NEW DRUGS FOR DIABETES

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NEW DRUGS FOR DIABETES

• Dr Helen Gray
• Consultant Physician
• CGH

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Objectives

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

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Approved diabetes Medications
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New Drugs

• Incretins
• GLP1 analogues Exenatide (Byetta)
• DPP4 Inhibitors Sitagliptin (Januvia)

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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
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GLP-1 and GIP Are Incretin Hormones
1. Meier JJ et al. Best Pract Res Clin Endocrinol
Metab. 200418587606. 2. Drucker DJ. Diabetes
Care. 20032629292940.
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The Incretin Effect in Healthy Subjects
Oral Glucose
Intravenous (IV) Glucose
200
2.0
1.5
Incretin Effect
100
1.0
Plasma Glucose (mg/dL)
C-peptide (nmol/L)
0.5
0
0.0
Time (min)
Time (min)
N 6 Mean SE P?0.05Nauck MA, et al. J Clin
Endocrinol Metab. 198663492-498.
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Loss of Incretin Effect
Nauck M,et al. Diabetologia 19862946-52.
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Incretins The medications
GLP1 analoguesExenatide (Byetta) DPP4
InhibitorsSitagliptin (Januvia)
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New Therapies Incretin System
S e c t i o n 12, 12.2
Glucose dependent
? Insulin (GLP-1andGIP)
? Glucose uptake by peripheral tissue
Ingestion of food
Pancreas
Release of active incretins GLP-1 and GIP
Beta cells Alpha cells
? Blood glucose in fasting and postprandial states
GI tract
X
Glucose- dependent
DPP-4 enzyme
Exenatide
? Hepatic glucose production
? Glucagon (GLP-1)
Sitagliptin
Inactive GLP-1
Inactive GIP
GLP-1glucagon-like peptide-1 GIPglucose-depende
nt insulinotropic polypeptide.
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New Therapies Incretin System
S e c t i o n 12, 12.2
Glucose dependent
? Insulin (GLP-1andGIP)
? Glucose uptake by peripheral tissue
Ingestion of food
Pancreas
Release of active incretins GLP-1 and GIP
Beta cells Alpha cells
? Blood glucose in fasting and postprandial states
GI tract
X
Glucose- dependent
DPP-4 enzyme
Exenatide
? Hepatic glucose production
? Glucagon (GLP-1)
Sitagliptin
Inactive GLP-1
Inactive GIP
GLP-1glucagon-like peptide-1 GIPglucose-depende
nt insulinotropic polypeptide.
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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

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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

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DPP-4 Inhibitors and Incretin Mimetics
Sitagliptin prescribing information, 2006.
Exenatide prescribing information, 2007.
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DPP-4 Inhibitors and Incretin Mimetics
Sitagliptin prescribing information, 2006.
Exenatide prescribing information, 2007.
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Comparison DPP-4 Inhibitors and Incretin Mimetics
(1) Nauck M, et al. Diabetologia 19862946-52.
(2) Triplitt C, et al. Pharmacotherapy
200626360-374. (3) Drucker D, et al. Lancet
20063681696-1705
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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/inapprop
  riate
• Continue only if HBA1c drop of 0.7 by 6 months
• May be preferable to TZD those in whom weight
  gain an isuue

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NICE Guidance GLP-1 mimetic

• Consider adding to SFU and metformin if-BMIgt 35
• -BMIlt35 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

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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?

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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 ??

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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/l- started
  gliclazide 160mg bd
• Would you send him to hospital for admission?
• What next?

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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

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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?

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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

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Questions
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DIABETES AND PREGNANCY

• Dr Helen Gray
• Consultant Physician
• CGH

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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 x4.7 Death of baby in first
four weeks x2.6 Major congenital anomaly
x2 Neural tube / cardiac anomalies x3.4
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Glycaemic control and outcome
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DIABETES AND PREGNANCY

• Contraception
• Preconception Type 1 Type 2
• Antenatal care
• Postnatal care

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NICE JULY 2008

• Diabetes in pregnancy
• Management of diabetes and its complications
  from pre-conception to postnatal period
• Type 1/Type 2 and GDM

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Contraception in Diabetes

• A Reliable Method is more important than risk
• Most reliability associated with the OCP
• Most risk associated with the OCP

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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

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PRE-PREGNANCY(2)

• 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

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SAFETY OF MEDICATIONS

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

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BLOOD GLUCOSE MONITORING AND TARGETS PRE
-PREGNANCY

• Individualised targets
• Monthly HbA1C (aim lt6.1 if safe)
• Any reduction may reduce risks
• Advise women with HbA1c gt 10 to avoid pregnancy
• Remember risks of of rapid optimisation of
  glycaemic control and retinal changes

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PRACTICAL ADVICE

• Refer all women with diabetes for pre conceptual
  counselling
• Actively advice not to conceive if HbA1cgt10
• Start folic acid 5mg od
• Continue metformin
• Antenatal care is NOW at GRH

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THANKS

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

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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 ?

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DIABETES AND PREGNANCY

• 35 year old Type 2 for 5 years
• Gravida 2 (68 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?

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DIABETES AND PREGNANCY

• 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?

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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