**Criteria for Non-formulary Use of Thiazolidinediones**

**VHA Pharmacy Benefits Management Service and the Medical Advisory
Panel**

*The following recommendations are based on current medical evidence and
expert opinion from clinicians. The content of the document is dynamic
and will be revised as new clinical data becomes available. The purpose
of this document is to assist practitioners in clinical decision-making,
to standardize and improve the quality of patient care, and to promote
cost-effective drug prescribing. The clinician should utilize this
guidance and interpret it in the clinical context of the individual
patient situation.*

**Pioglitazone is the agent of choice for patients newly starting on a
thiazolidinedione (TZD). For patients currently receiving
rosiglitazone** **the decision to continue rosiglitazone should be made
in light of the available data only after a discussion of the risks and
benefits of this and alternate therapies with the patients.**

+-----------------------------------------------------------------------+
| **Exclusions (if ONE is selected, patient is not eligible)**          |
+-----------------------------------------------------------------------+
| □ Type 1 Diabetes Mellitus                                            |
|                                                                       |
| □ Pre-diabetes: impaired fasting glucose (IFG) or impaired glucose    |
| tolerance (IGT)^1^                                                    |
|                                                                       |
| □ New York Heart Association (NYHA) Class III or IV heart failure     |
|                                                                       |
| □ Evidence of active liver disease or an ALT \> 2.5 x the upper limit |
| of normal                                                             |
|                                                                       |
| □ Developed significant heart failure while taking another            |
| thiazolidinedione (TZD)                                               |
|                                                                       |
| □ Experienced jaundice while taking another TZD                       |
+-----------------------------------------------------------------------+
| **Inclusions for patients with Type 2 diabetes**                      |
+-----------------------------------------------------------------------+
| **The following must be acknowledged before proceeding**              |
|                                                                       |
| □ Fluid status must be monitored for all patients; however, extra     |
| vigilance is required for patients with NYHA Class                    |
|                                                                       |
| I/II heart failure or patients with risk factors for heart failure    |
| and/or when combining a TZD with insulin.                             |
|                                                                       |
| Both TZDs carry a Black Box Warning that use is not recommended in    |
| symptomatic heart failure.                                            |
+-----------------------------------------------------------------------+
| **[Use as monotherapy (both must be selected)]{.underline}**          |
|                                                                       |
| □ Is intolerant of or has contraindications to both sulfonylureas and |
| metformin                                                             |
|                                                                       |
| □ Target value for HbA1c based on VA/DoD Guidelines                   |
| <http://www.oqp.med.va.gov/cpg/DM_base.htm> is likely to              |
|                                                                       |
| be attainable based on clinical trial data                            |
|                                                                       |
| Insulin may be considered at anytime prior to using a TZD; however,   |
| it should be considered if patient is symptomatic or a greater        |
| reduction beyond what is achievable by TZDs is desired.               |
|                                                                       |
| In the pivotal trials the AVERAGE decrease in HbA1c ranged from       |
| 0.6-0.8%. The mean decrease was greater in those with higher baseline |
| HbA1c (e.g 2.5% in those with baseline HbA1c of 10%)                  |
+-----------------------------------------------------------------------+
| **[Combination (2 drug) oral therapy]{.underline}**                   |
|                                                                       |
| □ Target value for HbA1c based on VA/DoD Guidelines                   |
| <http://www.oqp.med.va.gov/cpg/DM_base.htm> is likely to              |
|                                                                       |
| be attainable based on clinical trial data                            |
|                                                                       |
| **AND one of the following**                                          |
|                                                                       |
| □ Inadequate glycemic control on monotherapy with a sulfonylurea (at  |
| [\>]{.underline} 50% maximal dose or highest                          |
|                                                                       |
| tolerated dose) AND is intolerant of or has contraindications to      |
| metformin^2^                                                          |
|                                                                       |
| □ Inadequate glycemic control on monotherapy with metformin (at       |
| [\>]{.underline} 2g/d or highest tolerated dose) AND is               |
|                                                                       |
| intolerant of or has contraindications to sulfonylureas               |
|                                                                       |
| Insulin may be considered at anytime prior to using a TZD; however,   |
| it should be considered if patient is symptomatic or a greater        |
| reduction beyond what is achievable by TZDs is desired.               |
|                                                                       |
| In the pivotal clinical trials the AVERAGE decrease in Hba1c ranged   |
| from 0.5 -1.6% for the combination of a SU +TZD and 0.6-1.0% for      |
| metformin + TZD                                                       |
+-----------------------------------------------------------------------+
| **[Triple oral therapy (all 3 must be selected)]{.underline}**        |
|                                                                       |
| □ Inadequate glycemic control on 2-drug therapy with a sulfonylurea   |
| (at [\>]{.underline} 50% maximal dose or highest                      |
|                                                                       |
| tolerated dose) and metformin (at [\>]{.underline} 2g/d or highest    |
| tolerated dose) ^2^                                                   |
|                                                                       |
| □ Patient is not a good candidate for or refuses addition of insulin  |
|                                                                       |
| □ Target value for HbA1c based on VA/DoD Guidelines                   |
| <http://www.oqp.med.va.gov/cpg/DM_base.htm> is likely to              |
|                                                                       |
| be attainable based on clinical trial data                            |
|                                                                       |
| In the triple oral therapy trials, the AVERAGE decrease in HbA1c      |
| ranged from 0.4 -- 1.9%                                               |
+-----------------------------------------------------------------------+

+-----------------------------------------------------------------------+
| **[TZD + insulin]{.underline}**                                       |
|                                                                       |
| □ Evidence of insulin resistance (e.g. acanthosis nigricans,          |
| polycystic ovary disease, total insulin dose \> 1 unit/kg/day         |
|                                                                       |
| or \> 100 units/day - these doses are considered as guidance and are  |
| not intended as absolute) and not at target                           |
|                                                                       |
| HbA1c goal                                                            |
|                                                                       |
| **OR**                                                                |
|                                                                       |
| □ Inadequate glycemic control with insulin therapy (e.g. due to       |
| hypoglycemia, patient refusing intensification of                     |
|                                                                       |
| insulin regimen)                                                      |
|                                                                       |
| Consider use of metformin prior to a TZD unless contraindicated       |
|                                                                       |
| The dose of rosiglitazone when combined with insulin should not       |
| exceed 4mg daily. The dose of pioglitazone should begin at 15 or 30   |
| mg once daily and titrated according to glucose response.             |
|                                                                       |
| In the clinical trials, where a TZD was added to insulin, the AVERAGE |
| decrease in HbA1 ranged from 0.6 to 1.5%. In one study,               |
|                                                                       |
| HbA1c decreased by [\>]{.underline} 0.7% in 27% of patients. The mean |
| decrease in insulin dose was 23% (32% had at least a 30% decrease in  |
|                                                                       |
| insulin dose)                                                         |
+-----------------------------------------------------------------------+
| **Renewal Criteria**                                                  |
+-----------------------------------------------------------------------+
| A significant minority of patients do not have a response to TZDs;    |
| therefore, to continue use, meaningful improvement in glycemic        |
| control after 3-6 months of therapy in the absence of significant     |
| adverse events must be demonstrated.                                  |
|                                                                       |
| In the case of TZD + insulin in patients with significant insulin     |
| resistance, a meaningful decrease in insulin dose and/or improvement  |
| in glycemic control must be demonstrated.                             |
+-----------------------------------------------------------------------+

^1^The use of TZDs to prevent the development of diabetes in this
population is not recommended. Although rosiglitazone had recently been
shown to reduce the frequency of diabetes in individuals with IFG/IGT,
the incidence of adverse cardiovascular events (secondary outcome) was
higher in those receiving rosiglitazone. Lifestyle interventions (diet
and exercise), which have also been shown to be effective, should be
emphasized and initiated first.

^2^If patient is near their glycemic goal (e.g. \<0.5% from goal),
consider increasing sulfonylurea to the maximum approved daily dose

> **Adverse Events and Monitoring**

+----------+-------------------------+--------------------------------+
|          | **Warnings/Adverse      | **Monitoring**                 |
|          | Events**                |                                |
+----------+-------------------------+--------------------------------+
| **Edema/ | Use of TZDs whether     | Careful assessment of the risk |
| Cardiac  | alone or in combination | versus benefit of TZD therapy  |
| F        | with other oral agents  | must be performed in patients  |
| ailure** | or insulin can cause    | with NYHA Class I or II heart  |
|          | fluid retention         | failure, patients with risk    |
|          | resulting in peripheral | factors for heart failure, and |
|          | edema, development of   | patients with depressed        |
|          | or exacerbation of      | ejection fraction.             |
|          | heart failure, and      |                                |
|          | abnormalities in        | -   Close monitoring of fluid  |
|          | hematological           |     status is necessary.       |
|          | parameters such as      |                                |
|          | hemoglobin and          | -   Observe patients for signs |
|          | hematocrit. The risk    |     and symptoms of heart      |
|          | appears to be greatest  |     failure.                   |
|          | when combining TZDs     |                                |
|          | with insulin            | -   Discontinue TZD if         |
|          |                         |     deterioration in cardiac   |
|          |                         |     status occurs.             |
|          |                         |                                |
|          |                         | -   For more information refer |
|          |                         |     to                         |
|          |                         |     <http://care.diabetesjour  |
|          |                         | nals.org/cgi/reprint/27/1/256> |
|          |                         |                                |
|          |                         | Patients should be instructed  |
|          |                         | to report weight gain, edema   |
|          |                         | or shortness of breath         |
|          |                         | particularly if the onset is   |
|          |                         | acute or the amount progresses |
|          |                         | rapidly.                       |
+----------+-------------------------+--------------------------------+
| **Weight | Dose dependent increase | Patients should be instructed  |
| gain**   | in weight of 1-5.4 kg   | to inform their provider if    |
|          | (median values) can     | significant weight gain (e.g.  |
|          | occur with these        | \> 3kg) develops within first  |
|          | agents. The greatest    | few months of TZD use or after |
|          | median increase in      | an increase in dose.           |
|          | weight was seen when    |                                |
|          | used in combination     |                                |
|          | with insulin.           |                                |
+----------+-------------------------+--------------------------------+

+----------+-------------------------+--------------------------------+
| **H      | Phase II and III trials | -   Liver function tests       |
| epatic** | have shown that         |     (LFTs) and bilirubin       |
|          | rosiglitazone and       |     should be checked prior to |
| **E      | pioglitazone do not     |     the initiation of a TZD,   |
| ffects** | cause hepatotoxicity    |     then periodically          |
|          | any more than placebo.  |     thereafter.                |
|          | In post-marketing       |                                |
|          | experience with these   | -   Patients with mildly       |
|          | agents, hepatitis and   |     elevated values (ALT 1-2.5 |
|          | elevation of liver      |     x upper limit normal) at   |
|          | enzymes                 |     baseline or anytime during |
|          | [\>]{.underline} 3      |     therapy should be          |
|          | times the upper limit   |     evaluated to determine the |
|          | of normal has been      |     cause of lever enzyme      |
|          | reported; however,      |     elevation. Initiation or   |
|          | causality has not been  |     continuation of therapy    |
|          | established.            |     with the TZD in patients   |
|          | Nevertheless monitoring |     with mildly elevated       |
|          | for liver function      |     values should proceed with |
|          | tests (LFTs) is         |     caution and include        |
|          | recommended.            |     appropriate follow-up      |
|          |                         |                                |
|          |                         | -   If ALT \> 2.5 -            |
|          |                         |     [\<]{.underline} 3 x upper |
|          |                         |     limit of normal, LFTs      |
|          |                         |     should be evaluated more   |
|          |                         |     frequently until the       |
|          |                         |     levels return to normal or |
|          |                         |     pretreatment values. If    |
|          |                         |     ALT \> 3 x the upper limit |
|          |                         |     of normal, while taking a  |
|          |                         |     TZD, recheck another level |
|          |                         |     as soon as possible. If    |
|          |                         |     ALT remains \> 3x the      |
|          |                         |     upper limit, discontinue   |
|          |                         |     use.                       |
|          |                         |                                |
|          |                         | Monitor for signs and symptoms |
|          |                         | suggestive of hepatic          |
|          |                         | dysfunction including nausea,  |
|          |                         | vomiting, abdominal pain,      |
|          |                         | fatigue, anorexia, or dark     |
|          |                         | urine and jaundice. Patients   |
|          |                         | should be instructed to inform |
|          |                         | their provider should these    |
|          |                         | symptoms develop.              |
+----------+-------------------------+--------------------------------+
| **Lipid  | Increases in            | Assess and maintain            |
| c        | low-density             | cholesterol levels according   |
| hanges** | lipoprotein-cholesterol | to current standards of care   |
|          | (LDL-C), high-density   |                                |
|          | lipoprotein-cholesterol |                                |
|          | (HDL-C), and total      |                                |
|          | cholesterol have been   |                                |
|          | observed with the TZDs. |                                |
|          | Data suggest that the   |                                |
|          | increase in LDL-C is    |                                |
|          | predominantly due to    |                                |
|          | the larger buoyant      |                                |
|          | particles of LDL, which |                                |
|          | may be less atherogenic |                                |
|          | than the small, dense   |                                |
|          | LDL. The LDL/HDL ratio  |                                |
|          | is preserved, although  |                                |
|          | with rosiglitazone,     |                                |
|          | there is a lag time of  |                                |
|          | several months before   |                                |
|          | HDL-C rises relative to |                                |
|          | LDL-C. Triglycerides    |                                |
|          | decrease with           |                                |
|          | pioglitazone, whereas   |                                |
|          | the effect with         |                                |
|          | rosiglitazone is        |                                |
|          | variable.               |                                |
+----------+-------------------------+--------------------------------+
| **Ovu    | Rosiglitazone and       | Need for contraception should  |
| lation** | pioglitazone may induce | be discussed with the patient  |
|          | ovulation in            | as appropriate.                |
|          | premenopausal           |                                |
|          | anovulatory patients    |                                |
|          | and/or in those with    |                                |
|          | Polycystic Ovarian      |                                |
|          | Syndrome.               |                                |
+----------+-------------------------+--------------------------------+
| **Fra    | Both rosiglitazone and  | Assess and maintain bone       |
| ctures** | pioglitazone have been  | health according to current    |
|          | associated with an      | standards of care              |
|          | increased risk of upper |                                |
|          | and lower limb bone     |                                |
|          | fractures in female     |                                |
|          | patients. These sites   |                                |
|          | of fractures differ     |                                |
|          | from hip or spine       |                                |
|          | fractures that are      |                                |
|          | typically associated    |                                |
|          | with post-menopausal    |                                |
|          | osteoporosis.           |                                |
+----------+-------------------------+--------------------------------+
| **M      | There have been rare    | Patients should have an eye    |
| acular** | post-marketing reports  | exam at least annually by an   |
|          | of new onset or         | ophthalmologist.               |
| *        | worsening macular edema |                                |
| *Edema** | with the TZDs, which    | Patients reporting any kind of |
|          | have been described as  | visual symptoms should be      |
|          | decreased visual acuity | promptly referred to an        |
|          | or blurred vision or    | ophthalmologist                |
|          | were diagnosed on       |                                |
|          | routine ophthalmologic  |                                |
|          | exam. Concurrent        |                                |
|          | peripheral edema was    |                                |
|          | frequently reported. In |                                |
|          | some cases,             |                                |
|          | discontinuation of the  |                                |
|          | TZD or dosage reduction |                                |
|          | resulted in resolution  |                                |
|          | of the macular edema.   |                                |
+----------+-------------------------+--------------------------------+