sitagliptin

X
Inactive GLP-1

DPP-4 enzyme

Inactive GIP

GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide.

New Therapies: Incretin System

Ingestion of food Release of active incretins GLP-1 and GIP Pancreas Glucose dependent Insulin (GLP-1and GIP)
Glucose uptake by peripheral tissue

Beta cells Alpha cells

Glucosedependent Glucagon (GLP-1)
Hepatic glucose production

GI tract

Blood glucose in fasting and postprandial states

Exenatide Sitagliptin

X
Inactive GLP-1

DPP-4 enzyme

Inactive GIP

GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide.

GLP-1 ANALOGS

Stable analog not cleaved by DDP-4 Exendin-4 in saliva of Gila Monster lizard is 50% similar to human GLP-1 Exenatide ( Byetta) is a synethic formof this

DDP-4 Inhibitors

DDP-4 inhibitor and so prolong action of endogenous GLP-1 Sitagliptin (Januvia)-OD Vildagliptin (Galvus)-OD with SFU,bd with metformin or TZD

DPP-4 Inhibitors and Incretin Mimetics

Sitagliptin (Januvia)
Indication Management of type 2 diabetes mellitus - monotherapy - combo with metformin or TZD

Exenatide (Byetta)
Management (adjunctive) of type 2 diabetes mellitus - metformin, sulfonylurea, and/or TZD Initial: 5mcg bid within 60 minutes prior to a meal (morning and evening) After 1 month, may be increased to 10mcg bid

Dose

100mg daily

Avoid if creat clear<50ml/min Route: oral

CrCl < 30ml/min: not recommended Route: SC

Sitagliptin prescribing information, 2006. Exenatide prescribing information, 2007.

DPP-4 Inhibitors and Incretin Mimetics

Sitagliptin (Januvia) Adverse Reactions Monotherapy: nasopharyngitis Combination with TZDs: upper respiratory tract infxn, headache GI: abdominal pain, N/V/D

Exenatide (Byetta) Monotherapy: N/V/D Combination with sulfonylurea: hypoglycemia Anti-exenatide antibodies Weight loss

Long-term unclear

Comments

Should NOT be used in type 1 diabetes or for treatment of diabetic ketoacidosis

Sitagliptin prescribing information, 2006. Exenatide prescribing information, 2007.

Comparison: DPP-4 Inhibitors and Incretin Mimetics

DPP-4 Inhibitors (Sitagliptin)
Advantages

Incretin Mimetics (Exenatide)

Route: oral No weight gain Promote b-cell proliferation Once daily dosing

Weight loss independent of nausea Promote b-cell proliferation and islet neogenesis Induces satiety, suppresses appetite

Disadvantages

Unwanted effects on immune function (possible safety issues) Less potent compared with injectable incretin mimetics

Route: SC Twice daily dosing Dose-dependent nausea and vomiting Fixed dosing (Pen)

(1) Nauck M, et al. Diabetologia 1986;29:46-52. (2) Triplitt C, et al. Pharmacotherapy 2006;26:360374. (3) Drucker D, et al. Lancet 2006;368:1696-1705

NICE Guidance DPP-4 inhibitors

Consider adding 2nd line therapy instead of SFU with metformin if risk of hypoglycaemia Instead of metformin if intolerant As triple therapy if insulin unacceptable/inappropriate Continue only if HBA1c drop of 0.7% by 6 months May be preferable to TZD those in whom weight gain an isuue

NICE Guidance GLP-1 mimetic

Consider adding to SFU and metformin if:-BMI> 35 -BMI<35 and wt loss would benefit other significant co morbities Continue if HbA1C 1% reduction at 6 months AND wt loss of at least 5% at 1 year-and maintained

PATIENT 1 RPV

52 year old staff nurse BMI 40 WT 80.5kg Type 2 DM 2003 HbA1c 9.5% RX Metformin 1g BD AND Gliclazide 80 mg BD What next?

PATIENT 1 RPV
Take metformin regularly Started Orlistat 6 months later Wt 82.1KG but HbA1c 7.5% What next? Started Byetta 3 months later Wt 81kg BUT HbA1c 6.7% and advised to reduce gliclazide because of hypos and eating to prevent these Further 3 month review ??

PATIENT 2 AC

57 year old man (awaiting TKR ) 2008 Morbid obesity (Wt 151kg BMI 50) with Obstructive sleep apnoea 2009 Type 2 Diabetes FPG 26 mmol/lstarted gliclazide 160mg bd Would you send him to hospital for admission? What next?

PATIENT 2 AC

Started on OD Lantus-and Orlistat added 1 month later HBGM 6-12 2 months later BMI Wt 143.4kg and hypos so Lantus reduced 4 months later Wt 141.5 kg BMI 47 and still hypos so insulin stopped ALT 169 ?NASH-confirmed on U/S-metformin and statin started Aim Wt 120kg BMI 40 to be eligible for surgery

PATIENT 3 AL

45 year old HGV driver Type 2 Diabetes 1999 BMI 32 Rx Gliclazide and Metformin Asymptomatic BUT HbA1c 9.0% What next?

PATIENT 3 AL

Add glitazone-but what about wt gain? Add DDP-4 inhibitor Or consider Byetta Will lose his licence with insulin And tackle all other risk factors agressively

Questions

DIABETES AND PREGNANCY

Dr Helen Gray
Consultant Physician CGH

Key finding 1: Outcome

Babies of women with diabetes in England, Wales and N Ireland continue to have an increased risk of perinatal mortality and congenital anomaly Stillbirths Death of baby in first four weeks Major congenital anomaly Neural tube / cardiac anomalies x4.7 x2.6 x2 x3.4

Glycaemic control and outcome

Median Hba1c test results at various stages of pregnancy according to perinatal outcome
9 8.5 Malformations

Median HbA1c (%)

8 7.5 7 6.5 6 5.5 5 Prepregnancy <13+0 weeks 18+0 to 23+6 weeks 27+ weeks Normally formed stillbirths/NND Alive at 28 days, no congenital malformation

DIABETES AND PREGNANCY

Contraception Preconception : Type 1 & Type 2 Antenatal care: Postnatal care

NICE JULY 2008

Diabetes in pregnancy Management of diabetes and its complications from pre-conception to postnatal period

Type 1/Type 2 and GDM

Contraception in Diabetes
A Reliable Method is more important than risk Most reliability associated with the OCP Most risk associated with the OCP

PRE CONCEPTION CARE

Starting from adolescence Risk of diabetes and pregnancy establishing good glycaemic control will reduce risk of miscarriage, congenital malformation and still birth

PRE-PREGNANCY(2)
1) 2) 3) 4) 5) 6) 7) 8) 9)

Planned pregnancy Diet/tablets to insulin as part of plan Good glycaemic control (with hypo education) Nausea and DKA Retinal screening and BP/renal assessment Other medication? Folic acid 5mg Alcohol and smoking Clinic information/contacts

SAFETY OF MEDICATIONS

Continue Metformin Stop statins and ACE/ATII blockers All insulin safe (NICE suggest Isophane insulin as long acting of choice!)

BLOOD GLUCOSE MONITORING AND TARGETS PRE -PREGNANCY

Individualised targets Monthly HbA1C (aim <6.1% if safe) Any reduction may reduce risks Advise women with HbA1c > 10% to avoid pregnancy Remember risks of of rapid optimisation of glycaemic control and retinal changes

PRACTICAL ADVICE

Refer all women with diabetes for pre conceptual counselling Actively advice not to conceive if HbA1c>10% Start folic acid 5mg od Continue metformin Antenatal care is NOW at GRH

THANKS

Richard Hayman (Consultant Obstetrician) Helen Giles,Julie Campbell (DSNS) Penny Lock Pullan (Dietician) Peter Scanlon and all retinal screening team

DIABETES AND PREGNANCY

27 year old primagravida,Type 1 15 years. HbA1c 9% Microalbuminuria on ACE Hypercholesterolaemia on Statin Hypothyroid on thyroxine Wants to become pregnant What Advice does she need ?

DIABETES AND PREGNANCY

35 year old Type 2 for 5 years Gravida 2 (6&8 years old) BMI 35 Gestational diabetes in first pregnancy HbA1c 8.5 % on Metformin 850mg bd On antihypertensives, statin and aspirin Wants another baby What do you advise?

DIABETES AND PREGNANCY

1.

2.

3.

4. 5.

Can a woman with diabetes bear children successfully? Is the pregnancy dangerous to the mother? What are the short term risks to the foetus? Will the baby develop diabetes? What about the mothers long term health?

DIABETES AND PREGNANCY

Risk of death same as for any pregnant woman Congenital malformations but remember even with poor control only 10-20% risk of abnormality Risk of Type 1 is 1.3% if mother has diabetes but 6.1% if father ris the affected parent Risk of Type 2 15-30% Risk of worsening renal disease and retinopathy