DM Medication.pdf

Diabetes Mellitus Medication, Pharmacology

1. Diabetes Mellitus (DM)
Medications
Presenter: Saleh Alkhalid(R2 Family Medicine)
Supervisor: Dr. Abdullah Alzahrani(Consultant Diabetologist)

2. Outline
•Classes of Oral Hypoglycemic Agents
•General Information
•Mechanism of Action
•Renal Adjustments
•Cardiovascular Benefits
•Side Effect
•Investigation

3. Classes
•Biguanides
•Sulfonylureas
•Thiazolidinediones (TZD)
•α-Glucosidaseinhibitors & Lipase inhibitors
•Meglitinides
•DipeptidylPeptidase-4 Inhibitor (DPP4i)
•Glucagon-like peptide-1 receptor agonists (GLP 1agonist)
•Sodium Glucose Cotransporter2 Inhibitor (SGLT2i)
•Insulin

4. Biguanides -Metformin

6. General Points About Biguanides -
Metformin
•First line medication.
•Weight maintenance(Neutral weight effect)
•Cardiovascular protective medication.
•Efficacy on A1C: Strong: 1-2. %
•No hypoglycemia
•Low cost

7. Mechanism of Action

9. Dose of Metformin
•Maximal dose is 2500-3000 mg.
•750 mg: used once daily, more tolerable, less GI SE.
•Start the dose 500, and double it every week.
•The practical dose is 1500-2000 mg per day.

10. Dose of Metformin
•Available Doses:

11. Doses
•Immediate-release:
Initial dose: 500 mg orally twice a day or 850 mg orally once a day
Maximum dose: 2550 mg/day
Extended-release:
Initial dose: 500 to 1000 mg orally once a day
Maximum dose: 2000 mg/day

12. CVS and Metformin
CV Effects:
•Reduces risk of MI by 39%.
•Diabetes-related death by 42%.
•Mortality by 36%.
•(UK Prospective Diabetes Study UKPDS)
Clinical Use in Patients with CVD:
•Not indicated in the presence of acidosis or
dehydration.

13. Newer CKD guidelines are based on estimated glomerular
filtration rate (eGFR), not on serum creatinine
If 30-45
and not
already on
metformin
> start
insulin

14. Side Effects of Metformin
•Most common:Gastrointestinal side effects
•To decrease side effect: slow release metformin XR 750 mg
•Most serious: Lactic acidosis, and VitB 12 deficiency

15. Investigations
•Labs :
•Before starting Metformin:
•CBC
•Renal function.
•Annual:
•Vitamin B12 level.

16. Sulfonylureas (SU)

17. General Information About SU
•MOA: Inhibit ATP-K channels, stimulating increase Caand insulin
release and secretion from pancreatic beta cells.
•Mimic normal physiology of glucose.
•Indication: Non pregnant, non obese type 2 DM
•Strong A1C reduction : 0.8-2 %
•Low cost

18. Classification

19. SU: Gliclazide
•Gliclazide:
•Modified release: 30or 60 mg tablet.
•Maximal dose is 120 mg .
•It mainly affect the fasting blood glucose
•Better to take it before breakfast .

20. Renal adjustments & SU
•Gliclazide:
•Reduce dose if eGFR< 30
•Not recommended if eGFR< 15
•Glimepiride:
•Avoid use if eGFR< 60
•Glipizide:
•No dose adjustment required
•Glibenclamide:
•Avoid use in patients with eGFR< 60

21. Cardiovascular System & SU
•CV Effects:
•Reduction of microvascularcomplications (UKPDS)
•Increased CV mortality (UGDP trial)
•Precautions should be taken in patients with multiple comorbidities, HF, and advanced CKD
(stages IV and V)

22. Side Effects of SU
•SE: hypoglycemia, weight gain
•High risk for hypoglycemia
•Glibenclamide:
•Most common
•It is the worst for cardiac patients
•Gliclazide: least hypoglycemias

23. Investigation
•Labs to order before:
•Renalprofile

24. Thiazolidinediones (TZD)
Rosiglitazone& Pioglitazone
Improve Insulin Action

25. General Information About TZD
•MOA:
•Act on nucleus:
•Activating peroxisome proliferative activating receptor gamma (PPAR-G):
•Increase Glut 4 transporter:
•Increase insulin sensitivity.
•Strong effect on A1C: 1-1,5 %.
•Low cost?
Most potent insulin sensitizer

26. Increase insulin sensitivity by acting on adipose
muscle & liver to increase glucose utilization &
decrease glucose production

27. TZD & Lipid Profile
•Goodeffect on lipid profile:
•Stable LDL.
•Decrease TG.
•Increase HDL.

28. Renal Adjustment &TZD
•No dose adjustment is needed.
•Only caution in hypovolemia.

29. Cardiovascular System & TZD
•CV Effects
•Improve diabetic dyslipidemia
•Increase HF hospitalization

30. Side Effects of TZD
•Weight gain, mainly by increasing fluids retention
•Edema
•Heart failure exacerbation.(Cardiovascular toxicity)
•Can cause osteoporosis.
•Potential increase in MI( Rosiglitazone)
•Potential increase in bladder cancer (pioglitazone)

31. Contraindicationsof TZD
•SymptomaticHF
•NYHA class III or IV
•Active bladder cancer or H/O bladder cancer
•H/O fracture or high risk for fractures
•(e.g. postmenopausal women with low bone mass)
•Active liver disease
•T1DM
•Pregnancy

32. For Your Information
•If it is not working by 2 months, patient is compliance,
•Give history of weight loss:
•Suspects insulin deficiency (most common sign for insulin deficiency is weight loss)
•Delayed effect:
•4-8 weeks to observe effect
•So, follow up with A1C not fasting blood sugar readings.

33. α-GlucosidaseInhibitors
Acarbose

34. General Information About Acarbose
•Very safe.
•Weight neutral effect.
•Doesn’t cause hypoglycemia.
•Can be used in severe renal cases.
•Decrease HbA1c 0.7–1.0%.
•Decrease post prandial glucose level.
•Low –moderate cost

35. Mechanism of Action of Acarbose
•Inhibit glucose absorption in the gut
•Delayed absorption of carbohydrates in intestine or prevent breakdown of
polysaccharide to monosaccharide
•So, dosing should be with meal

37. Dosing of Acarbose
•Dosage according to weight:
•If < 60 kg : 50mg TID
•If > 60 kg : 100mg TID

38. Renal Adjustment & Acarbose
•Avoid if eGFR< 30

39. Side Effects of Acarbose
•Gastrointestinal upset: diarrhea and flatulence
•Side effect if taken with carbohydrates
•High serum aminotransferaseconcentration

40. Investigations
•Renal profile
•Creatinine level

41. Meglitinides
Repaglinide& Nateglinide

42. General Information About Meglitinides
MOA:
•Stimulate insulin secretion (rapidly & for a short duration) in the presence of glucose.
•Taken with meals
Efficacy:
•Decrease peak postprandial glucose level
•Reduce A1C 0.5-2.0%
•Moderate cost

43. Renal Adjustments & Meglitinides
•Repaglinide(Novonorm):
•Initial dose of 0.5 mg before meals when eGFR< 30
•Nateglinide:
•Caution when used with eGFR< 30
•Initiate with 60 mg before meals

44. Side Effects of Meglitinides
•Hypoglycemia
•Weight gain

45. DipeptidylPeptidase-4
Inhibitor (DPP4i)
Sitagliptin, Linagliptin

46. General Information About DPP4i
•No effects on body weight or risk of hypoglycemia
•Patient call it “مظنم”
•Drugs:
•Sitagliptin(Jenovia): need renal adjustment.
•Linagliptin: no need for renal adjustment.
•Saxagliptin
•Vildagliptin
•Alogliptin

47. Mechanism of Action of DPP4i
•MOA:
•Inhibit DPP from degrading GLP 1.
•Increase satiety.
•Decrease emptying.
•Increase insulin secretion.
•Decrease glucagon.
•Efficacy: decrease HbA1c 0.5–0.9%.
•High cost

48. Renal Adjustments & DPP4I
•Sitagliptin:
•50 mg OD if eGFR30-50
•25 mg OD if eGFR< 30
•Saxagliptin:
•2.5 mg OD if eGFR< 50
•Linagliptin:
•No dose adjustment is required.
Alogliptin:
•1.25 mg OD if eGFR30-50
•<0.625 mg OD if eGFR<30 Or on Hemodialysis

49. Dosing and Renal Adjustment (Sitagliptin)
•Based on GFR:
•If GFR > 60:
•100 mg
•If GFR 30-59:
•50 mg
•If GFR < 30:
•25 mg

50. Cardiovascular System & DPP4I
•CV Effects
•Well tolerated
•Increased risk of HF with saxagliptinand alogliptin

51. Side Effects of DPP4I
•Can cause significant appetite loss
•Cause pancreatitis
•Associated with pancreatic cancer ?
•Headache
•Nasopharyngitis
•URTI
•Angioedema –Urtecaria

52. Investigation
•Renal Profile:
•Linagliptinis the only one if there is renal injury
•Lipase & Amylase: If the patient have history of
pancreatic issues

53. Glucagon-like peptide-1
receptor agonists
(GLP 1 agonist)
Leraglutide

54. General Information About GLP 1 agonist
•No hypoglycemia.
•Efficacy: reduction of HbA1c by 0.55 –1.2 %
•Have good weight reduction effect:
•Approved for obesity, Dose: 3 mg .
•Decrease weight by 5-10% in 1 year + exercise and diet .
•Decrease post prandial glucose level
•Highcost

55. GLP-1 agonist
•Short –Acting
Exenatidetwice daily
Lixisenatide
•Long –Acting
Liraglutide(Victoza)
Exenatideonce weekly
Dulaglutide
Semaglutide

56. Liraglutide
T2DM: Victoza
•Dose: 0.6 mg SC daily for 1 week initially, then
increase to 1.2 mg daily. If glycemic control not
achieved, can increase to 1.8 mg daily
•Initial dose of 0.6 mg SC daily: minimize GI side
effects but it does not provide glycemic
control.
•To reduce the risk of major adverse
cardiovascular events
Obesity: Saxenda
•Indicated as an adjunct to a reduced-calorie diet and
increased physical activity for chronic weight management
in adults
•BMI of ≥30
•BMI of ≥27 + 1 weight-related condition
•E.g, HTN, T2DM, & DLP
•Initiate at 0.6 mg SC daily for 1 week; increase by 0.6
mg/day in weekly intervals until a dose of 3 mg/day is
achieved
•If patients do not tolerate an increased dose during dose
escalation, consider delaying dose escalation for ~1
additional week
•Discontinue if a patient cannot tolerate the 3 mg dose, as
efficacy has not been established at lower doses (eg, 0.6,
1.2, 1.8, 2.4 mg)

57. Liraglutide
T2DM: Victoza
•Dose: 0.6 mg SC daily (No glycemic control effect) for 1 week initially, then increase to 1.2
mg daily.
•If glycemic control not achieved, can increase to 1.8 mg daily.
•To reduce the risk of major adverse cardiovascular events.

58. Liraglutide
Obesity: Saxenda
•Indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight
management in adults:
•BMI of ≥ 30.
•BMI of ≥ 27 + 1 weight-related condition. E.g, HTN, T2DM, & DLP.
•Initiate at 0.6 mg SC daily for 1 week; increase by 0.6 mg/day in weekly intervals until a dose of 3
mg/day is achieved.
•If patients do not tolerate an increased dose during dose escalation, consider delaying dose
escalation for ~1 additional week.
•Discontinueif a patient cannot tolerate the 3 mg dose, as efficacy has not been established at
lower doses (eg, 0.6, 1.2, 1.8, 2.4 mg)

59. Mechanism of Action of GLP 1 agonist

60. Renal Adjustment & GLP-1 Agonist
•Liraglutide(0.6-1.8 mg):
•No restrictions if eGFR> 30
•Once daily injection
•Dulaglutide(0.7-1.5 mg):
•No dose modifications on any renal
impairment.
•Exenatide(QD=5-10 mcg; QW= 2 mg):
•eGFR30-50 : Dose < 5 mcg Daily
•eGFR< 30: Use with Caution
•Lexisenatide(10,20 mcg):
•-Avoid if eGFR< 50

61. Renal Adjustment & GLP-1 Agonist
•Limited data in patients with advanced CKD (stages IV and V).
•Exenatideis eliminated by renal mechanisms and should not be given in patients
with severe ESRD.
•Liraglutideis not eliminated by renal or hepatic mechanisms, but it should be used
with caution since there are only limited data in patients with renal or hepatic
impairment.

62. Cardiovascular System & GLP-1 agonist
•Significant reductionof composite CV endpoints in LEADER and SUSTAIN-6
trials.
•No significant effects on CV mortality, nonfatal MI, and hospitalization for
HF with Liraglutideand Semaglutide
•Reducedrisk of nonfatal stroke with Semaglutide

63. Side Effect of GLP-1 agonist
•Nauseabut tolerated with time.
•Disappear in 2 weeks not like Acarbose takes 2 years
•Start low dose 0.6mg then increase till 1.8mg
•Injection site reactions

64. Precautions with GLP-1 agonist
•Patients with history of pancreatitis
•T1DM
•Patients with a personal or family history of Medullary
Thyroid Cancer or Multiple Endocrine Neoplasia 2A or 2B
Very Important

65. For Your Information
•In animal study: GLP-1 causes Beta cells regeneration
•It is post-prandial effect.
•So, if the patient is on insulin and want to start GLP-1:
•Better to decrease the prandial insulin (Aspart) as it might cause hypoglycemia if
patient is near control.

66. Sodium Glucose Co-transporter
2 Inhibitor (SGLT2i)

67. General Information About SGLT2i
•Stop the reabsorption of glucose in the proximaltubule in the kidney and execrating the glucose. (glucose
dependent) .
•Cardio-protectivemedication:
•Canagliflozin, Empagliflozin.
•Expensivemedication
•Weigh loss effect
•Anti hypertension medication effect (Lowers BP by 2-4 mm/Hg).
•Decrease BP, increase LDL and Cr
•A1C effect : 0.6 % , LEAST medication to decrease A1C.

68. Examples of SGLT2i
•Canagliflozin
•Empagliflozin
•Dapagliflozin
•Ertugliflizin

69. Renal Adjustment & SGLT2I
•Canagliflozin(100,300)
•eGFR> 60 : No dose adjustment required
•eGFR45-59: 100 mg daily
•Empagliflozin(10, 25):
•eGFR> 45: No dose adjustment required
•eGFR< 45: Do not initiate
•eGFRfalls < 45: D/C

70. Cardiovascular System & SGLT2I
•In the EMPA-REG OUTCOME trial:
•Empagliflozinreduced CV death, HF hospitalization, and total mortality by 38%, 35%,
and 32%, respectively
•No direct effect on the rates of MI or stroke with Empagliflozin
•Reduction of systolic and diastolic BP

71. Side Effects ofSGLT2I
•Genitourinary infection
•Masked DKA (euglycemic).
•They have normal glucose while in DKA
•Bladder cancer
•Risk of amputation
•Avoid in case of peripheral vascular disease.

72. Contraindications
•T1DM
•T2DM with eGFR< 45
•Prior DKA

73. Avoid SGLT2I
•Frequent bacterial UTIor genitourinary yeast infections
•High risk of fractures or falls
•Foot ulceration
•Factors predisposing to DKA( ketosis prone Diabetes, pancreatic
insufficiency, drug or alcohol addiction)

74. Insulin Therapy

75. Insulin
Variable cost

77. Rapid Acting

78. Rapid Acting

79. Short Acting

80. Basal Insulin

81. To Sum Up

86. Insulin Sensitizer
•Metformin
•Thiazolidinedione

87. Insulin Secretion
•Sulfonylureas
•Meglitinide

88. Multiple Action
•DPP4-I
•GLP-1 Agonist

89. Increasing Urinary Glucose Excretion
•SGLT2 inhibitors

90. References
•Up to date
•ADA
•PubMed
•AAFP
•Diabetes UK
•KDIGO
•Medscape

91. Thank You
Hope You Learned Something or New Thing
Any Feedback or Point For Improvement is Appreciated