ORAL HYPOGLYCEMICS

See section on Insulin for discussion of combined insulin-oral hypoglycemic treatment

Note--Both sulfonylureas and metformin decrease serum glucose by 40-50 mg/dl and HbA1c by 1.5-2.0%. While sulfonylureas cause wt gain of 3-7 lbs, metformin usually causes wt loss of 3-5 lbs.

Sulfonylureas
Metformin
Thiazolidinediones
Metiglinides
Combined alpha- and gamma-PPAR agonists ("Glitazars")
Alpha-Glucosidase Inhibitors
Dipeptidyl Peptidase-4 (DPP-4) Inhibitors

I. Studies of combination therapy with > 1 oral hypoglycemic:

1. In a randomized trial in 639 type 2 diabetics 35-75yo with HbA1c 7.5-11.0% despite tx with maximal dose of a sulfonylurea, randomized to addition of metformin (titrated to max 850mg TID) vs. pioglitazone (titrated to max 45mg/d), HbA1c's at 1y were nonsig. lower in metformin group (7.45% vs. 7.61%) (Diab. Care 27:141, 2004--JW)
2. In 44 pts already on a sulfonylurea, repaglinide 0.5-2mg before breakfast & dinner didn't alter mean glycemic control but did lower postprandial glucose peaks.
3. In a study of 62 pts with HbA1c > 8.0% on maximal doses of metformin + a sulfonylurea randomized to pioglitazone vs. NPH insulin QHS, both tirated up as needed; over 16wks, there was no sig. diff. in degree of A1c reduction but insulin group had sig. more hypoglycemic episodes (Am. J. Med. 116:230, 2004--AFP) 
4. In a study of 365 pts with HbA1c 7.1-10% despite maximal doses of metformin + glyburide randomized to rosiglitazone vs. placebo, at 24wks, the mean HbA1c was sig. lower (by 1%) in pts on rosiglitazone (Am. J. Med. 116:223, 2004--AFP)

II. Studies comparing different oral hypoglycemics:

1. In a study of1199 patients with type 2 DM not controlled on diet alone randomized to metformin (titrated up to 850mg TID) vs. pioglitazone (titrated up to 45mg/d); At 1y there was no sig. diff. in mean HbA1c reduction, but LDL reduction was sig. greater in metformin group, though pioglitazone group had sig. greater increases in HDL and reductions in TG (J. Clin. Endo. Metab. 89:6068, 2004--JW)
2. Nateglinide 60-120mg TID was less effective at glycemic control than Glyburide 10mg QD in one randomized trial (unpublished study cited in Med. Lett. 43:29, 2001)

SUFONYLUREAS

First generation sulfonylureas:

Second generation sulfonylureas:

• All can cause very severe and long-lasting hypoglycemia
• Main mechanism: Increase insulin secretion (and secondarily, increasing # of periph ins. receptors and thus tissue uptake of glucose)
  • Produce hyperinsulinemia; this could theoretically accelerate atherogenesis and lead to adverse CV events
• Predominantly renal excretion, except chlorpropamide
• Monitor effect with fasting FSG--usually produce 50-60mg/dl reduction in fasting glucose, 1-2% reduction in HbA1c
• Start with low dose and don't change dose > Q3-4wks
• Tend to be ineffective in pts with little residual insulin secretory capacity (this tends to occur 5-10y after initiating tx), severely obese pts, and pts with fasting glu > 270
• Tend to cause 3-6lb weight gain
• Chlorpropamide has a long t-1/2, high tendency towards hyponatremia & prolonged hypoglycemia; prob. not good in elderly; start with 50 Qam, increase as needed to 250 Qam
• Glyburide also has an especially long t-1/2 and has some active metabolites
• Tolbutamide has shortest t-1/2; glipizide also short

METFORMIN

I. Pharmacology

1. Stimulates glucose uptake in peripheral tissues
2. Decreases hepatic gluconeogenesis
3. Does not affect insulin secretion and requires presence of insulin to work
4. Take with food
5. Renally excreted
6. Can be used alone or in conjunction with a sulfonylurea, thiazolidinedione, or insulin

II. Contraindications (associated with rare but fatal lactic acidosis)

1. Cr > 1.5 for men, > 1.4 for women
2. Heart Failure
   1. Thought to increase risk of lactic acidosis, but evidence may not support this
   2. Metformin use was NOT associated with significantly increased risk of mortality or (mortality or hospitalization) in a reprospective cohort study of 1,883 pts with CHF; there were no deaths due to lactic acidosis in the cohort. (Diab. Care 28:2345, 2005--JW)
3. Liver disease (increases risk of lactic acidosis)
4. COPD
5. EtOH abuse

III. Stop Rx with intercurrent illness or 2d before procedures which may decrease renal perfusion, e.g. cardioresp. failure, shock, septicemia, IV contrast, surgery.

IV. Main side effects:

1. Nausea, anorexia, metallic taste, flatulence, diarrhea
2. Can lower vit. B12 and folate levels (through decreased absorption)
3. Tends to cause 2-4lb weight loss; may lower LDL and TG levels
4. Lactic acidosis: rare in pts with normal renal function at recommended doses; usually requires some degree of renal impairment; can be fatal.

V. Dosing: Starting dose: 500 QD or 250 BID, increase by 250 Qwk to 850 BID as needed, max. daily dose 2550/d

THIAZOLIDINEDIONES

I. Pharmacology

1. Decrease insulin resistance by binding to "gamma"-type nuclear peroxisome proliferator-activated receptors ("PPAR") involved in transcription of insulin-responsive genes; in the presence of insulin, decrease gluconeogenesis and increase skeletal muscle and adipose glucose uptake; also increase peripheral clearance of insulin
2. May also decrease triglycerides and BP; maximum effects may require up to 12wks of tx
3. Can combine w/sulfonylureas, metformin, and/or insulin
4. Ass'd with decrease in HbA1c of 1-1.5%
5. See very little change in glucose if change from sulfonylurea monotherapy to troglitazone monotherapy
6. Because of hepatotoxicity, probably not a good idea for monotherapy

II. Side effects

1. 1-2% had mild increase in serum transaminase levels with troglitazone (since removed from the market); also reports with Rosiglitazone and Pioglitazone
   1. Monitor LFT's at baseline, Qmo x 12mos then Q3mos; d/c if > 3x normal or signs/sx of hepatotoxicity
2. May lower serum concentrations of oral contraceptives
3. 15-20lb weight gain
4. May cause edema & fluid overload
5. May cause mild anemia, possibly due to fluid retention
6. May increase the risk of Heart Failure
   1. Ass'd with HR of 1.76 (sig.) c/w other oral hypoglycemics after adjustment for confounders in one retrospective study (Diab. Care 26:2983, 2003--JW)
   2. In a meta-analysis of 42 randomized trials involving over 28,000 pts, rosiglitazone was associated with sig. increase risk for MI (OR 1.43) compared with controls of other glucose-lowering drugs or placebo (NEJM 356:2457, 2007-JW)
   3. In a study in 4,458 pts with Type 2 DM and HbA1c 7.0%-9.0% on either sulfonylurea or metformin monotherapy randomized to (add rosiglitazone) vs. (receive both metformin + sulfonylurea), over 5-7y f/u, incidence of (cardiovascular death or hospitalization) was not sig. diff. for the two groups though rosiglitazone was associated with sig. increased risk of (death or hospitalization from heart failure) (HR 2.1); also, lower-limb fx were sig. more common in women in the rosiglitazone group (RR 2.93) ("RECORD" trial; Lancet 373:2125, 20009-JW)
   4. In a meta-analysis of 42 randomized trials in over 28,000 pts comparing rosiglitazone with other hypoglycemic drugs or placebo, rosiglitazone was associated with sig. increased incidence of MI (OR 1.43) (Nissen and Wolski, NEJM e-pub ahead of printing, 6/14/07).
7. Effects on bone density
   1. Rosiglitazone found to reduce bone mineral density in postmenopausal women  (seen in one 2wk randomized trial; J. Clin. Endocrin. Metab. 92:1305, 2007--JW) and to be associated with an increased risk of fractures in a prospective study (NEJM 355:2427, 2007--JW)
   2. See above Lancet 2009 reference re: effects on fracture risk
   3. In a meta-analysis of 10 randomized trials involving over 14,000 pts, use of rosiglitazone or pioglitazone was associated with sig. increase in risk of fractures (OR 1.45); subgroup analysis showed sig. increased risk in women (OR 2.23) but not in men. (CMAJ 180:32, 2009-JW)

III. Dosing

1. Troglitazone (Rezulin)-Removed from U.S. market due to concerns over hepatotoxicity
2. Rosiglitazone (Avandia) 4-8mg/d divided either QD or divided BID--Raises HDL and LDL 12-19%
3. Pioglitazone (Actos) 15-45mg QD--slightly longer t-1/2 than rosiglitazone

(Source: Med. Lett. 39:49, 1997, 41:71, 1999)

METIGLINIDES

I. Pharmacology

1. Work by binding to K channels on pancreatic beta cells and increasing insulin secretion; intended to increase insulin response to meals, the idea being it would be less likely to result in serious hypoglycemia if a meal is missed
2. Rapidly metabolized--plasma t-1/2 is about 1h
3. Hepatically metabolized; use w/caution in pts with impaired hepatic function

II. Clinical studies

1. Unpublished data indicate repaglinide 1-4mg before meals lowers HbA1c by 1.3-1.9%
2. Can cause hypoglycemia though less than with sulfonylureas; no other adverse effects except for slightly higher incidence of serious cardiovascular events in comparison trials with glyburide or glipizide (4% vs. 3%; cited in Med. Lett. rvw.)

III. Specific meds

1. Repaglinide (Prandin)
   1. Dose:  0.5mg before each meal; can increase to max 4mg QID
   2. Approved for monotherapy or use in combination w/metformin though has been studied in combination with sulfonylureas as well
2. Nateglinide (Starlix)
   1. Dose: 1-4mg TID before meals

(Sources include Med. Letter 40:55, 1998; 43:29, 2001)

COMBINED ALPHA- AND GAMMA-PPAR AGONISTS ("GLITAZARS")

I. Pharmacology

1. Combined alpha- and gamma-peroxisome proliferator-activated receptor agonists
   1. Thiazolidinediones ("glitazones") are PPAR-gamma agonists
   2. Fibric Acid Analogs are PPAR-alpha agonists
2. Reduce HbA1c (PPAR-gamma-mediated)
3. Increase HDL (PPAR-alpha-mediated)
4. Reduce triglycerides (PPAR-alpha-mediated)

II. Specific Drugs

1. Muraglitazar (Pargluva)
2. Tesaglitizar (Galida)

Note--Development of both these agents was discontinued in 2006 by their respective manufacturers before either was approved by the FDA, due to concerns regarding an association with increased risk of cardiovascular events.

III. Adverse effects

1. In a review of five randomized placebo-controlled trials involving 3,725 adults with type 2 DM, muraglitazar 5mg/d c/w placebo was associated with sig. increased incidence of (death, MI, or CVA) (1.47% vs. 0.67%) (JAMA 294:2633, 2005--JW)

ALPHA-GLUCOSIDASE INHIBITORS

I. Pharmacology

1. Inhibit digestion of CHO in gut
2. Can cause troublesome GI side effects (diarrhea, flatulence)
3. Contraindicated in pts with pts with serious intestinal disorders, e.g. inflammatory bowel disease
4. May increase the risk of hypoglycemia in patients who are also on a sulfonylurea
5. In patients on an alpha-glucosidase inhibitor, treat hypoglycemia with oral GLUCOSE not oral sucrose because the medication will inhibit breakdown of the latter into fructose and glucose

II. Dosing

1. Acarbose (Precose) 50-100mg TID
   1. Avoid in pts with inflammatory bowel disease or Cr > 2.0
   2. Decreases HbA1c 0.5% or so; fasting blood glucose by 16-20mg/dl
   3. May cause hepatotoxicity
   4. In one study of 90 pts with DM and inadequate control on a suflonylurea and metformin, Acarbose 100 TID vs. placebo ass'd with sig. 6mo HbA1c (down 0.5% vs. up 0.1% w/placebo) (Diab. Care 21:1154, 1998-JW)

2. Miglitol (Glyset) 50mg TID before meals (start at 25mg TID and increase after 4-8wks; max 100mg TID)
   1. Decreases HbA1c by 1.5 or so
   2. May have less tendency to hepatotoxicity than Acarbose
3. Voglibose (investigational as of 2009)

DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITORS

DPP-4 is an enzyme that degrades incretins (like glucagon-like peptide 1 and glucose-dependent insulinoptropic peptide), which are intestinal hormones secreted in response to a meal, and which stimulate insulin secretion and suppress glucagon release.

I. Vildagliptin (Galvus)

1. Associated with reduced HbA1c both alone and in combination with pioglitazone

II. Sitagliptin (Januvia)

1. Associated with reduced HbA1c alone (0.7-0.8% c/w placebo) and in combination with either metformin or pioglitazone

III. Saxagliptin (Onglyza)

1. Dose 2.5-5mg PO QD (max 2.5mg for adults with mod-severe renal impairment)