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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

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

comparing studies intervention it vs ct
Comparing Studies- Intervention(IT vs CT)

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

study comparisons outcomes it vs ct
Study Comparisons- Outcomes(IT vs CT)

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


What does it mean?

  • 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
  • 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
  • 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?
  • 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



Abbott Navigator

322 people with type 1 DM on IT
    • 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


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

**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)

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

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

what about monitoring in type 2 diabetes
What about monitoring in type 2 diabetes?
  • 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

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
  • 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

  • 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
  • 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
  • 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:
  • TZD: pioglitazone (Actos) or rosiglitazone (Avandia)
  • Exenatide (Byetta- GLP1 agonist)
  • Sitagliptin (Januvia- DPP4 inhibitor)
  • Insulin
considerations with tzds
Considerations with TZDs
  • 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 in 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)

Exogenous GLP-1


A1c  ~ 1-2%


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

Weight loss

Sitagliptin (Januvia)

Enzyme inhibitor


A1c  ~ .8-1%


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?
  • 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

  • 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

Basal Onset Peak Duration


initiation of insulin
Initiation of Insulin

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



(Basal) Insulin

(ie Lantus or NPH)

+ Oral Agent(s)

Background and

Mealtime Insulin


 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


Premixed studies



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

Injection frequency and monitoring

Abilities, comprehension and safety


BG patterns



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


Algorithm 2: Patient self-adjustment


Insulin dose

Algorithm 1

(n = 2,315)

Algorithm 2

(n = 2,273)

Algorithm 1

Algorithm 1

Algorithm 2

Algorithm 2











Insulin dose (IU)

FBG (mg/dl)



A1C (%)




























Weeks since randomization

P < 0.001

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

continuation of oral agents
Continuation of Oral Agents

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
  • 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
  • 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…

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

pearls for diabetes management
Pearls for Diabetes Management
  • 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
when to consider adding insulin
When to consider adding insulin?

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
  • 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?
  • 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
intensive therapy in newly diagnosed type 2 dm
Intensive Therapy in Newly Diagnosed Type 2 DM
  • 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

  • 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
initiation of insulin1
Initiation of Insulin

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