1. Management of Diabetes
Ranjna Garg
Consultant Physician and Diabetologist
Princess Alexandra Hospital NHS Trust

2. The pathophysiology of T2DM
Insulin deficiency
Islet
Alpha cell
produces excess glucagon
Beta cell
produces less insulin
Pancreas
Diminished insulin
Liver
Diminished insulin
Excess glucose output
Beta-cell dysfunction is a major factor that contributes to the pathology and occurs across the spectrum of the disease from prediabetes to diabetes. Beta-cell dysfunction develops early in the pathologic process and does not necessarily follow the stage of insulin resistance.
Hyperglycemia
Muscle and fat
Insulin resistance (decreased glucose uptake)

3. Step up Approach Oral Diet and life style GLP-1RA + GLP -1RA Or
Insulin
GLP-1RA

4. Balancing the risk Hyperglycemia Hypoglycemia
Limits tightening diabetes control
Increased risk for hypoglycemia
Significant problems in people with diabetes
Driving
Long duration of diabetes
Reduced awareness

5. Management of Hypergycemia: Approach
Not
Modifiable
Modifiable
Diabetologia. 2015;58(3)

6. NICE Targets in Type 2 Diabetes
HbA1c 6.5% (48 mmol/mol)
Diet and first 2 treatment steps
On drugs not associated with hypoglycemia
HbA1c 7.5% (53 mmol/mol)
On drugs associated with hypoglycemia
Individualized HbA1c target of 7.5% or more
Older
Risk of hypoglycemia or reduced awareness
Unlikely to achieve long term risk reduction benefit ( reduced life expectancy)
Multiple comorbidities

8. Diabetes Management:Recommendation
ADA, EASD, Diabetes UK, IDF
Target HbA1C : 48 :With “good functional status”
HbA1C < appropriate
Individualized care
BP: 140/80 unless microvascular complication (130/70)
Lipids: TC < 4, LDLC < 3, TG < 2, HDL >1
ACR: Check annually, repeat within a month if abnormal (once UTI is R/O)
Creatinine: yearly, Calcium and PTH if creatinine abnormal
Eye : yearly at least
Feet: regular yearly, unless neuropathy: Regular podiatrist
Yearly TFT in all
Pre conception advise to women in productive year
Effective contraception/pre pregnancy counseling: folic acid
Aspirin: Not for primary prevention
50 years or more Treated HT --Previous vascular disease

9. Setting targets: How Diabetes Duration Life expectancy Comorbidities
Established cardiovascular comp;ications
Patient attitude and treatment engagement
Resourecs and support system
Risk of hypoglycaemia and adverse effects

10. Case

11. Case 48 year female, BMI 31 AF, HT
School teacher, Sedentary life style
Type 2 DM diagnosed 2 weeks ago
HbA1C 62 mmol, BG between mmol/l
BP 156/88,
eGFR >78
Agents: ? which

12. Case
Target: A1C :
Aim: Good glycemic control + risk factor optimisation
BP (140/80) and lipid control
Weight management
Agents Options:
Metformin SU
DPP-IV
SGLT-2RI
GLP-1
Insulin

13. Case Metformin Life style adv Structured education Target: A1C : 48
Aim: Good glycemic control + risk factor optimisation
BP (140/80) and lipid control
Weight management
Agents Options:
Metformin SU
DPP-IV
SGLT-2RI
GLP-1
Insulin
Metformin
Life style adv
Structured education

14. Who should receive Metformin?
Overweight and obese patients with Type 2 Diabetes and HbA1c > 6.5%
Probably central obese patients, even if BMI is not elevated
However, tolerability problems in many patients and dose may be limited
Start Low and go slow

15. Metformin A1C reduction 1-2% No risk of hypoglycemia, weight benefit
S/E: GI upset (start low and go slow)
Risk of lactic acidosis
Renal/hepatic failure
Sepsis
Pulmonary disease
hospitalisation
Withhold use
Hospitalisation
Contrast use expected
Pre Operative
Avoid if S Creatinine >130 or eGFR <30 (<45 under supervision) or Cr Clearance <30 ml/min

16. When not to use Metformin?
Progressive CKD – review when eGFR < 45 ml/min
Monitor renal Fx monitoring if continued
Absolutely contra-indicated eGFR <30 ml/min, Creatinine >150mmol/l
Moderate and severe heart failure
Liver failure
Respiratory failure

17. Case: 3 Month check Lost 7 Kg Taken up walking 4 times/week BP 156/88
HbA1C 54
BG between 6-7 mmol/l
eGFR >78
Metformin maximised

18. Progress : 9 months DPP-IV added HbA1C: 64 Weight loss 2.3 kg
Planned review in 6 months
DNA appt
DNA next appt in further 3 months
DPP-IV added

19. DPP-IV inhibitor

20. DPP-4 inhibitors: Flexibility in Treatment Options
Can be used in mono/dual/triple therapy with metformin, sulfonylurea, thiazolidinediones
When administered concomitantly with metformin, their GLP-1-increasing effects are additive
Combination with insulin has been approved

21. DPP-4s - Tolerability & Safety
Well tolerated
None/minimal GI Side effects
Preserve beta cell function
Particularly beneficial in
Overweight patients (weight neutral)
Elderly patients and in diabetics who are at risk of and from hypoglycaemia
Tatjana Ábel, A New Therapy of Type 2
Diabetes: DPP-4 Inhibitors (2012)

22. Case 12 month Target HbA1C : 75 BP: 156/88 Creatinine 110 eGFR 68
T Cholesterol : 5.9
LDL Chol: 4.2
Weight: gained 4 kg
- Hba1C: 48 (6.5%) - BP target 140/80 - T Chol: LDL Chol: Weight: 10% reduction

23. Case: Treatment Option
Glycaemic agents Options:
On Metformin + DPP-IV SU
SGLT-2RI
GLP-1
Insulin

24. Achieving targets: Aims
Weight neutral or positive
Minimal risk of hypo
Oral preferably
Monitoring
Driving

25. What about Suplphonuylurea?

26. Sulfonylurea Enhanced insulin release Risk of hypos, weight gain
Avoid in renal disease
Biliary elimination for Glimpiride (Amaryl): Safe in people with renal impairment
Need for monitoring
Driving: DVLA
Use with caution if
Renal/liver failure
“Start low and go slow”
Erratic/inconsistence meals: risk of prolonged hypos
Poor appetite

27. SGLT-2 RI Case: Options SU: risk of hypos, require BM monitoring
DDP-IV: weight neutral
SGLT-2 inhibitor: weight loss
Glitazone
Suitable for GLP-1
Insulin
SGLT-2 RI

28. SGLT-2 Inhibitor: Summary
Highly selective SGLT2 inhibitor
Action insulin-independent glucose lowering
Associated calorie loss in the urine Weight loss
Significant and sustained in HbA1C reductions
Blood pressure reduction
Low risk of hypoglycaemia
Once a day dosing
Cardiovascular benefits

29. Considerations when prescribing SGLT-2 Inhibitors
Caution in:
- Patients treated concomitantly with pioglitazone
- Patients receiving loop diuretics
- Volume depleted (withhold, if needed)
- Low BP (do not start at same time as anti-HT
- Reduce dose of insulin/SU
- Rec UTI/GU infection

30. Stepwise Management of
Type 2 Diabetes
Biggest Clinical Hurdle???
Insulin
Oral + injectable therapy + +
Oral combination +
βcell deterioration and associated insulin resistance represent a clinical challenge, as many conventional agents by either increasing insulin secretion or enhancing insulin action, maintaining glucose target becomes difficult as cell dysfunction progresses.
Oral monotherapy
Diet &
exercise
Adapted from Williams G. Lancet 1994; 343:

31. Progress : 18 months On Metformin + DPP-IV + SGLT-2RI HbA1C 68
Lost 2.8 Kg weight
Creatinine 138
eGFR 45
BMI 44

32. Case On Metformin + DPP-IV + SGLT-2RI DDP-IV: weight neutral
On SGLT-2 inhibitor: weight loss but declining eGFR: Should not be started but can continue
Glitazone: not suitable as on SGLT-2rI
GLP-1
Insulin
GLP-1RA commenced
Metformin reduced by 50%
DPP-IV Stopped
SGLT cont

33. Other Options ?

34. Case On Metformin + DPP-IV + SGLT-2RI DDP-IV: weight neutral
On SGLT-2 inhibitor: weight loss but declining eGFR: Should not be started but can continue
Glitazone: MI so not suitable
GLP-1
Insulin
Start insulin
Reduce Metformin by 50%
DPP-IV Cont (dose reduced)
SGLT cont

35. Why not Glitazones?

36. Thiazolidinedione  Glucose uptake  Gluconeogenesis  FFA
PPAR-
 Adipogenesis,  Fatty acid uptake
 Glucose uptake,  Adiponectin
 TNF- ,  Resisitin
 Glucose uptake
 Gluconeogenesis
 FFA
 Blood Glucose
Bailey, 2005

37. Thiazolidinedione
PPAR- sensitiser: Reduce insulin resistance (adipose tissue and muscle): Pioglitazone
May preserve -cell function
Slow onset
No risk of hypos in monotherpay
S/E: Fluid retention, weight gain, precipitate heart failure
Avoid in liver disease, people at risk/past Hx of bladder cancer
Risk of fracture: rosiglitazone (withdrawn)

38. Do not use Pioglitazone
Risk or history of heart failure
hepatic impairment
diabetic ketoacidosis
current, or a history of, bladder cancer
Uninvestigated macroscopic haematuria 

39. GLP-1

40. When to use GLP1-agonists
HbA1c >58 mmol/l + oral agents
Overweight
With metformin/Pioglitizone/SGLT2 inhibitors
Stop DPP-4 and Sulphonylurea
Or with basal insulin:
To avoid further weight gain
To reduce hypoglycaemia

41. Limitation of use Not as first-line therapy Not for treatment of
T1DM
DKA/HHS
Not suitable for patients with pre-existing severe gastrointestinal disease.
Contraindicated in patients with medullary thyroid cancer and in patients with multiple endocrine neoplasia 2 (MEN-2)1
FOUR TYPES OF THYROID CANCER
There are four types of thyroid cancer: medullary (a contraindication to GLP-1 agonists), papillary, follicular, and anaplastic.
Medullary thyroid cancer is extremely rare in humans, with 976 cases diagnosed from 1992 to 2006 in the United States, compared with 36,583 cases of papillary and 4,560 cases of follicular cancer. Anaplastic cancer is also rare (556 cases).2 The highest incidence rates of medullary thyroid cancer are in people of Hispanic descent (0.21 per 100,000 woman-years and 0.18 per 100,000 man-years).2
1. Subramanian K 2015 Should we be concerned about thyroid cancer in patients taking glucagon-like peptide 1 receptor agonists? Cleveland Clinic Journal of Medicine Mar;82(3):

42. GLP-1 analogues and DPP-4 inhibitors
(saxagliptin, sitagliptin, vildagliptin)
GLP-1 analogues (exenatide, liraglutide)
HbA1c reduction %
Weight neutral
Oral administration
No significant GI side effects
Low rates of hypoglycaemia
Improved meal-related insulin secretion, reduce glucagon release
HbA1c reduction %
Significant and sustained weight loss generally observed
Injected therapy (once-daily, twice-daily, once-weekly)
GI side effects most common (nausea, diarrhoea, in particular with initiation)
Low rates of hypoglycaemia
This slide compares and contrasts the main characteristics of the GLP-1 agonists and the DPP-4 inhibitor classes of glucose-lowering therapies
Reference:
Kendall DM, et al. Clinical application of incretin-based therapy: therapeutic potential, patient selection and clinical use. Am J Med. 2009;122:S37-S50.
Pancreatitis: Warning is taken off the label now
GI = gastrointestinal; ↑ = increased; ↓ = decreased.
Adapted from Kendall DM, et al. Am J Med. 2009;122:S37-S50. 42

43. Insulin

44. Insulin Used alone or with oral agent Limitation Injection need: carer
Risk of hypos
Injection need: carer
weight gain
Need blood glucose monitoring
Devices use may require dexterity
Visual impairment may cause problems
Risk of hypos in renal failure: reduce dose

45. Insulin All T1DM T2DM later in disease Gestational diabetes
During acute metabolic decompensation
DKA/HHS
During acute illness
Surgery

46. Insulin Type (trade name)
Types of Insulin
2016
Insulin Type (trade name)
Onset
Peak
Duration
Bolus (prandial) Insulins
Rapid-acting insulin analogues (clear):
Insulin aspart (NovoRapid®)
Insulin glulisine (Apidra™)
Insulin lispro (Humalog®)
Insulin lispro U200 (Humalog® 200 units/mL)
min h
1 - 2 h
3 - 5 h h
Short-acting insulins (clear):
Insulin regular (Humulin®-R)
Insulin regular (Novolin®geToronto)
30 min
2 - 3 h
6.5 h
Basal Insulins
Intermediate-acting insulins (cloudy):
Insulin NPH (Humulin®-N)
Insulin NPH (Novolin®ge NPH)
1 - 3 h
5 - 8 h
Up to 18 h
Long-acting basal insulin analogues (clear)
Insulin detemir (Levemir®)
Insulin glargine (Lantus®)
Insulin glargine U300 (Toujeo®)
Insulin glargine (BasaglarTM)
90 min
Up to 6 h
Not applicable
Up to 24 h (detemir h)
Up to 24 h (glargine 24 h)
Up to 30 h

47. Insulin: Duration of Action
Lispro, aspart, glulisine
Regular human
NPH
Detemir
Relative Glycemic Effect
Glargine 12
Hours 24
Can be used in combination with continuing insulin sensitisers:
metformin, Gliptin or glitazones(risk of heartfailure)
Biphasic insulin preparartions (not shown) combine short-acting insulin with neutral protamine Hagedorn (NPH) insulin.

48. Case: 2 years On Metformin, DPP-IV, SGLT 2 and Insulin (Pre Mix BD)
New diagnosed retinopathy and raised ACR
Admitted with hypoglycaemia (BM 3.2)
HbA1C 53
BMI 44
Creatinine 153
eGFR 30

49. What is next On Metformin, DPP-IV, SGLT 2RI and Insulin (Pre Mix BD)
Insulin reduced
SGLT 2RI stopped (renal)
DPP-IV dose adjusted

50. Case: 4 years (Age 52)
DNA few appointments. Developed arthritis and been on/off steroids.
Though working full time, stopped playing golf and admits to being “naughty” when it comes to diet
On Metformin, DPP-IV and Insulin (Pre Mix BD)
Admitted with dense stroke
On PEG feed, bed bound
HbA1C 75 BP 182/96
Creatinine 128 eGFR 46
Statin, Aspirin
Losartan, Amlodipine

51. What is the Target HbA1c? HbA1C < 53 HbA1C < 58
Bianchi C, Del Prato S. Metabolic Memory and Individual Treatment Aims in Type 2 Diabetes – Outcome-Lessons Learned from Large Clinical Trials. The Review of Diabetic Studies : RDS 2011;8(3):

52. The right treatment at the right time
Be mindful of local guidelines
Remember they are guidelines!
Set individual HbA1C targets
Consider side-effects such as hypoglycaemia
When discussing medications consider patient needs, e.g. overweight/obese, erratic lifestyles2
If patients are not achieving their HbA1C target, increase dose (within SPC) or intensify treatment – stop procrastination!
Avoid treatment inertia
Reference:
Nathan DM et al. Medical management of hyperglycemia in type 2 diabetes: A consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009;32:193–203.
NICE clinical guideline 87. Quick reference guide. (Accessed May 2013).
1. Nathan DM et al. Diabetes Care 2009:32:193–203
2. NICE clinical guideline (Accessed May 2013) 52

53. Factors Influencing Choice of Regimen
Is the persons lifestyle variable – shift worker, travel, sports, eating habits, job
Do they have special needs – dexterity, eyesight, cognitive dysfunction
Would they need help in administering insulin
Is weight an issue
Is the number of injections an issue
Is there a particular risk of hypoglycaemia or could hypo put them
at particular risk – elderly, Ramadan
Does a move to insulin affect QoL – occupation, driving regulations
Are there any specific cultural needs or reasons which may affect perception of insulin therapy

54. Diabetes Management:Recommendation
ADA, EASD, Diabetes UK, IDF
Target HbA1C : 48 :With “good functional status”
HbA1C < appropriate
Individualized care
BP: 140/80 unless microvascular complication (130/70)
Lipids: TC < 4, LDLC < 3, TG < 2, HDL >1
ACR: Check annually, repeat within a month if abnormal (once UTI is R/O)
Creatinine: yearly, Calcium and PTH if creatinine abnormal
Eye : yearly at least
Feet: regular yearly, unless neuropathy: Regular podiatrist
Yearly TFT in all
Pre conception advise to women in productive year
Effective contraception/pre pregnancy counseling: folic acid
Aspirin: Not for primary prevention
50 years or more Treated HT --Previous vascular disease

55. Case Aims: Current HbA1C (75) acceptable Reduce/Stop metformin
Minimise further CV risk
Minimise risk of Hypos
Current HbA1C (75) acceptable
Reduce/Stop metformin
Stop SGLT-2ri
Support insulin dose adjustment/delivery

57. Summary Diabetes management: Step up approach
Patients’ need: Changing goal
Individualized care plan

58. Patient-Centered Care Plan
Consider comorbid condition
Identify complications
Establish the patient’s health care goals and preferences for treatment
Prioritise treatment options
BP and lipid control (benefits obvious in 2-3 year)
Glycemic benefits (8 years)
Continued eye/feet/ACR screening
Young females get pregnant !

59. Thank You