Acarbose

1. Acarbose
An update

2. Way Back When!!
•1980 –one oral med for Type 2 DM- few animal derived
insulins
•No published standards of care
•No home glucose monitors
•The United Kingdom Prospective Diabetes Study (UKPDS)
was years away
•Primary objective was to prevent hyperosmolar coma and
diabetic ketoacidosis
•Today several classes of oral medications
•Home glucose monitors, insulin pumps, some with built in
glucose monitors
•Most importantly “Standards of Care”

3. Diabetes a Challenging Disease
•Complex challenge with use of various meds
•Complex challenge with the psyche of each individual
patient
•My patients are experimental models and they are told that
•Patients are told we will work together to find the right
combination of meds, exercise and diet to control their
sugars
•Patients lifestyle has to be considered:
–Activity level
–Hours of work
–Timing of meals

4. Today’s agenda
•Understanding diabetes criteria
•Understanding carbohydrate metabolism
•Understanding acarbose
•Studies with Acarbose
•Competitors
•Summary

5. ADA DM Criteria using FBG (2003)
DIABETES MELLITUSDIABETES MELLITUS
IMPAIRED FASTING IMPAIRED FASTING
GLUCOSEGLUCOSE
NORMALNORMAL
FBGFBG *
³³ 126126 ( or 2-hr PG ³³ 200; or random BG ³³
200 + symptoms)
100-125100-125

<100<100

(* Diagnosis of DM or IFG needs confirmation on another day)

6. 1998 WHO Criteria for DM and Impaired 1998 WHO Criteria for DM and Impaired
Glucose Tolerance using FBG and 2-hr PG Glucose Tolerance using FBG and 2-hr PG
((Diabetes Med 15: 539, 1998)
FBG (mg/dL) 2-hr PG (mg/dL)
³126 OROR ³ 200
<126 ANDAND 140-199
<126 ANDAND <140
IGT, impaired glucose tolerance; PG, postprandial glucose
(Diagnosis of DM or IGT needs confirmation on another day)
DMDM
IGTIGT
NORMALNORMAL

7. Glucose intolerance
Normal ® Impaired glucose tolerance ® Type 2 diabetes
T i m e

8. IGT and CV outcomes
•IGT but not FPG predicted later CV disease in
Japan (1999, Diabetes Care)
•2-hr PG but not FPG predicted mortality in
DECODE study (1999, Lancet)
•2-hr PG predicted CV outcomes better than
FPG in Framingham study (2002, Diabetes
Care)
•2-hr PG had greater predictive value for
coronary events and overall CV mortality than
FPG in Finland (2002, Euro Heart J)
•Conclusion: Postprandial glucose, reflecting
glucose intolerance, is more predictive
of CV risk and mortality than FPG.

9. IGT and Risk of Vascular
Disease
Macrovascular
coronary disease, etc.
Microvascular
retinopathy, nephropathy
Marked increased risk
No increased risk

10. Fate of Absorbed Glucose
G
Glycogenesis
Glycolysis
Muscle Cells 50 %
G
Glycolysis
Lipogenesis
G
Glycogenesis
Glycolysis
Liver Cells 30 %
Fat Cells 5 %

11. Glucose Ingestion/Absorption
•Dietary intake of complex or simple carbs- mono-, di-, or
polysaccharides
•Rapid transit from mouth through esophagus to stomach
–Gastric emptying, regulated by duodenal osmoreceptors and
inhibitory GI hormones and peptides
•Intestinal digestion to monosaccharides by amylases and
intestinal disaccharidases
–Rapid intestinal glucose uptake (sodium-coupled)
•Entry into portal blood with delivery to liver (first) and then
peripheral blood (glucose “excursions”)
•Disposal of glucose (rapid=glucose tolerance; slow=glucose
intolerance)

12. Some Ways to Blunt Glucose
Excursions into Blood
•Reduce total caloric intake per day and per meal
•Reduce % of calories as carbs (low carb)
•Eat/drink slower
•Slow gastric emptying ( ­ in early type 2 DM)
•Increase fiber composition of the diet
•Block enzymatic digestion of complex
carbohydrate to monosaccharide
–acarbose (PrecoseR) or meglitol (GlysetR)

13. Fate today
•There is an increasing preference for
antidiabetic treatments to regulate post-meal
blood glucose.

14. What are alpha-glucosidase
inhibitors?
Understanding Acarbose

15. The α-Glucosidase Inhibitors:
Basic Characteristics of Acarbose & Miglitol
•Alpha-glucosidase inhibitors are saccharides that act
as competitive inhibitors
–of enzymes needed to digest carbohydrates: specifically
alpha-glucosidase enzymes
–in the brush border of the small intestines.
•The membrane-bound intestinal alpha-glucosidases
hydrolyze oligosaccharides, trisaccharides, and
disaccharides to glucose and other monosaccharides
in the small intestine.

16. The α-Glucosidase Inhibitors:
Basic Characteristics of Acarbose & Miglitol
•Acarbose also blocks pancreatic alpha-amylase in
addition to inhibiting membrane-bound alpha-
glucosidases.
•Pancreatic alpha-amylase hydrolyzes complex starches to
oligosaccharides in the lumen of the small intestine.
•Since alpha-glucosidase inhibitors are competitive
inhibitors of the digestive enzymes, they must be taken at
the start of main meals to have maximal effect.
•Their effects on blood sugar levels following meals will
depend on the amount of complex carbohydrates in meal.

17. The α-Glucosidase Inhibitors:
Basic Characteristics of Acarbose & Miglitol
•Inhibition of these enzyme systems reduces the rate
of digestion of carbohydrates.
•Less glucose is absorbed because the carbohydrates
are not broken down into glucose molecules.
•In diabetic patients,
–the short-term effect of these drugs therapies is to
decrease current blood glucose levels:
–the long term effect is a small reduction in hemoglobin
A1c levels.

18. The α-Glucosidase Inhibitors:
Basic Characteristics of Acarbose & Miglitol
•Examples of alpha-glucosidase inhibitors include:
–Acarbose- Precose
–Miglitol - Glyset
–Voglibose
•Even though the drugs act similarly, there are subtle
differences between acarbose and miglitol.
–Acarbose is an oligosaccharide, whereas miglitol resembles a
monosaccharide.
–Miglitol is fairly well-absorbed by the body, as opposed to
acarbose.
–Moreover, acarbose inhibits pancreatic alpha-amylase in addition
to alpha-glucosidase.

19. The α-Glucosidase Inhibitors:
Basic Characteristics of Acarbose & Miglitol
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139.
4-7
Mechanism of actionDelays carbohydrate absorption
Depends upon Postprandial hyperglycemia
Power Decreases HbA
1c
0.5% to 1%
Dosing 3 times daily
Side effects Flatulence
Main risk Liver enzyme elevation (rare)

20. The α-Glucosidase Inhibitors:
Basic Characteristics of Acarbose & Miglitol
Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139.
4-7
Best candidates Marked postprandial
Not recommended inIntestinal or liver disease
Starting dosage 25 mg QD for 2-4 weeks
25 mg QD for 2-4 weeks
25 mg BID for 2-4 weeks
25 mg TID for 2-4 weeks
50 mg TID, if needed
Adjust dosage Weekly, if needed and tolerated
Monitoring method SMBG, including postprandial

21. α - Glycosidase Inhibititor
•Acarbose
–Indicated for type 2 diabetes
•In addition with diet
•In addition with other anti-diabetic therapies
•Mode of action:
–Poorly absorbed 1% (act locally in G.I.T.)
–Inhibits α glucosidase, so inhibits CHO degradation
•Dose:
–50mg to 100mg 3 times daily before meals

22. Acarbose
•Side effects:
–Flatulence (77%), Diarrhea, Abdominal pain (21%)
•Since alpha-glucosidase inhibitors prevent the degradation of
complex carbohydrates into glucose, the carbohydrates will
remain in the intestine.
•In the colon, bacteria will digest the complex carbohydrates,
thereby causing gastrointestinal side effects such as flatulence
and diarrhea.
•Since these effects are dose-related, it is generally advised to
start with a low dose and gradually ↑ the dose to the desired
amount.
–Decreased iron absorption

23. Acarbose
•Side effects:
–If a patient using an alpha-glucosidase inhibitor suffers
from an episode of hypoglycemia, the patient should eat
something containing monosaccharides, such as glucose
tablets.
–Since the drug will prevent the digestion of
polysaccharides (or non-monosaccharides), non-
monosaccharide foods may not effectively reverse a
hypoglycemic episode in a patient taking an alpha-
glucosidase inhibitor.

24. Clinical studies
Acarbose

25. Meta-analysis of 7 long-term studies
M Hanefeld et al. Eur Heart J 25:10; 2004
Acarbose reduces the risk for AMI in
type 2 diabetic patients:
Kaplan-Meier survival curve for the time to develop any
CV event during treatment with either acarbose/placebo

26. placebo
acarbose
GLUCOSE
meal snack

27. STOP-NIDDM trial using Acarbose
•The STOP-NIDDM Trial was done to check the
effect of Acarbose on the probability of
remaining free of CVD
•1429 patients from 9 countries with IGT
–Men and women equally represented; ave. BMI =
30.9
–Randomized to placebo or acarbose, 100 gm tid with
meals
JL Chiasson et al. JAMA 290:486; 2003.

28. STOP-NIDDM trial using Acarbose
JL Chiasson et al. JAMA 290:486; 2003.

29. STOP-NIDDM trial using Acarbose
JL Chiasson et al. JAMA 290:486; 2003.

30. MAJOR CV EVENTSMAJOR CV EVENTS

31. HYPERTENSIONHYPERTENSION