Diabetes-Oral Monotherapy and Combination Therapy
Diabetes-Oral Monotherapy and Combination Therapy
Diabetes-Oral Monotherapy and Combination Therapy
127
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9
Median A1C (%)
Conventional
8
Chlorpropamide
Glyburide
7
Insulin
Metformin
6
0 3 6 9
Years
FIGURE 8-1. Natural history of oral monotherapy: glycemic
response in UKPDS obese substudy.2
Mode of Action*
Improve Delay
Improve Insulin Gastro-
Stimulate Hepatic Action in Intestinal
Insulin Response Muscle/ Glucose
Secretion to Insulin Fat Absorption
Sulfonylureas
and
Secretagogues
Metformin
Glitazones
α-Glucosidase
Inhibitors
Contraindications to an agent
Synergy of mechanisms of action
Lack of the expected therapeutic response
Occurrence of side effects
Hypoglycemia
Weight gain
Fluid retention
Problems with cost
Convenience and adherence
Not overweight
No family history of type 2 diabetes
Family (or personal) history of autoimmune disorders
A positive laboratory test for anti-glutamic acid decarboxy-
lase (GAD) autoantibodies confirms the LADA diagnosis
and calls for immediate insulin therapy.
–20
–40
–60
0 2 4 8 12 16
Weeks of treatment
FIGURE 8-2. Temporal onset of glycemic improvement with three
classes of oral therapies.13-15
Nateglinide
Acarbose
Repaglinide
Rosiglitazone
Pioglitazone
Glimepiride
Glipizide GITS
Metformin
Major
Typical Patient Contraindication
higher A1C values (>8%) may have a more rapid clinical response
to a sulfonylurea because, unlike metformin, these agents do not
require slow titration to minimize side effects other than hypo-
glycemia.
A remaining question regarding sulfonylureas is whether they
are all interchangeable. Several are available in conventional for-
mulations at very low generic prices (notably glyburide and glip-
izide). In some formularies, other sulfonylureas are excluded,
including long-acting agents that can be taken once daily (e.g.,
extended-release glipizide and glimepiride). However, beyond the
127-144.CADRE08.QX 4/27/04 5:56 PM Page 136
Maximal
Therapeutic effect
Effect
Half-maximal
Side effect
Half-maximal Maximal
Dose
FIGURE 8-4. Dose-effect relationship for antihyperglycemic
monotherapy. Graphic representation of theoretical dose-effect
relationship for many oral antihyperglycemic drugs. Half-maximal
dosages yield far more than one-half the maximal therapeutic
effect, while side effects rise sharply as dosage nears maximum.34
Other Combinations
Individualized combinations are also possible. Notably, a rapid-act-
ing secretagogue can be substituted for a sulfonylurea when meal
patterns are erratic, when unpredictable hypoglycemia has proved
a problem, or when postprandial hyperglycemia is judged espe-
cially important to control.37 Similarly, an α-glucosidase inhibitor
can be substituted for either metformin or a glitazone in these
combinations when one or both is contraindicated or not toler-
ated.38 The combination of an α-glucosidase inhibitor and a
rapid-acting secretagogue is not logical, because both target post-
prandial glycemia and have little effect on basal glucose control.
Single-Pill Combinations
Recently single-pill combinations of agents have been introduced,
although their roles are not yet well defined.These are Glucovance
(glyburide plus metformin), Metaglip (glipizide plus metformin),
and Avandamet (rosiglitazone plus metformin).39-41 These fixed-
dose combination formulations are suggested to be simpler to take
and therefore to encourage higher adherence, but this has not been
proven. In fact, the number of pills with fixed-dose combination
therapy is usually not less than with separate pill combinations. For
example, full-dose sulfonylurea plus metformin can be taken as 4
mg glimepiride once daily plus 1,000 mg metformin twice daily
(three pills). This compares with two Glucovance 0.5/500-mg
tablets twice daily (four pills) for the same effect. Further, it seems
unlikely that fixed-dose combinations will be less expensive in the
long run. Finally, dose titration designed to minimize side effects
(notably those of metformin and glitazones) is likely to be more dif-
ficult with fixed-dose combinations. Future combinations of lower
doses of glitazones with metformin, and potentially with long-act-
ing sulfonylureas, have the potential for simpler once-daily combi-
nation therapy options in early type 2 diabetes. For the present,
these combinations cannot be assigned standard treatment status, but
they may be appropriate for individualized use by some patients.
127-144.CADRE08.QX 4/27/04 5:56 PM Page 140
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