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An Update in Outpatient Type 2 Diabetes. Elizabeth Stephens, MD Endocrinology- PACE Clinic Providence Portland Medical Center January 2009. Many topics to discuss…. What should our goal A1c be in those with type 2 diabetes and cardiovascular disease?

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An update in outpatient type 2 diabetes

An Update in Outpatient Type 2 Diabetes

Elizabeth Stephens, MD

Endocrinology- PACE Clinic Providence Portland Medical Center

January 2009


Many topics to discuss…

  • What should our goal A1c be in those with type 2 diabetes and cardiovascular disease?

  • Does continuous glucose monitoring help improve control in diabetes?

  • Are there any other new updates?

    • ADA guidelines 2009, monitoring in type 2 dm, aspirin in diabetes

  • A brief review of a case that illustrates treatment options and frequent questions


Can intensive glucose control it reduce the risk of cvd in high risk type 2 dm
Can intensive glucose control (IT) reduce the risk of CVD in high risk type 2 DM?

  • ACCORD (NEJM 2008;358:2545)

    • 2X2 factorial design to also look at lipid and BP

    • Due to increased mortality in IT group, study was halted 18 months early

  • ADVANCE (NEJM 2008;358:2560)

    • IT included gliclazide (long-acting sulfonylurea)

      • Also looked at BP lowering with ACEI + diuretic

    • Study extended at 3 yrs due to low event rates

  • VADT (NEJM 2009;360)

    • Identical treatment of BP, lipids and lifestyle


Comparing studies baseline
Comparing Studies- Baseline high risk type 2 DM?

Skyler J et al, Diabetes Care 2009;32:187


Comparing studies intervention it vs ct
Comparing Studies- Intervention high risk type 2 DM?(IT vs CT)

Skyler J et al, Diabetes Care 2009;32:187


Study comparisons outcomes it vs ct
Study Comparisons- Outcomes high risk type 2 DM?(IT vs CT)

Skyler J et al, Diabetes Care 2009;32:187


What does it mean? high risk type 2 DM?

  • Benefit likely differs with diabetes duration and underlying complications/CVD

  • Treatment strategies probably critical, especially between ACCORD and ADVANCE

  • Hypoglycemia effect important but it’s role in outcomes not clear yet…


Benefits of early intensive glucose control
Benefits of Early Intensive Glucose Control high risk type 2 DM?

  • UKPDS Follow-Up (9 yrs after completion), 4209 pts, newly dx type 2 dm at enrollment, managed with IT or CT

    • Between group differences were lost < 1 year

    • Reduction in microvascular risk were maintained and MI/death emerged during post-trial follow-up

  • 382 Chinese with newly dx type 2 dm

    • Randomized to IT with pump, injections or oral agents

    • More achieved glucose control with insulin, and 51% in remission at one year (no meds) after pump therapy

Holman RR et al. NEJM 2008;359:1577; Weng J et al. Lancet 2008;371:1753


Summary of ada glycemic control section 2009
Summary of ADA Glycemic Control Section-2009 high risk type 2 DM?

  • Lowering A1c < 7% has been shown to reduce microvascular & neuropathic complications in type 1 & 2 DM

  • RCT have not shown significant reduction in CVD with IT in type 1 & 2 DM

    • Long-term f/u of DCCT and UKPDS suggest benefit with A1c at or below 7%

      • This may be a better target for those with shorter duration of DM, longer life expectancy and no significant CVD

    • Less stringent goals may be appropriate for those with a history of severe hypoglycemia, limited life expectancy, extensive complications/comorbidities, and those where the general goal is “difficult to attain”

Diabetes Care 2008;32:S19


What is continuous glucose monitoring
What is continuous glucose monitoring? high risk type 2 DM?

  • Measures glucose levels in interstitial fluid (skin)

  • Readings every 1-5 minutes

    • With alarms set by wearer

  • Costs between $800-1400 for device

    • $35-60 per sensor


Continuous glucose monitoring systems
Continuous Glucose Monitoring Systems high risk type 2 DM?

Medtronic

DexCom

Abbott Navigator


  • 322 people with type 1 DM on IT high risk type 2 DM?

    • Randomized to sensor or home monitoring

  • Stratified by age and baseline A1c

    • 67-85% were managed with insulin pumps

    • Monitoring on average 5-7 times per day

  • Evaluated change in A1c at 26 weeks

NEJM 2008;359


Results
Results high risk type 2 DM?

34% vs 9% got to

A1c 7% (p=.005)

  • Benefit seen in those > 25 yo

    • A1c  .53%

    • Also used more frequently in adults

    • No difference in hypoglycemia

  • Effect likely reflects abilities and understanding of technology

No difference

In control

27% vs 12% reached A1c 7% (p=.01)


Management of hyperglycemia in type 2 diabetes 2009 tier 1 step 1
Management of Hyperglycemia in Type 2 Diabetes 2009: Tier 1- Step 1

Nathan DM et al, Diabetes Care 2009; 32:193-203


Management of hyperglycemia in type 2 dm tier 1 step 2
Management of Hyperglycemia in Type 2 DM: Tier 1- Step 2 Step 1

**In 2009 guidelines, TZD’s removed as step 2 therapy…

Nathan DM et al, Diabetes Care 2009; 32:193-203


Management of type 2 dm tier 2 less well validated
Management of Type 2 DM: Tier 2 (Less well validated) Step 1

Nathan DM et al, Diabetes Care 2009; 32:193-203


Management of hyperglycemia in type 2 dm other therapy
Management of Hyperglycemia in Type 2 DM: Other Therapy Step 1

Nathan DM et al, Diabetes Care 2009; 32:193-203


What about monitoring in type 2 diabetes
What about monitoring in type 2 diabetes? Step 1

  • 2 recent studies in those on orals:

    • 184 pts with newly diagnosed type 2 dm, randomized to SMBG (8x per week) or none (O’Kane MJ et al, BMJ 2008;336:1174)

      • No difference in A1c, and those monitoring scored worse on the depression subscale

    • 453 pts with non-insulin treated type 2 dm, A1c > 6.2% and not monitoring, randomized to intensive SMBG, SMBG or usual care (Simon J et al, BMJ 2008; 336:1177)

      • At 1 year, costs with SMBG were higher and SMBG groups had lower quality of life compared with usual treatment

  • Monitoring still recommended for those using insulin


Aspirin use in diabetes jpad and popadad

2539 Japanese with type 2 dm Step 1

81/100mg aspirin vs non-aspirin group, rx for 4.37 years

No difference in events overall

Hazard Ratio .80 (95% CI 0.58-1.10)

Marginal significant in those > 65 (HR 0.68; 95% CI, 0.46-0.99)

 risk of GI bleed/retinal hemorrhage with ASA

Generalizability of results?

1276 Scottish with type 1 or 2 + ABI < .99

Rx PBO, ASA +/- antioxidant

Median followup 6.7yrs

No benefit with ASA

HR .98 (95% CI, .76 -1.26)

No benefit with anti-oxidant

HR 1.21 (95% CI, .78 -1.89)

Study underpowered and controversial

Aspirin Use in Diabetes- JPAD and POPADAD

Ogawa H et al. JAMA 2008; 300: 2131-2141;Belch J et al. BMJ 2008;337:a1840


Other updates for 2008
Other Updates for 2008 Step 1

  • Inhaled insulin was taken off the market

    • Six cases of primary lung malignancies in users

  • Exenatide (Byetta) had warning added for pancreatitis

    • Once- weekly formulation likely available in 2010

  • More DPP-IV medications likely to come available

    • Saxagliptin, alogliptin

  • Labeling for metformin changed (CHF now a warning)

  • Average glucose to be reported with A1c results


New data on Average Mean Blood Glucose Step 1

  • Relationship defined between average blood glucose levels and A1c through regression analysis

  • Included data on 507 subjects

    • Obtained 2700 glucose values for each patient

  • Conversion calculator available at www.diabetes.org

  • Likely to be reported with A1c in the future

Nathan DM, Diabetes Care 2008;31:1473


Case for adding a third agent
Case for Adding a Third Agent Step 1

  • 58 year-old with history of hypertension, arthritis and type 2 diabetes

  • Now on metformin 1000mg bid, glipizide 10mg bid

  • A1c is 9.5%

  • What would you add?


Options at this point include
Options at this point include: Step 1

  • TZD: pioglitazone (Actos) or rosiglitazone (Avandia)

  • Exenatide (Byetta- GLP1 agonist)

  • Sitagliptin (Januvia- DPP4 inhibitor)

  • Insulin



Considerations with tzds
Considerations with TZDs Step 1

  • Both TZD’s are associated with fluid retention

    • Estimated as a 2-fold increase

    • Even greater with insulin use

  • Start with low doses:

    • Can sometimes see some benefit with rosiglitazone 2mg or pioglitazone 15 mg with less risk of side effects

  • Remember there is a slow response

    • Generally can take up to 3 months before maximal effect is seen

  • Contraindicated in those with ALT >2.5 x upperlimit of normal. Use with caution and monitor more often if ALT < 2.5 x upper limit of normal


  • GLP-1 Modulates Numerous Functions Step 1in Humans

    GLP-1: Secreted upon the ingestion of food

    Promotes satiety and reduces appetite

     cells:

     Postprandialglucagon secretion

    Liver: Glucagon reduces hepatic glucose output

     cells:Enhances glucose-dependent insulin secretion

    Stomach: Helps regulate gastric emptying

    Data from Flint A, et al. J Clin Invest. 1998;101:515-520;Data from Larsson H, et al.Acta Physiol Scand. 1997;160:413-422; Data from Nauck MA, et al. Diabetologia. 1996;39:1546-1553;Data from Drucker DJ. Diabetes. 1998;47:159-169.


    Options in glp 1 medications

    Exenatide (Byetta) Step 1

    Exogenous GLP-1

    Injectable

    A1c  ~ 1-2%

    Expensive

    Side-effects include nausea, vomiting which generally improve with use

    Weight loss

    Sitagliptin (Januvia)

    Enzyme inhibitor

    Oral

    A1c  ~ .8-1%

    Expensive

    Fewer side-effects

    Weight neutral

    Options in GLP-1 Medications


    Percentage of participants choosing each treatment option for the management of type 2 diabetes
    Percentage of Participants Choosing Each Treatment Option for the Management of Type 2 Diabetes

    Halperin F et al. N Engl J Med 2008;358:e8


    What would i have done for this patient
    What would I have done for this patient? for the Management of Type 2 Diabetes

    • Talked to him about options

      • Side effects, cost, need for injection

      • Consider exenatide (Byetta)

    • To get him to an A1c goal of < 7% your best bet at this point would be insulin


    Psychological Insulin Resistance for the Management of Type 2 Diabetes

    • From the patient

      • Loss of control

      • Poor self-efficacy

      • Personal failure

      • Perceived disease severity

      • Injection-related anxiety

      • Perceived lack of positive gain

    • From the provider

      • Fearful of time needed for education/mgmt

      • Avoiding confrontation

      • Concerns about

        • Hypoglycemia

        • Weight gain

    Polonsky WH et al, Clinical Diabetes 2004;22:147


    Insulin Options for the Management of Type 2 Diabetes

    Basal Onset Peak Duration

    Bolus


    Initiation of insulin
    Initiation of Insulin for the Management of Type 2 Diabetes

    Start with bedtime intermediate-acting insulin (NPH or Detemir) or bedtime or morning long-acting insulin (Glargine)

    Initiate with 10 units or .2 units/kg

    Check FBG daily and increase dose by 2 units every 3 days until fasting levels are in the target range (70-130mg/dl)

    Can increase the dose by larger increments (4 units) every 3 days if fastings are > 180 mg/dl

    If hypoglycemia occurs, reduce dose by > 4 units or 10% whichever is greater

    Nathan DM et al, Diabetes Care 2009;32:193


    Background for the Management of Type 2 Diabetes

    (Basal) Insulin

    (ie Lantus or NPH)

    + Oral Agent(s)

    Background and

    Mealtime Insulin

    (basal+bolus)

     Sensitizer(s)

    • Premixed Insulin

    • (ie 70/30)

    • Sensitizer(s)

    • Elevated FPG

    • Stable daytime BG

    • Overwhelmed

    • Desire single injection

    • Elevated PPG

    • Increasing daytime BG

    • Regular schedule

    • Desires to minimize

    • number of injections

    • Elevated fasting

    • and/or post-meal

    • Intensive control

    • More flexibility

    • Erratic schedule

    Adjust to Target Basal/Bolus

    Treat to target

    57-70%

    Premixed studies

    42-70%

    73%

    Insulin Initiation Regimens

    Glycemic Factors

    Patient Factors

    Glycemic Control Achieved

    % with A1c < 7% or <7%

    Courtesy of R. Bergestal, IDC, Minnestota


    Other patient issues to consider when starting insulin
    Other patient issues to consider when starting insulin for the Management of Type 2 Diabetes

    Injection frequency and monitoring

    Abilities, comprehension and safety

    Cost

    BG patterns

    Schedule

    Hypoglycemia

    Devices to make it easier


    Improvement of Glycemic Control in Subjects With Poorly Controlled Type 2 DiabetesComparison of two treatment algorithms using glargine

    Algorithm 1: physician-managed

    adjustment

    Algorithm 2: Patient self-adjustment

    FBG

    Insulin dose

    Algorithm 1

    (n = 2,315)

    Algorithm 2

    (n = 2,273)

    Algorithm 1

    Algorithm 1

    Algorithm 2

    Algorithm 2

    0

    50

    170

    Pt

    45

    -0.25

    150

    40

    MD

    -0.50

    Insulin dose (IU)

    FBG (mg/dl)

    130

    35

    A1C (%)

    -0.75

    MD

    30

    110

    Pt

    MD

    25

    -1.00

    Pt

    -1.08

    20

    90

    -1.25

    0

    2

    4

    6

    8

    10

    12

    14

    16

    18

    20

    22

    24

    -1.22

    Weeks since randomization

    P < 0.001

    Davies M et al. Diabetes Care 2005;28:1282-1288


    Continuation of oral agents
    Continuation of Oral Agents Controlled Type 2 Diabetes

    Metformin: Useful to continue to reduce insulin requirements and weight gain

    TZD’s: May help to reduce insulin requirements, but beware of additional weight gain and fluid retention when used in combination with insulin

    Not recommended now with rosiglitazone

    Sulfonylureas: May need adjustment/discontinuation if hypoglycemia exists or if starting prandial insulin


    Follow up
    Follow Up Controlled Type 2 Diabetes

    • After you start him on insulin (glargine 10 units Qhs) he relocates to California

    • He returns to see you for follow up 3 years later

    • His current regimen is:

      • 56 units of Glargine BID + 30 units Lispro with meals

    • He reports BG “all over the map” ranging from 50-330mg/dl but monitoring only 1-2 times per day

    • A1c 10.9%


    Issues to consider
    Issues to consider Controlled Type 2 Diabetes

    • NPH vs Glargine in significant insulin resistance

      • My experience has been that NPH, with a peak, tends to control BG better in those with more insulin resistance

    • Consider adding metformin

    • Make sure he is taking injections

      • Does he have the right size syringes?

        • .3cc= 30units, .5cc= 50units, 1cc= 100units

      • Teach him how to mix insulin for added convenience

    • Is he carrying his insulin when he is out?

      • The insulin he is currently using can be out of refrigeration for 30 days

    • Referral to Endocrinologist for U-500 insulin


    Diabetes management is complicated
    Diabetes Management is Complicated Controlled Type 2 Diabetes…

    Nathan DM et al, Diabetes Care 2009;32:193-203


    Pearls for diabetes management
    Pearls for Diabetes Management Controlled Type 2 Diabetes

    • Listen to the patient’s experience

    • Think about options to make it more convenient/easier to deal with if possible

    • Use insulin earlier, or at least start talking about it before you need it

    • Remember to deal with cardiovascular risk factors in those with type 2 dm- they may be more critical than tight glucose control in the long run


    The end

    THE END Controlled Type 2 Diabetes


    When to consider adding insulin
    When to consider adding insulin? Controlled Type 2 Diabetes

    Those with symptoms of hyperglycemia, presence of ketonuria, persistent BG > 250-300mg/dl or A1c > 10%

    Those who have implemented lifestyle changes + metformin + second agent and are still not at goal

    Might consider adding a third oral agent if A1c < 8% but this approach is more costly and may be less effective

    Nathan DM et al, Diabetes Care 2006;29:1963


    Take home points
    Take Home Points Controlled Type 2 Diabetes

    • Most appropriate target for A1c is still < 7% to reduce risk of microvascular disease

      • Lower targets may be appropriate for SOME with diabetes (type 1?) but recognizing risks (hypoglycemia)

    • Emphasis on management of cardiovascular risk factors

      • Lipids, aspirin, blood pressure


    What to take away
    What to take away? Controlled Type 2 Diabetes

    • Both TZD’s are associated with fluid retention

      • Estimated as a 2-fold increase

      • Even greater with insulin use

    • Both also associated with increased risk of fracture, particularly in women

    • New labeling on package insert for rosiglitazone does not recommend use with insulin or in those using nitrates

    • Pioglitazone may have CV advantages

      • Better lipid effects and no evidence of more vascular events in Proactive Trial


    It vs ct in newly diagnosed type 2 dm
    IT vs CT in Newly Diagnosed Type 2 DM Controlled Type 2 Diabetes


    Intensive therapy in newly diagnosed type 2 dm
    Intensive Therapy in Newly Diagnosed Type 2 DM Controlled Type 2 Diabetes

    • 382 Chinese with newly diagnosed type 2 diabetes

      • Randomized to intensive therapy with either insulin injections (MDI), pump (CSII) or oral agents

      • Outcome included time to glycemic control and remission at 1 year

      • Mean age was 51 years, BMI 25.0, and mean fasting plasma glucose ….

      • Of these 23 treated with insulin and 13 with orals did not reach goals and 7 pts withdrew due to intolerance of metformin

        • These were withdrawn from further analysis

    Weng J et al, Lancet 2008;371:1753-60


    Results1
    Results Controlled Type 2 Diabetes

    • More achieved glucose control with insulin

      • 97.1% with CSII, 95.2% with MDI and 83.5% with orals

    • Time to glucose control was shorter with insulin

      • CSII: 4 days; MDI 5.6 days; orals 9.3 days

    • Remission rates also higher with insulin at one year

      • 51.1% with CSII and 44.9% with MDI vs 26.7% with orals

    • Acute insulin response was sustained with insulin groups but declined with orals


    Other data that adds to murk
    Other Data that adds to Murk… Controlled Type 2 Diabetes


    Initiation of insulin1
    Initiation of Insulin Controlled Type 2 Diabetes

    If A1c > 7% after 2-3 months

    If FBG in target range check pre-meal BG and depending on results add second injection

    Can usually start with ~ 4 units and adjust by 2 units every 3 days until in BG in range

    If pre-lunch high, add rapid-acting with breakfast; if pre-dinner high, add NPH at AM meal, or rapid-acting at lunch, if pre-bed high, add rapid-acting at dinner

    If A1c still elevated after 3 months of added therapy

    Recheck pre-meal BG levels to add another injection or may need to check post-prandial BG at 2 hours after eating and adjust

    Nathan DM et al, Diabetes Care 2009;32:193


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