DIABETES IS A PROGRESSIV DISEASE AND WE NEED TO STAY ONE STEP AHEAD OF THE DISEASE.WE HAVE TO TITRATE THE MEDICATIONS EVERY THREE MONTHS AND THE TIME IS NOT OUR FRIEND AS FAR AS THE MANAGEMENT OF DIABETES IS CONCERNED

1. WHAT’S AFTER 3x PM
DR.RISHIKESAN K.V
SPECIALIST PHYSICIAN
VENNIYIL MEDICAL CENTRE
SHARJAH

2. Aims
To discuss the wide range of options for the sequence
of medications that should follow the ubiquitous
first – line use of Metformin in patients with
TYPE 2 DIABETES.

3. Learning Objectives
• Discuss the anti hyperglycaemic medications available
to physicians whose patients are not at their A1C goal
following Metformin and Lifestyle modification
• Learn the pros and cons of each medication.
• Select which medication we would prescribe to the fictional
patient mentioned here in this presentation

4. A 50 Y. old female visits your office to f/u her T2D. Her current medications include
Metformin 1000mg. BID, Lisinopril 10mg. and Atorvastatin 40mg. The most recent
HbA1C is 8.6 ; rest of her labs are within acceptable range. Which of the following
medications would you add to this patient’s regimen?
DPP-4 INHIBITORS
SULPHONYL UREA
BASAL INSULIN
TZD
SGLT-2 INHIBITORS
GLP-1 RA

5. Target HbA1c
American Diabetes Association (ADA) guidelines for
HbA1c targets
- <7% for most patients
- <6.5% for younger patients without comorbidities
- <8% for older patients with multiple comorbidities
The goal for our patient is 7%
https://doi.org/10.2337/dc15-S009

6. ADA / EASD Recommendations for
HbA1C

7. Is It easier to treat T2D today than it was 10 years ago ?
YES , it is easier now
NO, it has become harder

8. Background
• Nearly 50% of patients with T2D have an HbA1c above the target of
7%
• The combination of lifestyle management, with or without
metformin is recommended as the initial treatment for patients
with newly diagnosed T2D.
Inzucchi SE, et al .Diabetes Care.2015;38(1):140-19

9. Anti hyperglycaemic Therapy in T2D: General
Recommendations
• First-line therapy : Life style modification and
Diabetes self – education
• First-line medication: Metformin
• Metformin is a “No-Brainer”
• Even Metformin which is pretty much universally used first line is
not the ideal therapy for every one

10. For Profoundly Insulin Sensitive……
• For the patient who is profoundly insulin sensitive, Metformin may
not be the drug of choice
• Gastrointestinal tolerability is a clinical issue
• B12 Deficiency

11. Why Metformin?
• Metformin is safe
• Low risk of hypos
• Efficacious
• Affordable, low cost
But additional agents are often necessary to achieve adequate
glycaemic control
Skolnic N, Jaffa F, Kiriakov Y. J Fam Pract.2017;66(4)S4-S9

12. Metformin Advantages
• Metformin should remain a first-line therapy because its effect on
HbA1c is similar to other medications.
• Metformin has a long-term safety profile,
• It's weight neutral or helps people lose weight,
• It has gastrointestinal side effects but they are avoidable or tolerable
• Of course metformin looks better for cardiovascular mortality than
sulfonylureas

13. Metformin- FDA Label Update (2016)
• Contra indications of Metformin may be contradicted
• Expand metformin’s use in certain patients with reduced kidney
function
• Review of studies showed that metformin can be used safely in
patients with mild to moderate impairment in kidney function

14. Metformin and Renal Function
CKD STAGE eGFR, mL/min per 1.73sq.m Maximum total daily
dose, mg
1 More than or equal 90 2,550
2 60 -- < 90 2,550
3A 45 -- < 60 2,000
3B 30 -- < 45 1,000
4 15 -- < 30 Do not use
5 < 15 Do not use

15. The Continued Role of Metformin
Metformin remains as first line therapy if there are no
contraindications or intolerance .
- Extended release formulations may be better tolerated for some
patients
- Can be combined with other anti hyperglycaemic agents.
Favourable CV benefits seen with Metformin in UKPDS
ADA. Diabetes Care 2017;40(suppl 1):S1-S135
Garber AJ, et al. Endocr Pract 2017;23: 207-238
UKPDS Group. Lancet.1998;352:837-858

16. Clinical inertia
• It can take approximately 2 years to intensify therapy when patients
are not to goal on a single medication.
• An average of 7 years it may take ,when patients are not to goal on
2-3 oral medications.
Khunti K, et al. Diabetes Care.2013;36(11):3411-3417

17. ADA / EASD and AACE / ACE Guideline
Recommended several classes of antihyperglycaemic
medications for patients who have not achieved adequate
glycaemic control with metformin and life style management
alone

18. Criteria for Choosing Next Add-on Medications
• A1C Efficacy
• Hypoglycaemia Risk
• Weight Considerations
• Tolerable Side Effects and Adverse event Profiles
• Cost
These are the important attributes to second line therapy
Inzucchi S, et al.Diabetes Care.2015;38:140-149

19. Diabetes Oral Treatment Progression
ADA algorithm
-Metformin+ life style
-2nd oral agent based on patient profile
-3rd oral agent or injections
- Insulin by 1 year if not at goal
The favorable pattern
- Metformin + life style
- Cost is an issue – METFORMIN - SUs – PIOGLITAZONE
- Treatment preferences: Metformin-Pioglitazone-SGLT-2 inhibitor or
DPP-4 inhibitor

20. How many oral diabetes agents will you typically use before you
recommend an injection therapy for your patient ?
NONE , I START INJECTIONS DIRECTLY
ONE
TWO
THREE
I TRY TO AVOID USING INJECTION THERAPIES

21. The Sulfonylureas : better than nothing
• The most commonly prescribed second line agent for T2D
• If a patient still has lots of Beta cells , SUs can have nice effects in
lowering blood glucose
• But they cause
Weight gain
Hypoglycaemia
What really drives SU use is the cost
If a patient cannot afford anything else , they are better than nothing

22. SUs : Pros and Cons
HbA1C REDUCTION APPROXIMATELY 1%
GLYCAEMIC DURABILITY LIMITED
EFFECT ON WEIGHT INCREASE APPROX. 2.2KG
RISK OF HYPOGLYCAEMIA MODERATE
COST LOW
OTHER SAFETY CONCERNS
SULFONAMIDE HYPERSENSITIVITY , HYPOGLYCAEMIA,
HAEMOLYTIC ANEMIA, WEIGHT GAIN
Bolen S, et al. Agency for Healthcare Research and Quality.2016

23. ADA Algorithm
ADA Diabetes Care.2017;40 (suppl 1):S1-S135

24. Intensifying Glucose Lowering Therapy

25. Pioglitazone
This is not used much anymore, however IT IS NOT A TOTAL NON STARTER
It can be used in a patient population that is insulin resistant
It lowers TG
Raises HDL
It has benefits for NASH
May have some cardiovascular benefits
We know about its weight gain , and risk of heart failure, edema and fracture
risk
It is a potential add-on therapy that can have efficacy which outweighs safety
in some patients

26. TZDs
HbA1c REDUCTION APPROXIMATELY . 4 - . 9%
GLYCAEMIC DURABILITY GOOD
EFFECT ON WEIGHT INCREASE
RISK OF HYPOGLYCAEMIA LOW
COST LOW
ADVANTAGES ASSOCIATED WITH IMPROVEMENT IN HDL, TGs; MAY REDUCE THE RISK OF
RECURRENT CVA IN PATIENTS WITH INSULIN RESISTANCE BUT W/OUT DM
OTHER SAFETY CONCERNS HEART FAILURE, ISCHEMIC CARDIAC EVENTS, HEPATIC FAILURE, BLADDER CA,
EDEMA , WT.GAIN, FRACURES, MACULAR EDEMA, DECREASED Hb/Hct,
HYPOS WITH SU OR INSULIN
Bolen S, et al. Agency for Healthcare Research and Quality.2016
Lincoff AM, et al.JAMA2007;298(10):1180-1198

27. DPP-4 Inhibitors: MoA
• Inhibits the degradation of Glucose- dependent Insulinotropic
Polypeptide (GIP) and Glucagon-like peptide (GLP-1)
• Increases GIP and GLP-1 (INCRETIN) levels
• Inhibits glucagon release
• Increases Insulin secretion
• Decrease glucose levels
Thornberry NA, Gallwitz B. Clinical Endocrinology and Metabolism.2009;23(4):479-486

28. DPP-4 INHIBITORS
These are exceptionally tolerable agents
The efficacy may not be as great as the GLP-1 agonists
The risk of hypoglycaemia is low
They are weight neutral

29. DPP-4 Inhibitors
HbA1C REDUCTION APPROX . 0.4 – 0.5%
GLYCAEMIC DURABILITY GOOD
EFFECT ON WEIGHT NO CHANGE
RISK OF HYPOGLYCAEMIA LOW
COST HIGH
ADVANTAGES SAFETY AND TOLERABILITY
OTHER CONCERNS ACUTE PANCREATITIS, ARF, ALLERGIC AND HYPERSENSITIVITY
REACTIONS, ARTHRALGIA , CHF, HEPATIC FAILURE, HYPOS WITH SU
OR INSULIN
Skolnik N, Jaffa F, Kiriakov Y. J Fam Pract.2017;66(4):S4-S9

31. DPP-4 Inhibitors are a good choice in Elderly
Vildagliptin 100 mg daily resulted in better glycemic control, tolerability,
and fewer adverse events compared with metformin 1,500 mg daily in
drug-naive elderly patients with type 2 diabetes .
Vildagliptin is effective and well-tolerated in type 2 diabetic patients aged
75 years or older .
Sitagliptin also provides similar glycemic improvement with less
hypoglycemia in the elderly with type 2 diabetes compared to sulfonylurea.
In older adults with type 2 diabetes, reductions in HbA1c after treatment
with a DPP-4 inhibitor were not different from those in younger patients.
Treatment with DPP-4 inhibitors in older diabetic adults was associated
with a low risk of hypoglycemia, and these agents were weight neutral .

32. DPP4-Inhibitors Combination Therapy
• Sitagliptin/Metformin
• Saxagliptin/Metformin
• Linagliptin/Metformin
• Linagliptin/Empagliflozin
• Alogliptin/Metformin

33. The SGLT2 inhibitors
• They have got a non –insulin – dependent mechanism of action that is
highly applicable across the broad spectrum of Diabetes patients
• Their Glucose lowering efficacy is similar to the DPP-4 Inhibitors
• They have the benefit of promoting moderate weight loss
• They present “no hypoglycaemia risk”
• “Volume – related aspects” need to be considered when using these
agents

34. SGLT-2 Inhibitors: Summary of Physiologic Effects
Glucoretic effect of 60-80 grams of Glucose per day = 240-320
kcals/day
Typical weight reduction approx. 2-4 kg
Typical SBP reduction approx. 3-5 mmHg
2/3 of weight loss = adipose tissue
1/3 of weight loss = lean tissue
Of adipose tissue loss ½ = visceral fat; ½ = subcutaneous fat
DeFronzo RA, et al.DiabetesSpectrum.2014;27(2):100-112

35. Empagliflozin a Game
Changer ?

36. EMPA-REG OUTCOME: Which outcomes were observed in the study of
7020 patients with median follow up of 3.1 years
> 30% reduction in all cause mortality
>30% reduction in CV mortality (primary outcome)
>30% reduction in hospitalisation for CHF
All of the above

37. EMPA-REG OUTCOME
• Empagliflozin , the game changer SGLT2 inhibitor has got an
exceedingly impressive mortality data.
• 60% of our diabetes patients die from cardiovascular disease
• The recent update by Canadian Diabetes Association clinical practice
schedule states that if your diabetes patient has CVD you should
consider a SGLT2 inhibitor as second-line after Metformin
• Preventing cardiovascular death trumps any other parameter.

38. SGLT-2 Inhibitors Precautions
Genital mycotic infection rate approx. 5% in males, approx. 10% in
females
Bacterial UTI minimally increased
Orthostatic symptoms more common in:
-Age > 75 years of age
- eGFR 30- < 60mL/min/1.73sqM
- Patients using loop diuretics
Taylor SR & Harris KB.Pharmacotherapy.2013;33(9):984-999

39. SGLT-2 Inhibitors
HbA1C REDUCTION APPROX 0.5 -1%
GLYCAEMIC DURABILITY EXCELLENT
EFFECT ON WEIGHT DECREASE APPROX . 2 - 4 KG
RISK OF HYPOGLYCAEMIA LOW
COST HIGH
ADVANTAGES WEIGHT LOSS, BP REDUCTION, CVO STUDY SHOWED A SIGNIFICANT
REDUCTION IN COMPOSITE MACE OUTCOME, AS WELL AS ALL CAUSE
MORTALITY
OTHER SAFETY CONCERNS SEVERE RENAL IMPAIRMENT, ESRD, DIALYSIS, HYPOTENSION, KETOACIDOSIS ,
AKI/RENAL IMPAIRMENT, HYPERKALAEMIA, UROSEPSIS/PYELONEPHRITIS,
GENITAL MYCOTIC INFECTIONS, LDL RISE, BLADDER CANCER, BONE FRACTURE,
HYPOS WITH SU OR INSULIN, LEG AND FOOT AMPUTATION (canagliflozin)

40. GLP-1 RAs
WHAT ARE THE GLP-1 RAs?
 Class of injectable diabetes medications for T2D
What does GLP-1 RA stand for ?
 Glucagon-Like Peptide -1 Receptor Agonist
Some times called
 GLP-1 analogs
 Incretin mimetics .

41. The Newer Kids on the
Block
• Their efficacy is high
• They are applicable across a broad
spectrum diabetes patients
• They have a tendency to promote weight
loss
• Got a positive favourable factor for a
patient with insulin resistance.
• They have got a promised Cardiovascular
benefits as hinted at by LEADER
• However GI tolerability is a major clinical
barrier

42. Key Things to Know about GLP-1 RAs
Stimulate Glucose Dependent insulin secretion
- Results in very low rates of hypoglycaemia
All injectable – tools vary by products
Important warnings
- Pancreatitis
- Medullary Thyroid Cancer/MEN 2 Syndrome
- Gastroparesis
- Renal disease
Brunton S. The International Journal of Clinical Practice.2014;68(5):557-567

43. Indications for GLP-1 Medications
Second-line or beyond for most with options for combinations
other medications, including basal insulin
AACE algorithm notes as preferred agent with efficacy and
weight loss
Used in T2D to improve blood glucose and A1c

44. Why not always insulin ?
When a patient is on oral and advances to an injection
- GLP-1 RAs are comparable to basal insulin
- GLP-1 RAs often outperform meal-time insulin
 LESS HYPOS
 WEIGHT LOSS RATHER THAN WEIGHT GAIN
- Cost and GI Side effects must be balanced.

45. GLP-1 RA : Advantages over Insulins
• Less Hypoglycaemias
• May be fewer injections
• Less weight gain
• Similar efficacy as Insulin but less side effects

46. Treatment Suggestions
High Fasting Blood sugar
GLP – 1 RA LONG ACTING
LIRAGLUTIDE DAILY (VICTOZA)
EXENATIDE WEEKLY (BYDUREON)
ALBIGLUTIDE WEEKLY (TANZEUM)
DULAGLUTIDE WEEKLY (TRULICITY)
High Post-Prandial Glucose
GLP-1 RA SHORT ACTING
EXENATIDE BID (BYETTA)
LIXISENATIDE

47. GLP-1 RAs
HbA1C REDUCTION APPROX . 5 - 1.3%
GLYCAEMIC DURABILITY EXCELLENT
EFFECT ON WEIGHT DECREASE APPROX 2.5 KG
RISK OF HYPOGLYCAEMIA LOW
COST HIGH
ADVANTAGES WEIGHT LOSS, GOOD DURABILITY, REDUCTION IN SBP AND DBP, DATA TO
SUPPORT REDUCTION IN MACE, MICROVASCULAR EVENTS, NEPHROPATHY(LIRA)
OTHER SAFETY CONCERNS MTC, MENS, THYROID C-CELL TUMORS, PANCREATITIS, RENAL IMPAIRMRNT,
GASTROPARESIS, HYPERSENSITIVITY, N & V, HYPOS WITH SU OR INSULIN, BILE
DUCT /GB DISEASE, DIARRHOEA, INJ.SITE REACTIONS
Bolen S,et al. Agency for Healthcare Research and Quality.2016
Marso SP, et al. NEJM.2016;375(4):311-322

48. Insulin : The Little Black
Dress of Diabetes Therapy
• Insulin remains the safest
alternative after Metformin
when the pancreas starts to tire
• Basal Insulin is a good choice
after Metformin
• We give Metformin to address
insulin resistance , and then we
can use insulin

49. Treatment Suggestions High Fasting Glucose
Basal Insulin
 Detemir
 Glargine
 Insulin Glargine equivalent
 Insulin Glargine U 300 (Toujeo)
 Insulin Degludec (Tresiba)
 Insulin NPH

50. BASAL INSULINS
HbA1C REDUCTION THEORETICALLY UNLIMITED
GLYCAEMIC DURABILITY EXCELLENT
EFFECT ON WEIGHT INCREASE
RISK OF HYPOGLYCAEMIA HIGH
COST HIGH
OTHER SAFETY
CONCERNS
HYPOGLYCAEMIA, HYPOKALAEMIA, ALLERGIC REACTIONS, FLUID
RETENSION WITH TZD

51. Individualization
Recognititon of the benefits and limitations of each
class of medications as well as differences among
medications within each class will help clinicians to
customise treatment and improve patient outcomes

52. So What are the Choices?
First: Metformin + Life Style
If HbA1C below 8%, may choose 2nd oral agent
- Pioglitazone, SGLT-2 Inhibitor or DPP-4 Inhibitor, or SU
If HbA1C 8- 10%
- Basal Insulin or GLP-1 RA
If HbA1C above 10%
- Basal Insulin
- Meal time insulin or GLP-1 RA to follow

53. Why not always insulin ?
When a patient is on oral and advances to an injection
- GLP-1 RAs are comparable to basal insulin
- GLP-1 RAs often outperform meal-time insulin
 LESS HYPOS
 WEIGHT LOSS RATHER THAN WEIGHT GAIN
- Cost and GI Side effects must be balanced.

54. Basal Insulin/ GLP-1 RA Combination Medications
Two Promising combinations have
received the FDA-approval
• IDegLira : Combination of degludec and
liraglutide
• IGlarLixi : Combination of glargine and
lixisenatide
These combinations are appealing
because of
• Their high efficacy
• They are weight neutral
• They won’t be fit for all

55. Basal Insulin/GLP-1 RA Combination Medications
Advantages
Highest efficacy
Weight loss
No added hypoglycaemic risk
compared to basal insulin
Fewer GI side effects than GLP-1 RA
Disadvantages
Hypoglycaemia
GI side effects - fewer than GLP-RA
Maximum basal insulin dose
(Fixed combination product)

56. Clinical Pearls from CVOT Data
TYPE 2 DIABETES
METFORMIN 1000mg.TWICE DAILY
DPP-4 INHIBITOR GLP-1 RA SGLT-2 INHIBITOR
WELL TOLERATED IN PATIENTS WITH CVD
(LIRAGLUTIDE)
IN PATIENTS WITH CVD
(EMPAGLIFLOZIN)
WEIGHT NEUTRAL WEIGHT LOSS H/o HEART FAILURE OR AT RISK
OF HEART FAILURE
LOWER BLOOD PRESSURE WEIGHT LOSS
LOWER BLOOD PRESSURE

57. Conclusion
Skolnic N, Jaffa F, Kiriakov Y. J Fam Pract.2017;66(4)S4-S9

58. Summary and Key points
Many reasonable choices for additional therapy when a patient
is not at goal on Metformin
Key point 1: Individualise additional therapy
• The mantra is to individualize
• It is called patient centric therapy
Key point 2: Do something rather than succumb to clinical inertia
• The delay in intensifying therapy when a therapeutic goal is not achieved
• May reflect confusion about the next medication.
• May be the misconceptions/ perceptions about risk , and side effects.
• The general hesitancy to escalate therapy

59. Take Home Message
• Diabetes is a very progressive disease
• Time is not our friend
• We need to stay one step ahead of the disease
• Many choices including complementary oral therapies
• Titrate every three months
• We typically take too long to intensify therapy
• Consider using injectables earlier

60. References
1.Inzucchi SE, et al .Diabetes Care.2015;38(1):140-19
2.Skolnic N, Jaffa F, Kiriakov Y. J Fam Pract.2017;66(4)S4-S9
3.ADA. Diabetes Care 2017;40(suppl 1):S1-S135
4.Garber AJ, et al. Endocr Pract 2017;23: 207-23
5.UKPDS Group. Lancet.1998;352:837-858
6.Khunti K, et al. Diabetes Care.2013;36(11):3411-3417
7.DeFronzo RA, et al.DiabetesSpectrum.2014;27(2):100-112
8.Taylor SR & Harris KB.Pharmacotherapy.2013;33(9):984-999
9.Bolen S, et al. Agency for Healthcare Research and Quality.2016
10.Bolen S,et al. Agency for Healthcare Research and Quality.2016
11.Lincoff AM, et al.JAMA2007;298(10):1180-1198
12.Bolen S,et al. Agency for Healthcare Research and Quality.2016
13.Marso SP, et al. NEJM.2016;375(4):311-322
14.Brunton S. The International Journal of Clinical Practice.2014;68(5):557-567
15.Thornberry NA, Gallwitz B. Clinical Endocrinology and Metabolism.2009;23(4):479-486