acarbose

Acarbose

An update

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”

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

Today’s agenda

• Understanding diabetes criteria

• Understanding carbohydrate metabolism

• Understanding acarbose

• Studies with Acarbose

• Competitors

• Summary

ADA DM Criteria using FBG (2003)

DIABETES MELLITUSDIABETES MELLITUS

IMPAIRED FASTING IMPAIRED FASTING GLUCOSEGLUCOSE

NORMALNORMAL

FBGFBG *

126126 ( or 2-hr PG 200; or random BG 200 + symptoms)

100-125100-125

<100<100

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

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)

126 OROR 200

<126 ANDAND 140-199

<126 ANDAND <140IGT, impaired glucose tolerance; PG, postprandial glucose

(Diagnosis of DM or IGT needs confirmation on another day)

DMDM

IGTIGT

NORMALNORMAL

Glucose intolerance

Normal Impaired glucose tolerance Type 2 diabetes

T i m e

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.

IGT and Risk of Vascular Disease

Macrovascularcoronary disease, etc.

Microvascular

retinopathy, nephropathy

Marked increased risk

No increased risk

Fate of Absorbed Glucose

GGlycogenesis

Glycolysis Muscle Cells 50 %

GGlycolysis

Lipogenesis

GGlycogenesis

Glycolysis

Liver Cells 30 %

Fat Cells 5 %

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)

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)

Fate today

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

What are alpha-glucosidase inhibitors?

Understanding Acarbose

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.


• 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.


• 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.


• 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.


Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139.

4-7

Mechanism of action Delays carbohydrate absorption

Depends upon Postprandial hyperglycemia

Power Decreases HbA1c 0.5% to 1%

Dosing 3 times daily

Side effects Flatulence

Main risk Liver enzyme elevation (rare)


Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139.

4-7

Best candidates Marked postprandial

Not recommended in Intestinal or liver disease

Starting dosage 25 mg QD for 2-4 weeks25 mg QD for 2-4 weeks25 mg BID for 2-4 weeks25 mg TID for 2-4 weeks50 mg TID, if needed

Adjust dosage Weekly, if needed and tolerated

Monitoring method SMBG, including postprandial

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

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

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.

Clinical studies

Acarbose

Meta-analysis of 7 long-term studies

M Hanefeld et al. Eur Heart J 25:10; 2004Acarbose 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

placebo

acarbose

GLUCOSE

meal snack

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.

STOP-NIDDM trial using Acarbose

JL Chiasson et al. JAMA 290:486; 2003.

MAJOR CV EVENTSMAJOR CV EVENTS

HYPERTENSIONHYPERTENSION

acarbose

Health & Medicine

diabetes criteria

acarbose studies

acarbose competitors

sugars patients lifestyle

standards of care

right combination of

carbohydrate metabolism

primary objective