Pharmacologic treatment
of T2DM
Yassin Mustafa, MBBS, MD
Tight glycemic control


DCCT



UKPDS

Tight glycemic control prevents and slow the
progression microvascular disease i...
UKPDS
ADVANCE
25

Nephropathy
20

Standard
control

15

Cumulative
incidence (%)

10

Intensive
control

5
0
0

6

12

18

24 30...
ACCORD
Death from any cause
Microvascular disease
The results of the UKPDS, ADVANCE, and
ACCORD trials are consistent with those of
the DCCT for patie...
Macrovascular disease
No RCT has demonstrated a beneficial
effect of intensive therapy on
macrovascular outcomes in T2DM.
...
Recommendations
ADA
A1c (%)

Fasting plasma glucose
Postprandial plasma glucose

AACE

<7

≤6.5

70-130 mg/dL

<110 mg/dL
...
Target individualization
Multidisciplinary approach
Diabetes self management program

Anti-diabetic
medications
Medical nutrition treatment
Classes of medications
Metformin
 Sulfonylureas SU
 Meglitinides GLN
 Thiazolidindions
TZD
 Alfa glucosidase
inhibitor...
Metformin
The first choice for oral treatment of type
2 diabetes.
 Reduces A1C by 1-2%.
 Leads to modest weight reductio...
Mechanism of action
Metformin is effective only in the presence
of insulin
 Decrease hepatic glucose output
 Increases i...
Side effects
Gastrointestinal side effects are common
 Diarrhea
 Anorexia
 Nausea
 Abdominal discomfort
Vitamin B12 de...
Lactic acidosis
Very rare but potentially fatal
 Predisposing factor:
 Impaired renal function
 Intravenous contrast
 ...
Dosing
The usual effective dose is 1500 to 2000
mg/day per day
 Should be taken with meals.
 Extended release tablets ar...
Contraindications
Renal compromise with creatinine > 1.5 in
males and >1.4 in females
 Hepatic and heart failure
 IV con...
Sulfonylureas
The oldest class of oral hypoglycemic
agents.
 lowers A1C by 1-2%
 Effectiveness decreases over time
 Mon...
Mechanism of action


The sulfonylurea receptor is a component
of the ATP-dependent potassium channel
in the pancreatic b...
Side effects
Hypoglycemia is more common with longacting sulfonylureas may be severe and
prolonged
 Risk factors for hypo...
Cardiovascular Risk
May be associated with poorer outcomes
after a myocardial infarction
 Can be related to the effect of...
Meglitinides
Repaglinide and nateglinide are shortacting hypoglycemics
 Mechanism of action is similar to the
sulfonylure...
Dosing
Starting dose of repaglinide is 0.5 mg
 The maximum dose is 4 mg
 nateglinide is 120 before each meal
 Should be...
Thiazolidinediones
Includes rosiglitazone and pioglitazone
 Lowers A1C by 1-2%.
 More expensive than generic
sulfonylure...
Mechanism of action
Acts on adipose, muscle, and liver to
increase glucose utilization and decrease
glucose production
 A...
Effect on lipid

LDL

PIO

ROSI

HDL

TGA
Side effects
Weight gain: dose and time-dependent
 Fluid retention: prominent with
concomitant insulin therapy, and in
pa...
Side effects
Troglitazone has been removed from the
market in because of reports of severe
hepatocellular injury
 Macular...
Cardiovascular risk
The CVD benefit-risk is not entirely clear
 Data demonstrating their ability to
decrease CVD events a...
Alpha-glucosidase inhibitors
Acarbose and miglitol
 lowers A1C by 0.5-0.8%.
 The main side effects are flatulence and
di...
Incretin-based therapy
GLP-1 agonists
Exenatide and liraglutide are administered
subcutaneously.
 Lowers (A1C) by 1%
 GLP-1 analog has been dem...
Side effects
Nausea is the commonest adverse effect
but can be reduced with dose titration
 Vomiting and diarrhea
 Few r...
Dosing
Exenatide (5/10 mcg twice daily) before
meals
 Exenatide is contraindicated with severe
renal impairment CrCl<30 m...
DPP-4 inhibitors
Sitagliptin, saxagliptin, linagliptin,
vildagliptin and alogliptin
 Lowers A1C by 0.4-0.8%
 No weight g...
Dosing
Sitagliptin100 mg once daily, 50 mg (GFR
30-50) and 25 mg (GFR <30)
 Saxagliptin is 2.5 or 5 mg once daily, 2.5
mg...
Side effects
Well tolerated
 Dizziness, headache, nasopharyngitis,
URTI and UTI
 Reports of an increased risk of pancrea...
SGLT2-inhibitors
SGLT2-inhibitors
Dapagliflozin and canagliflozin
 Lowers A1C by 0.5-0.7%
 Lowers systolic BP by 1.3-7.3 mmHg
 Weight lo...
SGLT2-inhibitors
Increased incidence of vulvovaginal
candidiasis, genital infection and UTI
 Canagliflozin 100 mg once da...
Insulin
Patients with persistent hyperglycemia
despite being on oral hypoglycemic agents
may add insulin to oral medicatio...
Insulin preparations
Basal insulin
longer-acting and intermediate insulins
have similar glycemic control.
 NPH: cost advantage but increases
s...
Basal Dosing
Added to oral hypoglycemic drug therapy,
starting at 10 U or 0.1-0.2 U/kg
administered at bedtime
 Fasting b...
Premixed insulin






70%
70%
75%
50%

NPH/30% regular
NPA/30% aspart
NPL/25% lispro
NPL/50% lispro.

Premixed insuli...
Basal-bolus regimen
Rapid acting (aspart, lispro, glulisine) is
added to basal = 4 injections/day
 Intensive insulin regi...
Bolus dosing
If premeal insulin needs to be added, the
optimal dose depends on insulin sensitivity
factor, CHO content, an...
Insulin as initial therapy
A1C >9 %
 FBG >250 mg/dL
 Random glucose consistently >300 mg/dL
 Severe symptoms: with keto...
U-500
Insulin pump
Colesevelam
bile acid sequestrant that lowers lowdensity lipoprotein (LDL)
 Mechanism to improve glycemic control is
unce...
Bromocriptine
Dopamine agonist: new quick release
formulation of (Cycloset) has been
recently approved for the treatment o...
Orlistat
Lipase inhibitor
 Indicated in treatment of obesity
 may be a useful adjunct (but not primary)
therapy for pati...
Pramlintide
Amylin is a peptide hormone secreted by
pancreatic beta cells in with insulin
 Pramlintide is a synthetic ana...
Pharmacological treatment of type 2 DM - Yassin Mustafa, MD
Pharmacological treatment of type 2 DM - Yassin Mustafa, MD
Pharmacological treatment of type 2 DM - Yassin Mustafa, MD
Pharmacological treatment of type 2 DM - Yassin Mustafa, MD
Pharmacological treatment of type 2 DM - Yassin Mustafa, MD
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Pharmacological treatment of type 2 DM - Yassin Mustafa, MD

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Yassin Mustafa, MD
Endocrinology Fellow
Howard University Medical Center

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  • In the ADVANCE trial (see &apos;ADVANCE&apos; below), 5571 type 2 diabetes patients receiving intensive therapy to lower A1C (mean A1C 6.5 percent) had a reduction in the incidence of nephropathy, defined as development of macroalbuminuria, doubling of the serum creatinine to at least 2.26 mg/dL (200 micromol/L), the need for renal-replacement therapy, or death due to renal disease (4.1 versus 5.2 percent, hazard ratio [HR] 0.79, 95% CI 0.66-0.93) compared with 5569 patients receiving standard therapy (A1C 7.3 percent) [13]. There was no significant effect of glycemic control on the incidence of retinopathy202-446-4914
  • Pharmacological treatment of type 2 DM - Yassin Mustafa, MD

    1. 1. Pharmacologic treatment of T2DM Yassin Mustafa, MBBS, MD
    2. 2. Tight glycemic control  DCCT  UKPDS Tight glycemic control prevents and slow the progression microvascular disease in DM
    3. 3. UKPDS
    4. 4. ADVANCE 25 Nephropathy 20 Standard control 15 Cumulative incidence (%) 10 Intensive control 5 0 0 6 12 18 24 30 36 42 48 Follow-up (months) ADVANCE Collaborative Group. N Engl J Med 2008;358:24. 54 60 66
    5. 5. ACCORD Death from any cause
    6. 6. Microvascular disease The results of the UKPDS, ADVANCE, and ACCORD trials are consistent with those of the DCCT for patients with type 1 diabetes,  In the UKPDS each 1% fall in A1C was associated with a 35% reduction in microvascular endpoints. 
    7. 7. Macrovascular disease No RCT has demonstrated a beneficial effect of intensive therapy on macrovascular outcomes in T2DM.  ACCORD showed a significant increase in CVD events and mortality with intensive therapy with long term T2DM.  The UKPDS postinterventional study showed a benefit of initial intensive glycemic control on CVD in these individuals. 
    8. 8. Recommendations ADA A1c (%) Fasting plasma glucose Postprandial plasma glucose AACE <7 ≤6.5 70-130 mg/dL <110 mg/dL <180 mg/dL <140 mg/dL •American Diabetes Association. Diabetes Care. 2012;35 •American Association of Clinical Endocrinologists
    9. 9. Target individualization
    10. 10. Multidisciplinary approach Diabetes self management program Anti-diabetic medications Medical nutrition treatment
    11. 11. Classes of medications Metformin  Sulfonylureas SU  Meglitinides GLN  Thiazolidindions TZD  Alfa glucosidase inhibitors AG-i  GLP-1 agonist  DPP-4 inhibitors  SGLT-2 inhibitors  Bromocriptin  Colesevelam  Insulin  Pramlintide 
    12. 12. Metformin The first choice for oral treatment of type 2 diabetes.  Reduces A1C by 1-2%.  Leads to modest weight reduction  Obese patients may have decreased risk of all-cause mortality and macrovascular complications 
    13. 13. Mechanism of action Metformin is effective only in the presence of insulin  Decrease hepatic glucose output  Increases insulin-mediated glucose utilization in peripheral tissues particularly after meals  Increases intestinal glucose utilization via nonoxidative metabolism 
    14. 14. Side effects Gastrointestinal side effects are common  Diarrhea  Anorexia  Nausea  Abdominal discomfort Vitamin B12 deficiency
    15. 15. Lactic acidosis Very rare but potentially fatal  Predisposing factor:  Impaired renal function  Intravenous contrast  Decreased tissue perfusion or hemodynamic instability  Concurrent liver disease or alcohol abuse  Heart failure. 
    16. 16. Dosing The usual effective dose is 1500 to 2000 mg/day per day  Should be taken with meals.  Extended release tablets are also available as well as combination tablets 
    17. 17. Contraindications Renal compromise with creatinine > 1.5 in males and >1.4 in females  Hepatic and heart failure  IV contrast use  Critically ill and hospitalized patients 
    18. 18. Sulfonylureas The oldest class of oral hypoglycemic agents.  lowers A1C by 1-2%  Effectiveness decreases over time  Monotherapy is considered in patients who is not a candidate or cannot tolerate for metformin.  Efficacy of all available drugs is similar. 
    19. 19. Mechanism of action  The sulfonylurea receptor is a component of the ATP-dependent potassium channel in the pancreatic beta cells
    20. 20. Side effects Hypoglycemia is more common with longacting sulfonylureas may be severe and prolonged  Risk factors for hypoglycemia include increasing age, alcohol abuse, poor nutrition, and renal insufficiency.  Weight gain  Nausea, skin reactions and abnormal liver function tests 
    21. 21. Cardiovascular Risk May be associated with poorer outcomes after a myocardial infarction  Can be related to the effect of sulfonylureas on ATP-dependent potassium channels on cardiac cells and coronary vessels  Newer sulfonylureas, such as gliclazide or glimipride do not appear to be associated with increased risk 
    22. 22. Meglitinides Repaglinide and nateglinide are shortacting hypoglycemics  Mechanism of action is similar to the sulfonylureas  Can be used in patients who have allergy to sulfonylurea medications.  Less risk of hypoglycemia.  Repaglinide is principally metabolized by the liver 
    23. 23. Dosing Starting dose of repaglinide is 0.5 mg  The maximum dose is 4 mg  nateglinide is 120 before each meal  Should be skipped if the meal is missed. 
    24. 24. Thiazolidinediones Includes rosiglitazone and pioglitazone  Lowers A1C by 1-2%.  More expensive than generic sulfonylureas.  Durable 
    25. 25. Mechanism of action Acts on adipose, muscle, and liver to increase glucose utilization and decrease glucose production  Activate peroxisome proliferator-activated receptors (PPARs), which regulate gene expression  Decrease markers of inflammation and coronary and carotid thickness 
    26. 26. Effect on lipid LDL PIO ROSI HDL TGA
    27. 27. Side effects Weight gain: dose and time-dependent  Fluid retention: prominent with concomitant insulin therapy, and in patients with PVD  Can precipitate heart failure in vulnerable patients: contraindicated in NYHA III CHF  Skeletal: decreases bone density and increase fracture risk, particularly in women 
    28. 28. Side effects Troglitazone has been removed from the market in because of reports of severe hepatocellular injury  Macular edema: more in patients with peripheral edema  There is concern that pioglitazone use increases the risk of bladder cancer. 
    29. 29. Cardiovascular risk The CVD benefit-risk is not entirely clear  Data demonstrating their ability to decrease CVD events are unimpressive  Rosiglitazone demonstrated an increase adverse CVD events and has been withdrawn from use in Europe  PROACTIVE trial: decrease in the secondary composite end point of allcause mortality in pioglitazon 
    30. 30. Alpha-glucosidase inhibitors Acarbose and miglitol  lowers A1C by 0.5-0.8%.  The main side effects are flatulence and diarrhea which is dose dependant  Acarbose is available as 50 and 100 mg tablets which should be taken with each meal. 
    31. 31. Incretin-based therapy
    32. 32. GLP-1 agonists Exenatide and liraglutide are administered subcutaneously.  Lowers (A1C) by 1%  GLP-1 analog has been demonstrated to reduce weight with or without diabetes when compared to placebo Mean of -1.9 kg  No long-term data to assess clinically important health outcomes (cardiovascular events, mortality), or safety. 
    33. 33. Side effects Nausea is the commonest adverse effect but can be reduced with dose titration  Vomiting and diarrhea  Few reports of acute pancreatitis and pancreatic cancer  liraglutide was associated with benign and malignant thyroid C-cell tumors in rats. 
    34. 34. Dosing Exenatide (5/10 mcg twice daily) before meals  Exenatide is contraindicated with severe renal impairment CrCl<30 mL/min  Caution is suggested in prescribing for patients with confirmed gastroparesis.  Liraglutide (1.8 mg daily) 
    35. 35. DPP-4 inhibitors Sitagliptin, saxagliptin, linagliptin, vildagliptin and alogliptin  Lowers A1C by 0.4-0.8%  No weight gain or hypoglycemia  Expensive and no long term follow up data  When compared to GLP-1 they are less effective 
    36. 36. Dosing Sitagliptin100 mg once daily, 50 mg (GFR 30-50) and 25 mg (GFR <30)  Saxagliptin is 2.5 or 5 mg once daily, 2.5 mg (GFR ≤50)  Linagliptin 5 mg is a good choice as initial therapy in chronic kidney disease  Various combination with metformin single tablet are available 
    37. 37. Side effects Well tolerated  Dizziness, headache, nasopharyngitis, URTI and UTI  Reports of an increased risk of pancreatitis, subclinical pancreatic inflammation, pancreatic cancer  Cases of hepatic dysfunction (liver enzyme elevations, hepatitis) with vildagliptin and alogliptin 
    38. 38. SGLT2-inhibitors
    39. 39. SGLT2-inhibitors Dapagliflozin and canagliflozin  Lowers A1C by 0.5-0.7%  Lowers systolic BP by 1.3-7.3 mmHg  Weight loss of 2-3 kg  No hypoglycemia  ? efficacy and safety 
    40. 40. SGLT2-inhibitors Increased incidence of vulvovaginal candidiasis, genital infection and UTI  Canagliflozin 100 mg once daily before meals titrate to 300 mg if GFR>60 and contraindicated if GFR<45  Dapagliflozin 10 mg once daily and not recommended if GFR<60 
    41. 41. Insulin Patients with persistent hyperglycemia despite being on oral hypoglycemic agents may add insulin to oral medication or stop the oral drug and begin insulin.  Patients with T2DM require relatively large doses of insulin 
    42. 42. Insulin preparations
    43. 43. Basal insulin longer-acting and intermediate insulins have similar glycemic control.  NPH: cost advantage but increases symptomatic overall and nocturnal hypoglycemia  Degludec: ultra long > 42 concern regarding a potential increase in cardiovascular risk 
    44. 44. Basal Dosing Added to oral hypoglycemic drug therapy, starting at 10 U or 0.1-0.2 U/kg administered at bedtime  Fasting blood glucose should be measured every day.  Increase by 2-4 units of insulin periodically until mean FBG is controlled 
    45. 45. Premixed insulin     70% 70% 75% 50% NPH/30% regular NPA/30% aspart NPL/25% lispro NPL/50% lispro. Premixed insulin may be administered at the largest meal once daily or at the 2 largest meals twice daily.  Effective in reducing postprandial BG and overall glycemic control  Difficult to titrate and needs consistent meal plan 
    46. 46. Basal-bolus regimen Rapid acting (aspart, lispro, glulisine) is added to basal = 4 injections/day  Intensive insulin regimen with MDI is Offered for patient who failed oral-basal and split mixed  More flexible with meal timing and content  Needs motivated and educated patients. 
    47. 47. Bolus dosing If premeal insulin needs to be added, the optimal dose depends on insulin sensitivity factor, CHO content, and activity.  Starting 4-6 U or 1U/15 g carbohydrate .  Titration is better based on 2-hr PPG and should be slowly 
    48. 48. Insulin as initial therapy A1C >9 %  FBG >250 mg/dL  Random glucose consistently >300 mg/dL  Severe symptoms: with ketonuria  latent autoimmune diabetes in adults (LADA). 
    49. 49. U-500
    50. 50. Insulin pump
    51. 51. Colesevelam bile acid sequestrant that lowers lowdensity lipoprotein (LDL)  Mechanism to improve glycemic control is uncertain.  Lowers A1C by 0.5% in the short term  Side effects can include constipation, nausea, and dyspepsia. 
    52. 52. Bromocriptine Dopamine agonist: new quick release formulation of (Cycloset) has been recently approved for the treatment of DM  The mechanism of action in reducing blood sugar is unknown.  Lowers A1C by 0.5%  Common side effects include nausea, vomiting, dizziness, and headache. 
    53. 53. Orlistat Lipase inhibitor  Indicated in treatment of obesity  may be a useful adjunct (but not primary) therapy for patients with type 2 diabetes  Side effect: oily stool, incontinence, abdominal discomfort  Vitamin deficiency 
    54. 54. Pramlintide Amylin is a peptide hormone secreted by pancreatic beta cells in with insulin  Pramlintide is a synthetic analog of amylin that slows gastric emptying, reduces postprandial blood glucose, and modestly improves A1C concentrations when injected subcutaneously with meals.  Pramlintide is only approved for use in patients also taking insulin. 

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