ANTIDIABETIC MEDICATION


Sulfonylureas
Metformin

Thiazolidinediones
Insulin (including combined insulin-oral hypoglycemic treatment)
Metiglinides
Combined alpha- and gamma-PPAR agonists ("Glitazars")
Alpha-Glucosidase Inhibitors
Dipeptidyl Peptidase-4 (DPP-4) Inhibitors ("gliptins")
Glucagon-like peptide-1 (GLP-1) agonists
Free fatty acid receptor (FFAR1) agonists

GENERAL NOTES ON PHARMACOTHERAPY FOR DIABETES MELLITUS:

Note-Only 10% of people with Type 2 DM can achieve adequate glycemic control with lifestyle changes alone; most who can will show sig. changes within 6 wks, so give it at least that long.

I. Studies comparing insulin vs. oral agents as monotherapy

  1. 4,000 pts with newly diagnosed type II DM who failed dietary tx were randomized to one or the other. Insulin pts had lower fasting glucose but no diff. in HbA1c and hypoglycemic events and weight gain were more common in insulin pts (Ann. Int. Med 128:165, 1998--JW)

II. Studies of comparing different combination therapies:

  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 in 58 pts with type 2 DM with HbA1c normalized on insulin + metformin then randomized to (NoVoLog 70/30 BID + metformin) vs. (metformin + glyburide + pioglitazone), at 3y, there was no sig. diff. between the groups in mean HbA1c, mean weight gain, incidence of hypoglycemia, or qulaity-of-life measures. (Diab. Care 32:1789, 2009-JW)
  4. 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) 

II. Studies comparing different oral hypoglycemics:

  1. 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.
  2. 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)
  3. 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)

III. Studies comparing different hypoglycemics as adjuncts to metformin:

  1. In a meta-analysis of 31 studies in pts with inadequately-controlled DM on maximal-tolerated doses of metformin and not on insulin, all classes of antidiabetics showed sig. reductions in HbA1c compared with placebo including sulfonylurease, metiglinides, thiazolidinediones, and DPP-4 inhibitors;  Alpha-Glucosidase Inhibitors and Glucagon-like peptide-1 (GLP-1) agonists only showed sig. better reduction in HbA1c than placebo when starting hbA1c was 8% or more and only in studies lasting more than 24wks. (JAMA 303:1410, 2010-AFP)

SUFONYLUREAS

First generation sulfonylureas:

Drug Starting dose/d in mg Maximum dose/d in mg
Acetohexamide (QD or BID) 500 750
Chlorpropamide (QD) 100 375
Tolazamide (BID) 250 500
Tolbutamide (TID) 500 2000

Second generation sulfonylureas:

Drug Starting dose/d in mg Maximum dose/d in mg
Glyburide (QD or BID) 5mg (2.5 if elderly) 20
Micronized glyburide (QD or BID) 1.0 12
Glipizide (QD or BID) 5 40
Glipizide ex-rel (QD) 5 40
Glimepiride 1-2 8

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)
    1. Risk for B12 deficiency sig. greater than with placebo and increases with duration of treatment (BMJ 340:c2181, 2010-JW)
    2. Consider routine monitoring of B12 levels in pts on long-term metformin
  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. Clinical Trials

  1. 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. Adverse 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 and other adverse cardiovascular outcomes
    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, 2009-JW)
    4. In a retrospective study in pts > 65yo who were treated with rosiglitazone or pioglitazone and followed for up to 3y, there was no sig. diff. between the two drugs in associated with for acute MI but rosiglitazone use was associated with sig. higher risk of CVA (HR 1.25), heart failure (HR 1.14), and overall mortality (HR 1.18) (JAMA 304:411, 2010-abst) 
    5. 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).
    6. In an extension of the above meta-analysis, of 56 trials involving 35,531 pts randomized to rosiglizatone vs. control therapy for at least 24wks, rosiglitazone recipients had sig. higher incidence of MI (OR 1.28) but not for cardiovascular mortality (JAMA e-publication ahead of printing; http://dx.doi.org/10.1001/archinternmed.2010.207).
    7. In an observational cohort study (using claims data?) in 227,571 pts starting therapy with rosiglitazone or pioglitazone, over median 105d f/u, rosiglitazone recipients had sig. higher incidence c/w pioglitazone recipients of CVA (HR 1.27), heart failure (HR 1.25), and all-cause mortality (HR 1.14) (Arch. Int. Med. e-publication ahead of printing; http://dx.doi.org/10.1001/jama.2010.920)
    8. In a meta-analysis of 16 observational studies involving 810,000 pts with type 2 diabetes, rosiglitazone was associated with sig. increased risk c/w pioglitazone for MI (OR 1.16), HF (OR 1.22), and overall mortality (OR 1.14) (BMJ 342:d1309, 2011-JW)
  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)
  8. Possible association with Bladder Cancer
    1. Unclear as of 2010 but FDA is reviewing data on risk with long-term use of pioglitazone

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%-Under an FDA REMS program as of 2011 due to cardiovascular risk
  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)

 

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. May reduce risk of cardiovascular events in patients with impaired glucose tolerance ("STOP-NIDDM" Trial; JAMA 290:486, 2003)
  6. 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)
  1. 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
  2. Voglibose (investigational as of 2009)

DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITORS ("GLIPTINS")

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.

Doses must be lowered in patients with renal insufficiency

I. Specific drugs

  1. Vildagliptin (Galvus)-Associated with reduced HbA1c both alone and in combination with pioglitazone
  2. Sitagliptin (Januvia)-Associated with reduced HbA1c alone (0.7-0.8% c/w placebo) and in combination with either metformin or pioglitazone
  3. Saxagliptin (Onglyza) 2.5-5mg PO QD (max 2.5mg for adults with mod-severe renal impairment)
  4. Linagliptin (Tradjenta) 5mg PO QD
II. Comparisons with other glucose-lowering drugs
  1. A meta-analysis of trials involving over 14,000 adults with type 2 DM found that:
    1. Gliptin monotherapy was found to be associated with sig. smaller reductions in HbA1c than metformin monotherapy (mean difference 0.2%)
    2. Metformin + gliptin combination therapy was associated with sig. less HbA1c reduction vs. metformin + either sulfonylurea, GLP-1 agonist, or pioglitazone, though (metformin + sulfonylurea) was associated with sig. higher incidence of hypoglycemia than (metformin + gliptin). (BMJ 344:e1369, 2012-JW)

GLUCAGON-LIKE PEPTIDE-1 (GLP-1) AGONISTS

aka "Incretin Mimetics"

I. Exenatide (Byetta)

  1. 5 mcg SQ BID, 60min before breakfast & supper; may increase to 10 mcg after 1mo
  2. "Bydureon"-Q1wk formulation
  3. May increase the risk of hypoglycemia if used with a sulfonylurea so consider reducing sulfonylurea dose when starting treatment
  4. In a study in 491 adults with Type 2 DM and HbA1c 7.1%-11.0%, all on metformin, randomized to add exenatide 2mg Qwk, sitagliptin 100mg/d, or pioglitazone 45mg/d, after 26wks, exenatide pts had sig. greater reductions in mean HbA1c than sitagliptin or pioglitazone (1.5% vs. .9% and 1.2% respectively and also lots more weight (2.3kg vs. 0.8kg and gain of 2.8kg, respectively).  (Lancet 376:431, 2010-JW)
  5. Has been successfully combined with insulin in at least one clinical trial (Ann. Int. Med. 154:103, 2011-JW)
II. Albiglutide
  1. Administered subcutaneously
  2. Half-life is about 5 days; dosing intervals clinical trials has been Q1wk-Q1mo

III. Liraglutide (Victoza)

  1. Dose: 0.6mg SQ QD for first week then 1.2mg SQ QD; may increase to 1.8mg SQ QD
  2. Associated with sig. greater mean declines in HbA1c than exenatide in one randomized study in type 2 diabetics (Lancet 374:39, 2009-JW)
  3. Contraindicated with personal or family history of medullary thyroid cancer

IV. Lixisenatide (not yet marketed in U.S. as of 2011)

V. Pramlintide (Symlin)
  1. Can increase risk of hypoglycemia
  2. When starting, reduce insulin dose by 50%
  3. In type 2 DM, initiate at 60ug SQ immediately prior to meals, can increase to 120mcg as tolerated
An injectable treatment intended as an adjunct to insulin, when optimized insulin dosing fails to control glucose in type 1 or type 2 diabetics

FREE FATTY ACID RECEPTOR (FFAR1) AGONISTS

I. FFAR1 is found primarily on pancreatic beta cells
II. It promotes insulin secretion when activated, but only if glucose concentrations are also rising
III. TAK-875 is an oral selective agonist of FFAR1 which, in early trial,s has glucose-lowering effects similar to sulfonylureas with much less tendency to cause hypoglycemia (Lancet 2/27/2012 e-publication ahead of print-JW)

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)