This document discusses metformin and add-on therapies for type 2 diabetes management. It begins with an overview of diabetes and metformin's roles and benefits, including reducing cardiovascular events and mortality. It then discusses various add-on therapy options to metformin, including their effects on HbA1c levels and advantages/disadvantages like risk of hypoglycemia, weight gain, and safety issues. Guidelines for treating diabetes and selecting add-on therapies based on patient factors are also summarized.

1. Happy day
for all colleagues

2. MetforminRole In Medicine
&
Add –On Therapies to Metformin in
type 2 DM Management
DR./ADEL ELNAGGAR
Endocrinologist

3. DIABETES SPOT LIGHTS
METFORMIN ROLES
METFORMIN + combinations

4. :
A GROUP OF DISEASES
Characterized By High Levels Of Blood Glucose
Resulting From Defects In Insulin Production,
Insulin Action, Or Both
Diabetes Mellitus :
Metabolic Disorders
Cardio-metabolic Disorders
Complex Metabolic Disorders
Characterized By Hyperglycemia Due To An Absolute Or Relative
Lack Of Insulin
Or To A Cellular Resistance To Insulin

7. SAUDI ARABIA
1 IN 4

8. (LACK OF DIABETES
PYRAMID STRATEGIES):
BASE: Early detection;
diagnosis & prevention Programs
(Health Education).
BODY: Proper scientific socio-
economic Management
(Qualified Health Care
Providers).
TOP: Delay or prevent Diabetic
Complications (Reduce Morbidity
& Mortality).

10. Primary Endocrinopathies:
Treating a Moving Target
Insulin
Resistance
Type 2
Diabetes
b-cell
Dysfunction
Insulin
Resistance
Insulin
Concentration
Euglycaemia
b-cell Failure
Normal IGT ± Obesity Diagnosis Of T2DM Progression of T2DM
DISEASE

14. Pre-Diabetes
•Impaired fasting glucose (IFG)
•FPG 100-125mg/dL
•Impaired glucose tolerance (IGT)
•PPBG 140-199mg/dL
•HbA1c 6-6.5%

16. INSULIN RESISTANCE
METABOLIC SYNDROME
&
ADULT OBESITY
Central obesity (waist circumference)
IGT or IFG
High lipid profile
LDL-HDL/CHOLESTEROL/TRIGLYCERIDES
HIGH BP more than 130/90

17. MANAGEMENT OF DIABETES
METFORMIN
DPP4
PIOGLTAZONES
GLP1 ANALOUGES
SGLT2 INHIBITORS
SUs
INSULINs
PANCREATIC TRANSPLANTION
STEM CELLS
METABOLIC SURGERIES

18. CHOICES MODULES OF NON-INSULIN THERAPIES FOR
MANAGEMENT OF TYPE 2 DM
4 RIGHTS MODULE

20. Biguanides : improves insulin’s ability to
move glucose into cells (esp. muscle)
 Metformin
- Glucophage®, Fortamet®,
Riomet®
*only anti-diabetic drug that has been proven to reduce the complications of diabetes, as evidenced in a large study of overweight patients with
diabetes (UKPDS 1998).
- Metformin was first described in the scientific literature in 1957 (Unger et al).
- It was first marketed in France in 1979 but did not receive FDA approval for Type
2 diabetes until 1994.
NN
NN
N
R
R R
R
RR
R
N N
N
N
N
H
H
H
H H
+ HCl
- mechanism improves insulin sensitivity by increasing peripheral glucose
uptake and utilization.
- Zhou et al (2001) showed that metformin stimulates the hepatic enzyme
AMP-activated protein kinase
Metformin is a widely used monotherapy, and also used in combination with
the sulfonylureas in treatment of type 2 diabetes

23. Vascular effects of
metformin
Anti-atherogenic actions
Dec. cholesterol deposition
Dec. lipid peroxidation
Dec. oxidative stress
Inc. endothelial function
Anti-thrombotic actions
Dec. platelet activation
Dec. fibrin breakdown
Inc. blood flow
Anti-inflammatory effects
Dec. c-reactive protein

24. Metformin contra-
indicationsRenal dysfunction
Severe liver disease
Use of iv contrast media
Major surgical procedures
Congestive heart failure
Acute MI
History of lactic acidosis
History of alcohol abuse
FDA removed heart failure in 2007 as metformin contra-
indication.

25.  Studies have shown that medications have been
successful in preventing diabetes in some
population groups.
 In the Diabetes Prevention Program, people
treated with the drug METFORMIN reduced
their risk of developing diabetes by 31%
over 3 years.
 Treatment with METFORMIN was most effective
among younger, obese people (those 25-40 years
of age who were overweight) and less effective
among older people and people who were not as
overweight.
Prevention Or Delay
of DIABETES (Medications)

30. Drug ttt. For GDM
METFORMIN
INSULIN if metformin
contraindicated/side effects
offer immediate ttt. With insulin
±metformin if fpg ≥126 mg/dl
at diagnosis
Consider GLIBENCLAMIDE if blood
glucose targets not achieved with
metformin (or metformin intolerance)
and insulin therapy declined.
NICE feb 2015

31. Metformin ttt. For GDM• Less macrosomia
• Fewer admissions to scbu (special care baby unit)
• Reduced incidence of neonatal jaundice & hypoglycemia
• METFORMIN
1) Safe alternative to insulin
2) Less wt. gain
3) No risk of hypoglycemia
4) No injections
5) Can be comined with insulin
6) Avoid if fetal growth restriction
7) Not licensed for use in pregnancy
8) Endorsed in national guidelines
Balani et al Diabet Med 2009; 26:798-802

32. Is there association between
type 2 DM & cancer
Insulin
resistance
Hyper-
insulinemia
Tumour
development
Diabetes
&
obesity
cancer

35. INTERNATIONAL DIABETES FEDERATION (IDF)
2005 and 2011/12
AMERICAN GUIDELINES (ADA)
2006, 2008, 2009, 2012, 2015
EUROPEAN GUIDELINES (EASD)
2006, 2008, 2009, 2012, 2015
NATIONAL GUIDELINES (KSA –EGYPT)
WE LIVE IN A WORLD OF GUIDELINES
FOR MANAGING T2DM
AACE/ACE GUIDELINES
2009, 2013

36. “Getting to Goal”
Job done

37. ©LeicesterDiabetesCentre2012
GUIDANCE Study 7,597 T2DM patients
Gap exists between checking HbA1c and achieving target
HbA1c <7%
Stone MA et al. Diabetes Care. 2013 ; 36: 2628-38
Percent

38. “Failing to deliver
HbA1c targets”
“Guidelines”
“Is this the fault
of guidelines?”

40. Barriers to Diabetes Care
Clinical Practice
Therapeutic RegimenDisease Process
Patient Adherence

41. 7
6
Diagnosis +5 yrs +10 yrs + 15 yrs
9
8
Diet +
Metformin
Treatment ApproachesHbA1C%
Failure based treatment
of symptoms approach
HbA1C < 7% approach
Campbell. Br J Cardiol 2000; 7: 625-31
Clinical Practice
OHA 3 INSULIN
COMPLEX
INSULIN

42. DiabetesSeverity
Treatment Burden 
Pre-diabetes
Diabetes
progression
Adjuvant
therapy
with insulin
Insulin
resistant
states
Diagnosis
of
diabetes
Normal
Mono
therapy
Dual
tablet
therapy
Insulin
therapy
Progressive nature of diabetes means stepwise
increase in therapies to achieve optimal
outcomes in management

43. Antihyperglycaemic therapy in type 2
diabetes : ADA / EASD recommendations
Inzucchi SE et al. Diabetes Care 2015;38:140-149
Metformin
High Efficacy
Low risk of Hypos
Weight neutral/loss
GI/Lactic acidosis
Low cost
Reduces CVD events
Metformin

44. Diabetes-related deaths
All –Cause Mortality
Myocardial Infarction
UKPDS 80. NEJM 2008; 359: 1577-89
CV Complications and
Survival reduced
versus other therapies
UKPDS 34. Lancet 1998; 352: 854-65
POST-Trial
Monitoring
1997 - 2007
-30%
-27%
-33%
-42%
-36%
-39%
UKPDS Trial
Intervention
1977 - 1997
CV Complications and
Survival reductions
maintained
Legacy
effect
UKPDS Rury HolmanRobert Turner
Clinical Outcomes
for Metformin

45. Clinical Outcomes for
glibenclamide 1977-1997
Heart Attack F/NF (n=21)
Complications
Microvascular
Complications
 18%
Reduction
(p=0.018)
 22%
Reduction
(p=0.056)
 34%
Reduction
(p=0.017)
UKPDS
UKPDS 33 Lancet 1998; 352: 837-53
ADVANCE : Reduction of new and progressive nephropathy with gliclazide
ACCORD : Glimepiride

46. ADA-EASD
Audit of Anti-Diabetic Agents
Titration of Metformin
1) Start low – 500mg/day
2) Increment slowly – 2000mg/day
3) Reduce dose if GI side effects develop
4) Maximum dose is 3000mg/day given bid, tid
5) Consider once-a-day longer acting
formulation if standard metformin is not
suitable
2006 2008 2009
Metformin XR from 2005 onwards in the UK

47. UK Clinical Experience
with Metformin XR
 Retrospective chart review
 Prospective follow-up


Isle of Wight
Liverpool


London
Clatterbridge
Feher. Br J Diabetes Vasc Dis 2007; 7: 225-8
To determine
if patients with a history
of metformin intolerance
could tolerate 2000mg
extended release
metformin

48. Metformin XR – Tolerability Results
UK
Location
Liverpool
Isle of Wight b
Clatterbridge
London
Patient
No
22
24
28
21
(46)
(54)
(62)
(82)
(11)
(90)
(30)
(7)
(10)
a Tolerant < 1.5g/day b 2 patients lost to follow-up c Tolerant with minor symptoms
10
12a
15
23
3c
19
-
-
7
2
-
2
Tolerant
No (%)
Intolerant
No (%)
Feher. Br J Diabetes Vasc Dis 2007; 7: 225-8

49. Metformin XR once daily
and improved adherence
Donnelly LA. Diabetes ,Obesity and Metabloism 2009;11:338-342
Diabetes Audit and Research Centre in tayside, Scotland

50. Switchover to Metformin XR improves
adherence in routine general practice
20
40
60
80
100
Adherence(%)
P<0.0001
P=0.074
Adherence HbA1c
7.0
9.0
10.0
8.0
HbA1c(%)
Donnelly LA. Diabetes,Obesity &Metabolism 2009;11:338-342
Metformin Metformin XR

51. Issues with Metformin
Divided dosing Regimen
Tolerability
Contraindications (1970’s) USA
(PHENFORMIN)
Metformin XR

52. eGFR level
(ml/min per 1.73 m2)
Action
> 60
No renal contraindication to metformin
Monitor renal function annually
< 60 and > 45
Continue use
Increase monitoring of renal function
(every 3-6 months)
< 45 and > 30
Prescribe metformin with caution
Use lower dose (e.g., 50%, or half-maximal dose)
Closely monitor renal function (every 3 months)
< 30 Stop metformin
Lipska KJ et al. Diabetes Care 2011;34:1431-1437
Frid A et al Diabetes Care 2010;33:1291-1293

53. 2010
2010
2010
2011
2009
2009
2008
Metformin reduces risk of heart failure
and improves survival of those with HF
METFORMIN REDUCES
THE INCIDENCE OF NEW
HEART FAILURE
METFORMIN IMPROVES
SURVIVAL IN PATIENTS
WITH HEART FAILURE
Papanas N. Expert Opin Pharmacother 2012; 13: 1-8
N = 3
N = 11
*
*
*
*

54. Guideline support
for metformin use in Heart failure
1/. Canadian Diabetes Association recommend metformin
as first –line therapy in HF Can J Diab 2008;32(suppl1):S1-S200
2/. FDA in the US have removed HF as an absolute
contraindication to metformin Inzucchi N. Diabetes Care 2007;30:e129
3/. American Diabetes Association support the use
of metformin in stable HF provided renal function is normal
ADA Standards of Medical Care. Diabetes care 2011;34(suppl1) :S11-S61

55. Antihyperglycaemic therapy in type 2
diabetes : add-on therapy to metformin
Inzucchi SE et al. Diabetes Care 2015;38:140-149
Metformin

56. ADD –ON Therapies to Metformin
Drug Class HbA1c Advantages Disadvantages
Sulfonylureas 1.5% Long experience
Microvascular risk
reduced (UKPDS)
Low cost
Hypoglycaemia
Weight gain
MI preconditioning blunted ?
Low durability
TZDs 0.5-1.5% No hypoglycaemia
Durability
Raises HDL Chol
Weight gain
Oedema/Heart failure
Bone fractures
Raises LDL Chol (Rosi)
DPP-4 inhibitors 0.5-1.0% No hypoglycaemia
Well tolerated
Urticaria
Acute Pancreatitis ?
Heart Failure hospitalisation ?
GLP-1 agonists 1.5-2.0% No hypoglycaemia
Well tolerated
GI side effects
Acute pancreatitis ?
Thyroid neoplasm ?
SGLT2 Inhibitors 0.5-1.0% No hypoglycaemia
Weight loss
Blood pressure fall
Genitourinary infections
Polyuria
Volume depletion/hypotension
Raises LDL Chol
Your clinical judgement
and how important are these in your
clinical assessment:
Risk of Weight gain
Risk of Hypoglycaemia
Severity of co-morbidities
Long-term safety of new agents
Cost of medication to the patient
Adapted from Inzucchi SE et al Diabetologia 2015 ; 35: 140-149

57. IDF treatment algorithm to aid drug selection
in treatment programmes worldwide
www.idf.org/treatment-algorithm 2011-people-type-2-diabetes
and Global guidelines for type 2 diabetes 2012
SIMPLE TO FOLLOW
LOW COST

58. SAFETY AND
LONG-TERM USE
Clinical experience with Sulfonylureas
Sulfonylureas 58 years
Thiazolidinediones 15 years
Incretin agents 8 years
SGLT2 inhibitors 2 years

59. “Conclusion: in this nationwide registry of patients hospitalised for acute MI,
no hazard was associated with the use of SUs before the acute episode”
MORTALITY RISK OF SULFONYLUREAS
IN HIGH RISK PATIENTS PRE- MI
Antidiabetic
medication
%
mortality
Sulfonylureas 3.9%
Other OHAs 6.4%
Lifestyle 8.4%
Insulin 9.4%
FRANCE

60. Safety Issues
Sulfonylureas and Hypos
GLP1’s and GI disturbances
Pioglitazone and Bladder Cancer
Rosiglitazone and MI
DPP4’s,Heart failure & Mortality
SGLT2’s and Genital Infections
Pancreatitis

61. Incretin based therapies
and pancreatitis ( NIH sponsored )
Singh et al. JAMA Intern Med Feb 25th 2013 online doi:10.1001/jamainternmed.2013.2720
Gale EAM. BMJ 2013; 346:9
Population based study of 1269 patients
admitted to hospital with acute
pancreatitis matched with 1269 controls -
all T2DM.
Patients treated with GLP-1 drugs were
at twice the risk of developing
pancreatitis.
Long-term adverse effects of the GLP-1
class on the exocrine pancreas have yet
to be assessed accurately

62. EXAMINE
New CV outcome data for
the DPP4 inhibitors
S
V
O
R
Multicentre DB Randomised placebo controlled trials
White WB et al. N Engl J Med 2013 , 2nd September
Scirica BM et al. N Engl J Med 2013, 2nd September
No signal of increased CV
death, MI or stroke over
1.5 years (Examine) and 2.1 years
(SAVOR) follow-up.
but alSO ......no evidence of CV
BENEFIT and a 29% increased rate
of heart failure leading to
hospitalisation (saxagliptin).
Alogliptin
(n=5,380)
Saxagliptin
(n=16,492)

63. Saxagliptin, Alogliptin and Cardiovascular Outcomes
Letters to the Editor NEJM 2014; 370;483-484
“Alogliptin neither induced new –onset
heart failure nor worsened heart failure
in patients with a history of heart failure
after randomisation”
Post –publication analysis :
19% increase in HF hospitalisation that was non -significant

64. Heart Failure related Hospitalisation (SAVOR)
Unexpected safety signal not seen in pre-clinical
or pre-marketing studies. Why?- sicker patients !!
On-treatment analysis showed greater all-cause mortality
for saxagliptin. Why?
Major CV events in subgroups ( EXAMINE)
Increased CV risk in patients with renal impairment
diabetes duration > 10 years, or those on insulin. Why?
Endocrinologic and metabolic Drug Advisory Committee meeting April 14th 2015
FDA requests informed advice on benefit risk profile
of the DPP4 inhibitors – saxagliptin and alogliptin

65. Heart Failure for both gliptins
Change in labelling to improve safety profile
To undertake mechanistic studies to determine cause (sNDA)
All Cause Mortality ( saxagliptin)
Change in labelling to inform about unfavourable
renal changes
Endocrinologic and metabolic Drug Advisory Committee meeting April 14th 2015
Advice to the FDA on benefit risk profile
of the DPP4 inhibitors – saxagliptin and alogliptin
Change in labelling to improve safety profile
Renal impairment ( alogliptin)
WATCH OUT FOR TECOS AT ADA 2015

66. UKPDS
Therapy Major All
Lifestyle 0.1% 1.2%
glibenclamide 0.6% 17.7%
Insulin 2.3% 36.5%
UKPDS 33. Lancet 1998;352:837–853.
Add- on therapies to metformin
Safety Issues
glibenclamide/insulin & Hypos

67. Medications Most Commonly Associated with
Emergency Admissions in Patients >65 Years of Age
0%
5%
10%
15%
20%
25%
30%
35%
0
5,000
10,000
15,000
20,000
25,000
30,000
35,000
Percentageofadmissions
Numberofhospitaladmissions
Budnitz et al. N Engl J Med 2011;365:21
Data given are number and percentage of annual national estimates of hospitalisations. Data from the NEISS-CADES project.
ER visits n=265,802/Total cases n=12,666

68. Sulfonylureas and Hypos - solutions
REFORMULATION PATIENT SELECTION

69. SlametSSlametS
0 2 4 6 8 10 12
0
20
40
60
80
Plasmaglibenclamide(mg/L)
Time after dosing (h)
Metformin / Glibenclamide
FDC tablet
Metformin + free glibenclamide
co-administered tablets
Donahue et al. Clin Pharmacokinet 2002;41:1301-9
Met / Glib FDC tablet versus Metformin + free
glibenclamide co-administered ( Kinetics)
Lower
PPBG
Less
hypos Met + Glib Met / Glib
Mean AUC ( ug.h.L ) 434 431
Equivalent systemic exposure

70. Donahue et al. Clin Pharmacokinet 2002;41:1301-9
0
20
40
60
80
100
120
140
Met+Glib Met / Glib FDC
PostPrandial
GlucoseExcursion(mg/dl)
P=0.012
24%
Reduced postprandial glucose excursions
0 2 4 6 8 10 12
0
20
40
60
80
Plasmaglibenclamide(mg/L)
Time after dosing (h)
Metformin/ Glibenclamide
FDC tablet
Metformin+ Glibenclamide
Co-Administered
Met / Glib FDC tablet versus Metformin + free
glibenclamide co-administered – glucose lowering

71. Optimisation of Therapy
- Barriers to Diabetes Care
Disease Process
Therapeutic RegimenClinical Practice
Patient Adherence

72. Identical twins
Which one is adherent ?

73. C 2015 American Diabetes Association
Kirkman MS et al. Diabetes Care 2015 January 8th. DOI:10.2337/dc14-2098
Retrospective analysis (n >200,000) of T2DM on oral agents
Adherence defined as 80% plus of prescribed medication
Determinants (modifiable)
Duration of diabetes Pill burden -polypharmacy
Source of medication (GPs) Level of Education
Out-of-pocket expenses Income
Determinants ( non-modifiable)
Age Gender
RESULT = 67%

74. Available Fixed Dose Combinations
to reduce tablet burden
Product Drug Components Dosage strengths
Glucovance Metformin + glibenclamide 250/1.25 500/2.5 500/5.0 1000/5.0
Metaglip Metformin + Glipizide 250/1.25 500/2.5 500/5.0
Amaryl M Metformin + Glimepiride
Competact Metformin + Pioglitazone 500/15.0 850/15.0
Galvusmet Metformin + Vildagliptin 850/50 1000/50
Janumet Metformin + Sitagliptin 850/50 1000/50
Tandemact Pioglitazone + glimepiride 30/4.0 45/4.0
Bailey CJ Day C. Diabetes Obes Metab 2009; 11: 527-33
Schernthaner G. Diabet. Med 2010; 27 : 739-743

75. Expanding role of FDCs
UK Polypill Trial - 2010
Aspirin 75mg Simvastatin 40mg
Lisinopril 10mg Atenolol 50mg

76. How can we improve the achievement of
HbA1c targets?
Developing quality
measures
Education (CME)
Motivating and
supporting patients
on self-management
Personal
feedback to
HCPs
Adherence to
guidelines
Adherence to
medications
Effective use of
information
system
Zafar et al. Primary Care Diabetes 2010;4:203–7
CME, continuing medical education; HCP, healthcare practitioner

77. Conclusions
1/. Be aware that multiple barriers hinder optimisation of
glycaemic control.
2/. Metformin continues to be under-utilised.
3/. Add-on therapies to metformin fall into six categories
and therapy should be individualised.
4/. Adherence is not optimal and solutions include fixed dose
combination tablets and once-a-day tablets.
5/. Recognise that diabetes is a chronic illness that requires much
self-management, and minimise the 125 Billion Euros waste (WHO)
that accompanies long-term diseases

78. Quick Reminder of 4 barriers
Disease – Treatment Regime
Physician and Patient
Can you spot the odd one out ?

79. Me
At
work

80. Me
At home

81. I need urgent
Ophthalmology consultation

83. THANK YOU
DR./ ADEL EL NAGGAR