1. Diabetes Mellitus: Updates in Management
Mona Nasrallah M.D
American University of Beirut
Lebanese Society of Family Medicine
5th Annual Conference
November 11, 2006

2. Outline Target guidelines for metabolic control Current Therapy
American Diabetes Association 2006
Lebanese Society of Endocrinology 2006
Current Therapy
New and Upcoming therapies

3. ADA 2006 guidelines: control
HbA1C < 7 %
Preprandial glucose mg/dL
Postprandial glucose < 180 mg/dL
Targets may vary slightly with other recommendations (AACE, IDF)
Targets may vary according to patient (elderly, pregnancy, severe hypoglycemia)
Lower HbA1C associated with further benefit

4. ADA 2006: complications Microvascular Macrovascular
Yearly dilated retinal exam
Yearly spot urine albumin/creatinine ratio
Foot exam every 6 months
Macrovascular
BP < 130/80 mmHg
LDL < 100 mg/dL
Triglycerides < 150 mg/dL
HDL > 40 mg/dL men
> 50 mg/dL women
Smoking assessment
Antiplatelet therapy
LDL < 70 mg/dl if CAD
LDL % lower in those > age 40 years

5. Lebanese Guidelines OPTIMAL REASONABLE HbA1C (%) < 6.5 <7.5
Pre glucose (mg/dl)
80-120
<140
Post glucose (mg/dl)
<180
SBP (mmHg)
<130
DBP (mmHg)
<80
80-89
LDL-C (mg/dl)
<100 -
HDL-C (mg/dl)
>45 m, >55 w
Triglyceride (mg/dl)
<150
Non HDL-C (mg/dl)
Lebanese Endocrine Society- Ministry of Health- WHO

7. Lifestyle modification

8. Insulin Resistance & Insulin Deficiency:
At the time of diagnosis, both defects are already combined
Evolution of diabetes
Insulin
resistance
Fasting blood glucose
Insulin
secretion
Normal
Compensation phase
Diabetes
DeFronzo R.A. et al., Diabetes Care (1998)

9. Pharmacotherapy Increase insulin supply Decrease insulin demand
Sulfonylureas
Meglitinides
Insulin
Decrease insulin demand
Biguanides
Thiazolidinediones
Decrease intestinal glucose absorption
Alpha-glucosidase inhibitors

10. Current Oral Therapies Address Different Metabolic Defects in T2DM
Insulin demand
Insulin supply
Glucose influx
Insulin resistance
Glucagon secretion
Acute β-cell function
Chronic β-cell function
α-Glucosidase inhibitors
Biguanides
Sulfonylureas
The primary metabolic defects of T2DM are heightened insulin demand and deficient insulin supply, and another contributing factor is uncompensated glucose influx.
Many of these specific problems are addressed by one or another existing class of oral antihyperglycemic drugs, each of which has distinctive mechanisms.1
α-Glucosidase inhibitors moderate glucose influx by delaying intestinal carbohydrate absorption, thereby mitigating postprandial glucose excursions.1 The utility of these agents depends in part on proper dietary compliance and is more effective in populations whose diet does not consist of highly processed foods. The widespread use of these agents in Japan and Spain is an excellent example of their utility in populations where a rice and fish diet is prevalent.
Thiazolidinediones (TZDs) work primarily by enhancing both basal and insulin-mediated suppression of HGP and to some extent by augmenting insulin-stimulated muscle glucose utilization.2
Metformin (of the biguanide drug class) lowers glucose levels, chiefly by reducing HGP.1
Sulfonylureas lower the glucose threshold for triggering β-cell insulin release.1
Glinides resemble sulfonylureas in enhancing acute β-cell function. Their short metabolic half-lives enable them to produce brief, episodic stimulation of insulin secretion.1 Of the glinides, nateglinide is rapidly reversible, whereas repaglinide is not.
1. Inzucchi SE. Oral antihyperglycemic therapy of type 2 diabetes: scientific review. JAMA. 2002;
2. DeFronzo RA. Impaired glucose tolerance: do pharmacological therapies correct the underlying metabolic disturbance? Br J Diabetes Vasc Dis 2003;3(suppl 1):S24-S40.
TZD
Meglitinides
Insulin
Plasma glucose

11. Sulfonylureas Stimulate insulin secretion Weight gain, hypoglycemia
Increased cardiovascular risk?
Contraindication
Severe hepatic disease, renal failure

12. Sulfonylureas Drug Dose (mg) Freq Glimepiride 1-8 QD Glipizide 2.5- 40
BID
Glipizide-XL
2.5-20
Glyburide
Gliclazide
30-120

13. Meglitinides Stimulate insulin-secretion
Nateglinide ( mg) Repaglinide ( mg)
Shorter half-life (1 hour) and onset of action ideal for post-prandial hyperglycemia
Lower risk hypoglycemia
May be used in renal failure, but reduced dose

14. Biguanides
Increases hepatic GLUT4 and glucose uptake, ‘insulin sensitizer’
Metformin: mg per day
May use in children years
Effect on fasting glucose, lowers HbA1C %
20 % gastrointestinal side-effects

15. Metformin contraindications
Serum creatinine > 1.5 men, > 1.4 women
NYHA III-IV heart failure
Severe liver disease
Severe COPD, oxygen-requiring
Withhold metformin 1 day before and after any procedure using contrast
Withhold during severe acute illness and surgery

16. Thiazolidinediones PPAR-gamma agonists
Pioglitazone (15-45 mg)
Rosiglitazone (2-8 mg)
Enhance insulin action directly through improved transporters, and indirectly through decreased lipotoxicity.
Effect on muscle, liver, and adipose
Improve overall glycemia, HbA1C %

17. Thiazolidinediones Iki-Jarvinen 2004 NEJM 351: 1106
PPAR are nuclear receptors which regulate gene expression in response to ligand binding. This regulation is achieved in 2ways. In this week’s rev, which describes it: Transactivation: ligand activates PPAR which recruits a cofactor leading to heterodimerization with retinoid X receptor and altered gene expression. Different ligands can activate cofactors in slightly different ways which accounts for the slight heterogeneity seen by members of the same class. And thru transpression, which is DNA-independent, where it interferes with other transcription members. Effects are more immediate, for example antiinflammatory effect.
Iki-Jarvinen 2004 NEJM 351: 1106

18. TZD lower glucose and insulin levels. Stimulate FA uptake (FA steal)
TZD lower glucose and insulin levels. Stimulate FA uptake (FA steal). Pio and rosi each regulate more than 100 genes. Increase adiponectin in fat, decrease TNF, decrease 11-BHSD, decrease resistin.
Iki-Jarvinen 2004 NEJM 351: 1106

19. The clinical results are a decrease 1-1
The clinical results are a decrease 1-1.5% HbA1C, 2-4 Kg weight gain, lipid effects variable.
Net effect is decrease HbA1C 1-1.5, weight gain in periph tissue, variable lipid effects.
Iki-Jarvinen 2004 NEJM 351: 1106

20. Thiazolidinediones
May cause edema (5%), anemia, CHF exacerbation, macular edema with rosiglitazone
Weight gain 2-4 Kg, but redistribution of fat
Monitor transaminases quarterly
Contraindicated NYHA III-IV, moderate-severe liver disease (ALT > 2.5X normal)
Edema more with high dose insulin

21. Alpha-glucosidase inhibitors
Inhibit breakdown into monosaccharides
Acarbose: mg before meals
Effect on post-prandial glucose and reduction of HbA1c by 0.5-1%
Gastrointestinal side-effects limit use
May be used in children
Role in DM2 prevention

22. Combinations
The only combination which is unlikely to be of benefit is two secretagogues e.g glimepiride and repaglinide together

23. When to add insulin in DM2?
Severe hyperglycemia
Glucose toxicity
Inability to achieve control on maximal therapy
Comorbid chronic conditions
Acute inpatient hyperglycemic episodes
Sepsis
Steroid therapy

24. Hyperglycaemia due to an increase in fasting glucose
Treating fasting hyperglycemia lowers the entire 24-hour plasma glucose profile
400 20
T2DM
300 15
Plasma glucose (mg/dl)
200
Hyperglycaemia due to an increase in fasting glucose
Plasma glucose (mmol/l) 10
100 5
Normal
The curves denote the 24-hour plasma glucose profiles for individuals with and without T2DM.
The area between the curves highlights the excess glycaemic exposure in T2DM due to an increase in fasting glycaemia.
Treating fasting hyperglycaemia lowers the entire 24-hour plasma glucose profile.
Polonsky K, et al. N Engl J Med 1988;318:1231―9.
Meal
Meal
Meal 6 10 14 18 22 2 6
Time of day (hours)
Comparison of 24-hour glucose levels in control subjects vs patients with diabetes (p<0.001). Adapted from Polonsky K, et al. N Engl J Med 1988;318:1231―9.

25. Adding insulin to OHA
Usually 0.15 U/Kg at bedtime NPH or glargine or levemir
Dose is increased by 2 units every 3-7 days if fasting > 120 mg/dL
If daytime hyperglycemia not controlled, may need to add short-acting insulin before meals. Controversial whether secretagogues have additional role. Continue insulin sensitizers

26. Insulin formulations Type Onset Peak(h) Duration(h) Lispro/aspart
5-15 min
1-2
4-6
Regular
30-60
2-4
8-10
NPH/Lente
1-2 h
4-8
10-20
Ultralente
Variable
16-20
Glargine
Levemir -
Peakless 24

27. Insulin methods delivery
Subcutanously
Intermittent
Premix
Insulin pen
Continuous (pump)
Transmucosal and transpulmonary insulin

28. Inhaled insulin : ‘EXUBERA’
FDA approved in January 2006
Orally inhaled blisters deliver short-acting insulin
Given 10 minutes before meals
Approved starting age 6 y
Get baseline pulmonary function tests

29. New therapies

30. New and upcoming therapies
Inhaled insulin (FDA January 2006)
GLP-1 agonists (FDA June 2005)
DPP-IV inhibitors (FDA October 2006)
Amylin analogs (FDA March 2005)
Dual PPAR agonists (FDA Phase III)

31. Incretin concept

32. The Incretin Effect Superior Response of Insulin to Oral vs IV Glucose
Oral glucose
2.0
1.5
1.0
0.5
0.0
Oral glucose (50g) or isoglycemic infusion *
200
100
Plasma Glucose (mg/dL)
C-Peptide (nmol/L)
Food elicits dynamic changes in insulin secretion, beginning with the so-called cephalic phase, in which anticipation of a meal releases insulin. This is mediated by the CNS. An early prandial phase, mediated by gut-derived incretin hormones (eg, GLP-1 and GIP) occurs after food intake but before the ingested nutrients appear in the circulation.
To identify the contributions of these endogenous substances, 6 young healthy subjects were first given increasing oral glucose loads of 25 g, 50 g, and 100 g. They then received an isoglycemic intravenous glucose infusion that was designed to mimic the plasma profile achieved by the oral load.1 The intravenous glucose bypassed the gastrointestinal tract and therefore enabled an investigation of the role of incretins.
Shown here (left chart) is the response to 50 g oral glucose compared with the matched intravenous infusion, demonstrating essentially identical rises and falls in plasma glucose.
Yet the insulin secretory response (β-cell responses), demonstrated here by the connecting peptide (C-peptide) concentrations, were dramatically different (right chart). The oral challenge was followed by a robust increase in C-peptide levels. In contrast, insulin secretion following the isoglycemic intravenous glucose infusion was significantly less.
The difference is ascribed to incretins, which are secreted in response to the presence of food in the GI tract and not when glucose is administered parenterally. The incretin effect thus refers to the difference in the magnitude of insulin secretion seen after glucose is ingested compared with that seen after an isoglycemic intravenous infusion. These findings suggest that incretins, and not merely the direct actions of glucose, affect the insulin secretory response.
Reference:
Nauck MA, Homberger E, Siegel EG, et al. Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab. 1986;63: 60
120
180
Time (min) 60
120
180
Time (min)
Adapted from Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:

33. Duncan and Buse 2006 Up-To-Date 12.3:Amylin and GLP-1 based therapies

34. Glucagon-like peptide 1
Peptide secreted by intestinal L-cells
Role:
Potentiates glucose-dependent insulin release
Stimulates beta-cell proliferation
Inhibits glucagon release
Delays gastric emptying (inhibits appetite)

35. Incretin Hormones Regulate Multiple Metabolic Effects in Response to Food Intake
Metabolic Control
Regulation of
Glucose influx
Glucagon secretion
Acute β-cell function
Insulin secretion
Chronic β-cell function
Proliferation
Antiapoptotic effect
GLP-1
GIP
Food intake
The processing of nutrients that have entered the gut is achieved in part through the regulatory effects of 2 gut-derived incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), both of which are released only in response to ingested food.1
Their regulatory influence affects glucose influx, insulin resistance, glucagon secretion, and β-cell function, all of which in turn have important influences on the metabolic defects of T2DM.1
GLP-1 enhances β-cell function acutely by promoting insulin secretion.1
Preclinical studies suggest that GLP-1 also enhances chronic β-cell function by increasing insulin biosynthesis and promoting β-cell neogenesis.1
It has been demonstrated that persons with T2DM exhibit an impaired GLP-1 response to food intake.2,3
1. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;26:
2. Nauck M, Stockmann F, Ebert R, et al. Reduced incretin effect in type 2 (non–insulin-dependent) diabetes. Diabetologia. 1986;29:46-52.
3. Toft-Nielsen M, Damholt M, Madsbad S, et al. Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. J Clin Endocrinol Metab. 2001;86:
GIP = glucose-dependent insulinotropic polypeptide; GLP-1 = glucagon-like peptide–1

36. GLP-1 Mechanisms Address Both Insulin Supply and Insulin Demand
Glucose influx
Insulin demand
Insulin supply
Insulin resistance
Glucagon secretion
Acute β-cell function
Chronic β-cell function
Slows gastric emptying
Improves satiety
Inhibits hepatic glucose production
Improves glucose uptake in fat and muscle tissue
Inhibits glucagon secretion
Augments insulin secretion
Increases insulin biosynthesis*
Promotes β-cell differentiation*
This slide summarizes clinical and preclinical studies of GLP-1 and how they relate to insulin supply and insulin demand.
The GLP-1 mechanism has promise for addressing multiple metabolic defects.1
Glucose influx: Results from clinical studies show that GLP-1 slows gastric emptying. It also heightens the patient’s feeling of satiety.1
Insulin resistance: GLP-1 inhibits hepatic glucose production and improves glucose uptake by muscle (and also adipose) tissue.1
In pancreatic α-cells, GLP-1 inhibits glucagon secretion.1
In pancreatic β-cells, GLP-1 augments acute insulin secretion.1
In addition, results from preclinical studies suggest beneficial effects on chronic β-cell function, including increased insulin biosynthesis and promotion of β-cell neogenesis.
1. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;26:
GLP-1 offers a new mechanism with potential multiple effects on plasma glucose
*Preclinical data Adapted from Drucker DJ. Diabetes Care. 2003;26:

37. Postprandial GLP-1 Levels are Decreased in Patients with IGT and Type 2 Diabetes
Meal 20 * * * * * * * 15
GLP-1 (pmol/l) 10 *
Postprandial GLP-1 Levels are Decreased in Patients with IGT & Type 2 Diabetes
This slide shows data that indicate that postprandial GLP-1 concentrations are reduced in patients with type 2 diabetes and impaired glucose tolerance.
The top line represents GLP-1 concentrations in subjects with normal glucose tolerance (NGT); GLP-1 concentrations decrease in a statistically significant manner in patients with impaired glucose tolerance and type 2 diabetes, respectively.
This study was done by Toft-Nielsen and colleagues from Jens Holst’s group in Denmark.
Slide Background:
Fifty-four DM-2 (BMI 30.2, age 55.9, HbA1c 8.4%), 15 IGT (BMI 35.0, age 55.3, HbA1c 6.1%), and 33 NGT (BMI 29.6, age 56.2, HbA1c 5.9%).
All anti-diabetic medications were discontinued 3 days prior to study during which time subjects were fed a mixed meal (t=0) and blood samples taken for 6 subsequent hours.
Plasma concentration of GLP-1 were measured by means of RIA specific for C-terminus of GLP-1 and therefore measures the sum of GLP-1 (7-36) amide and its metabolite GLP-1 (9-36) amide. 5
NGT subjects
IGT subjects
T2DM patients 60
120
180
240
Time (minutes)
* P < 0.05
Toft-Nielsen et al. J Clin Endo & Meta. 2001; 86(8):

38. GLP-1 analogs Metabolism: Longer-acting GLP-1 receptor agonists
Degraded within minutes by enzyme dipeptidyl peptidase IV(DPP-IV)
Levels are low in DM2
Longer-acting GLP-1 receptor agonists
exenatide
liraglutide

39. Exenatide: from Gila monster saliva

40. Synthetic GLP-1 analog: Exenatide or ‘BYETTA’
FDA-approved June 2005 for use in DM2 in patients uncontrolled on combination therapy
Injected subcutaneously as 5-10 mcg twice daily within one hour of meals
AMIGOS trials compared addition of exenatide versus placebo to OHA
Reduction 1.1% HbA1C, weight loss (-4.5 Kg) at 82 weeks
Mild-moderate nausea and hypoglycemia
Lebovitz 2006 Atherosclerosis Suppl 7: 43-49

41. Change in HbA1C at 30 Weeks Stratified by Baseline HbA1C
Placebo
5 µg exenatide
10 µg exenatide
Baseline HbA1C <9%
Baseline A1C ≥9%
0.4
DISCUSSION POINTS:
Subjects with baseline A1C9% had greater reductions in A1C, compared to subjects with baseline A1C<9%.
SLIDE BACKGROUND:
Baseline A1C <9%: N=77 (Placebo), N=79 (5 µg), N=83 (10 µg)
Baseline A1C 9%: N=46 (Placebo), N=46 (5 µg), N=46 (10 µg)
113 – 30-week triple-blind, phase 3 study; patients with type 2 diabetes randomized to placebo or 5 or 10 µg exenatide BID w/SFU, ITT N=377
0.1%
0.1%
0.0
-0.4%
-0.4
-0.6%
Mean (±SE) Change in A1C From Baseline (%)
-0.7% *
-0.8 ** †
-1.2%
-1.2 **
-1.6
ITT, N = 377 (Placebo, n = 123; 5 µg exenatide, n = 125;
10 µg exenatide, n = 129) *P <0.01, **P < , †P <0.05
Buse J, et al. Diabetes 2004; 53(suppl 2):A82

42. Vildagliptin Sitagliptin
DPP IV inhibitors
Vildagliptin
Sitagliptin

43. GLP-1 Secretion and Inactivation
Intestinal
GLP-1
release
GLP-1 (9-36)
inactive
(>80% of pool)
GLP-1 (7-36)
active
Mixed meal
DPP-4
t½ = 1 to 2 min
Released by intestinal L-cells in response to ingested food (upper left), GLP-1 is rapidly and extensively inactivated (lower right).1
The kinetics of the inactivation process were explored in 8 healthy subjects and 8 T2DM patients,2 to all of whom the active amide GLP-1 (7-36) was administered subcutaneously or intravenously.
In all instances, the active amide was rapidly attacked at its N-terminal by dipeptidyl-peptidase–4 (DPP-4), leaving the inactive metabolite GLP-1 (9-36) and giving the active amide a half-life of only 1 to 2 minutes.
DPP-4 is a ubiquitous enzyme that circulates freely in plasma, exists at the surface of endothelial cells, and rapidly inactivates several biologically active peptides.
1. Kieffer TJ, McIntosh CH, Pederson RA. Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV. Endocrinology. 1995;136:
2. Deacon CF, Nauck MA, Toft-Nielsen M, Pridal L, Willms B, Holst JJ. Both subcutaneously and intravenously administered glucagon-like peptide I are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects. Diabetes. 1995;44:
Adapted from Deacon CF, et al. Diabetes. 1995;44:

44. Inhibition of DPP-4 Increases Active GLP-1
Intestinal
GLP-1
release
GLP-1 (9-36)
inactive
Mixed meal
GLP-1 (7-36)
active
DPP-4 inhibitor
DPP-4
Inhibition of DPP-4 by a drug designed to be highly selective and orally active may enable endogenous GLP-1 to avoid inactivation, augment the deficient incretin response seen in T2DM, and improve metabolic control across the multiple defects associated with the disorder.
Such hopes were the impetus for an exploratory trial1 in which 12 healthy persons fasted overnight and then ate a standardized breakfast 30 minutes after receiving single oral doses of placebo or the active drug NVP-DPP728.
The active drug increased the subjects’ plasma levels of prandial active GLP-1, with concomitant reduction in prandial glucose exposure. These findings, reported in 2000, were the first to provide direct evidence that inhibition of DPP-4 could be a viable pharmacological approach for potentiating the activity of endogenous GLP-1 in humans.1
1. Rothenberg P, Kalbag J, Smith H, et al. Treatment with a DPP-IV inhibitor, NVP-DPP728, increases prandial intact GLP-1 levels and reduces glucose exposure in humans [abstract]. Diabetes. 2000;49(suppl 1):A39. Abstract 160-OR.
Adapted from Rothenberg P, et al. Diabetes. 2000;49(suppl 1):A39.

45. DPP IV inhibitors: Sitagliptin or ‘JANUVIA’
FDA approved for use alone or with sensitizers
Prolongs half-life of endogenous GLP
Advantage orally administered once daily
Trials sitagliptin reveal HbA1C -0.5%
No effect on weight, no hypoglycemia, no adverse effects, needs renal adjustment
Lebovitz 2006 Atherosclerosis Suppl 7: 43-49

46. Amylin

47. Duncan and Buse 2006 Up-To-Date 12.3:Amylin and GLP-1 based therapies

48. Amylin Peptide hormone, co-secreted with insulin Low in DM1 and DM2
Suppresses post-prandial glucagon release (decreases hepatic glucose output)
Delays gastric emptying (inhibits appetite)
Duncan and Buse 2006 Up-To-Date 12.3:Amylin and GLP-1 based therapies in DM

49. Insulin and Amylin Mealtime Secretory Excursions30 25 20 15 10 5
Healthy Subjects
n = 6
600
400
200
Plasma amylin (pM)
Plasma insulin (pM)
Amylin
This slide shows plasma amylin and insulin concentrations during a 24-hour period in healthy subjects and demonstrates the mealtime excursions of both hormones. The arrows indicate the three main meals during the day and the graph shows the rise in both hormones immediately after each meal. The vertical axes show the respective concentrations of amylin (shown on the left) and insulin (shown on the right). In the plasma, the insulin:amylin molar ratio is approximately 20:1 during fasting and stimulated conditions.
Insulin
7 am
12 noon
5 pm
Midnight
Time
Adapted from Koda et al. Diabetes
9/18/2018 7:59:57 AM

50. Amylin is Deficient in Diabetes
Healthy (n=27) 5 10 15 20
Type 2 Insulin-Using (n=12)
Liquid meal
Mean (SE) plasma amylin (pmol/L)
Type 1 (n=190)
This slide shows similar data but also includes plasma amylin concentrations in a group of patients with type 1 diabetes (shown in green). In these patients, beta- cell function is negligible and insulin and amylin concentrations are often undetectable.
-30 30 60 90
120
150
180
Time after liquid meal (min)
Fineman et al. Diabetologia 1996 and unpublished data

51. Synthetic amylin analog: Pramlintide or ‘SYMLIN’
FDA approved for DM1 and insulin-requiring DM2 patients
Injected before meals, start with 25-50% dose and titrate as tolerated by nausea
Decrease premeal insulin dose by 50%
Mild weight loss, mild hypoglycemia, nausea
One year placebo-control revealed 0.6% reduction HbA1C and weight loss (1.4 Kg)
Duncan and Buse 2006 Up-To-Date 12.3:Amylin and GLP-1 based therapies in DM

52. Duncan and Buse 2006 Up-To-Date 12
Duncan and Buse 2006 Up-To-Date 12.3:Amylin and GLP-1 based therapies in DM
Originally from Clinical Diabetes 2002, 20: 137.

53. Dual PPAR agonists Muraglitazar and tesaglitazar
Stimulate both PPAR alpha and gamma with resulting benefit on lipids and glucose
Trial comparing muraglitazar 5 mg to pioglitazone 30 mg
HbA1C reduction 1.1 versus 0.9%*
Triglyceride (-27%), HDL-C (+16%)
More weight gain, similar edema
Long-term cardiovascular safety to be established
Lebovitz 2006 Atherosclerosis Suppl 7: 43-49

54. Pharmacotherapy summary
Glucose influx
Insulin demand
Insulin supply
Insulin resistance
Glucagon secretion
Acute β-cell function
Chronic β-cell function
α-Glucosidase inhibitors
Biguanides
Sulfonylureas
The primary metabolic defects of T2DM are heightened insulin demand and deficient insulin supply, and another contributing factor is uncompensated glucose influx.
Many of these specific problems are addressed by one or another existing class of oral antihyperglycemic drugs, each of which has distinctive mechanisms.1
α-Glucosidase inhibitors moderate glucose influx by delaying intestinal carbohydrate absorption, thereby mitigating postprandial glucose excursions.1 The utility of these agents depends in part on proper dietary compliance and is more effective in populations whose diet does not consist of highly processed foods. The widespread use of these agents in Japan and Spain is an excellent example of their utility in populations where a rice and fish diet is prevalent.
Thiazolidinediones (TZDs) work primarily by enhancing both basal and insulin-mediated suppression of HGP and to some extent by augmenting insulin-stimulated muscle glucose utilization.2
Metformin (of the biguanide drug class) lowers glucose levels, chiefly by reducing HGP.1
Sulfonylureas lower the glucose threshold for triggering β-cell insulin release.1
Glinides resemble sulfonylureas in enhancing acute β-cell function. Their short metabolic half-lives enable them to produce brief, episodic stimulation of insulin secretion.1 Of the glinides, nateglinide is rapidly reversible, whereas repaglinide is not.
1. Inzucchi SE. Oral antihyperglycemic therapy of type 2 diabetes: scientific review. JAMA. 2002;
2. DeFronzo RA. Impaired glucose tolerance: do pharmacological therapies correct the underlying metabolic disturbance? Br J Diabetes Vasc Dis 2003;3(suppl 1):S24-S40.
TZD
Meglitinides
GLP1
DPP IV inh
Dual PPAR
Insulin
inhaled
Amylin
Plasma glucose

55. Cost of therapy NAME FORM $ PRICE $ BYETTA 10 mcg 250mcg/ml 2.4 ml 230
EXUBERA
180 EA
Pack of 12
136
SYMLIN
0.6 mg
5 ml 96
JANUVIA
100 mg
100 tabs
525

56. When to refer to specialist?
Failure to achieve target control
DM2 with complications, e.g diabetic foot ulcer or proliferative retinopathy
Presence of comorbidities which restrict therapy, e.g severe CHF
Pregnancy

57. Thank you!