Drug update: oral agents for type 2 diabetes. (Clinical Rounds).

Treatment of type 2 diabetes has come a long way in a few years. Until 1994, the only drug options in the United States were sulfonylureas and insulin. Today, there are four additional classes of glucose-lowering drugs.

Diet and exercise remain the cornerstones of treatment. Medication is indicated when lifestyle measures fail to achieve the recommended hemoglobin [A.sub.1c] value within 2-4 months. Oral agents are usually the first line of drug treatment. Patients who present with exceptionally high blood glucose levels or symptoms such as polyuria, polydipsia, and glycosuria may initially need insulin, but these patients can often be switched to oral agents once their glucose levels normalize.

Two new trends have emerged as a result of the wider range of treatment options and greater recognition of the multiple defects that underlie type 2 diabetes. Metformin-which targets both insulin resistance and hepatic glucose production-has largely replaced the sulfonylureas as first-line monotherapy. And drug combinations are now used earlier. Even triple therapy-for which there are little supporting data-is now widely used, often with good results.

A new wrinkle is single-pill formulations that combine two different drugs: metformin plus glyburide (Glucovance), metformin plus glipizide (Metaglip), and metformin plus rosiglitazone (Avandamet). Combination therapy is state of the art, convenience is a plus, and it means patients buy one less pill. But each formulation is hampered by difficulties in delivering the optimal dose of both drugs.

While some recent data suggested that metformin and sulfonylureas are probably not teratogenic, the use of any oral glucose-lowering agent should still be avoided during pregnancy and breast-feeding. Women taking oral hypoglycemic agents who become pregnant should switch to insulin as soon as possible.

 
Drug                                 Dosage             Cost/Day * 
 
BIGUANIDE 
 
metformin                            500-2,000 mg/day,  $1.40 
                                     divided            (1,000 mg) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SULFONYLUREAS 
 
Oldest and cheapest oral agents; 
 long-acting insulin secretagogues. 
 Emphasize nutrition and physical 
 activity to avoid weight gain. 
 Newer-generation agents, which 
 produce less hypoglycemia, have 
 largely replaced the older 
 ones. Dosages are generally 
 lower when used with another 
 agent. 
glimepiride                          1-8 mg/day,        $0.46 
(Amaryl)                             once or divided    (2 mg/day) 
 
 
 
 
 
 
glipizide sustained-release          2.5-20 mg,         $0.38 
(Glucotrol XL)                       once daily         (5 mg) 
 
 
 
 
 
 
 
 
 
glyburide                            1.25-20 mg/day,    $1.12 
                                     once or divided    (10 mg) 
 
 
 
 
 
 
 
 
chlorpropamide                       250-375 mg/day,    $0.69 
                                     divided            (300 mg/day) 
 
 
 
 
 
FAST-ACTING INSULIN SECRETAGOGUES 
 
Technically repaglinide and 
 nateglinide are different classes 
 of chemicals, but for practical 
 purposes they are very similar. 
 Most useful in patients who are 
 candidates for a sulfonylurea but 
 have erratic schedules. Short 
 action allows premeal dosing and 
 skipping a dose if meal is missed. 
 Hypoglycemia risk is lower than 
 for sulfonylureas because the 
 drugs clear faster. Both drugs in 
 class are taken 5-15 minutes 
 before meals. 
 
nateglinide                          60-120 mg          $2.88 
(Starlix)                            beore meals        (60 mg t.i.d.) 
 
 
 
 
repaglinide (Prandin)                0.5-4 mg           $2.79 
                                     before meals       (1 mg t.i.d.) 
 
 
 
 
 
 
THIAZOLIDINEDIONES 
 
The insulin-sensitizing 
 "glitazones" (also known as TZDs), 
 hailed as a breakthrough when 
 they appeared in the 1990s, took 
 a hit when troglitazone (Rezulin) 
 was withdrawn from the market in 
 2000 because of liver toxicity. 
 The two available TZDs do not 
 appear to pose the same risk, 
 although liver monitoring 
 requirements remain. Generally 
 viewed as second-line or third- 
 line drugs, used in combinations. 
 Rosiglitazone and pioglitazone 
 have similar efficacy but differ 
 significantly in their lipid 
 effects. Both can cause weight 
 gain and edema and are 
 contraindicated in patients with 
 severe heart failure. 
 
pioglitazone                         15-45 mg/day       $4.74 
(Actos)                                                 (30 mg/day) 
 
 
 
 
 
 
 
 
 
 
rosiglitazone                        4-8 mg/day,        $2.56 
(Avandia)                            once or divided    (4 mg) 
 
 
 
 
 
 
 
 
 
GLUCOSIDASE INHIBITORS 
 
acarbose                             25-100 mg          $1.74 
(Precose)                            before meals       (50 mg t.i.d.) 
 
 
 
 
 
 
 
 
 
 
 
 
miglitol                             25-100 mg          $1.95 
(Glyset)                             before meals       (50 mg t.i.d.) 
 
 
 
Drug                                 Comment ** 
 
BIGUANIDE 
 
metformin                            Only biguanide currently available 
                                      in United States. Has become the 
                                      workhorse of diabetes treatment, 
                                      particularly for overweight 
                                      patients. Start dosage low (500 
                                      mg once daily) and titrate up 
                                      slowly to avoid gastrointestinal 
                                      side effects. Usually taken twice 
                                      a day or three times a day. Lower 
                                      dosages (1,000-1,700 mg/day) 
                                      generally used when combined with 
                                      another oral agent. Extended- 
                                      release form (Glucophage XR) with 
                                      once-daily dosing may be more 
                                      convenient but may not be more 
                                      tolerable. 
 
SULFONYLUREAS 
 
Oldest and cheapest oral agents; 
 long-acting insulin secretagogues. 
 Emphasize nutrition and physical 
 activity to avoid weight gain. 
 Newer-generation agents, which 
 produce less hypoglycemia, have 
 largely replaced the older 
 ones. Dosages are generally 
 lower when used with another 
 agent. 
glimepiride                          Second-generation agent. Major 
(Amaryl)                              advantages: comes in 1-mg; 2-mg, 
                                      4-mg, and 8-mg strengths, and 
                                      deeply scored tablets are easily 
                                      divided for more flexible dosing. 
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