Diabetes: Demonstrating Success

1
Glycemic control the Nitty-Gritty
David K. McCulloch, MD, FRCP, Group Health
Cooperative
2
Glycemic control the Nitty-Grittyif, how and
when to

• add bedtime insulin?
• add other oral agents
• Meglitinides?
• Gut-enzyme inhibitors?
• Glitazones?
• do pre-meal sliding scales?
• use Lantus, 70/30, Novolog?
• teach carb-counting?

3
Suggested approach to glycemic controlin type 2
diabetes
D E
D E MF
D E MF SU
D E BI MF
D E BI MF SU
D E BI MF PMI
????
4
Biguanidesimprove insulin resistance by
reducing hepatic glucose output.

• Metformin
• Does NOT cause weight gain.
• Improves cardiac outcomes.
• GI side effects (including diarrhea) are dose
  dependent.
• Lactic acidosis is overblown and can be minimized
  by never using metformin if the serum creatinine
  is above 1.5, if the patient has progressive
  heart or liver failure, and by stopping it before
  and during IV contrast studies.

5
Why use bedtime insulin before adding a second
pill ?
6
Yki-Järvinen, et. al. Ann Int Med 130 389-96,
1999
7
Yki-Järvinen, et. al. Ann Int Med 130 389-96,
1999
8
How do you do Bedtime Insulin?

• Check FBG every day and get weekly average.
• Target is mean FBG of 120 mg/dl.
• lt200lbs, FBGlt200 12U and up by 4U/w
• lt200lbs, FBGgt200 16U and up by 8U/w
• gt200lbs, FBGlt200 20U and up by 4U/w
• gt200lbs, FBGgt200 30U and up by 10U/w

9
If BI MF is not enoughthen what?

• Add sulfonylurea (or a meglitinide)?
• Add a gut-enzyme inhibitor?
• Add a glitazone?
• Add daytime NPH?
• Add pre-meal sliding scale aspart or lispro.
• Less weight gain
• Less hypoglycemia
• Lower HbA1c
• More logical and flexible (but also more work)

10
What about sulfonylureas?

• There is no convincing evidence that the newer
  ones differ in any important ways (except for
  dose and duration of action).
• It is still debated if use of sulfonylureas
  increases the risk of future CVD, but they
  certainly make the outcome of a coronary event
  worse (possibly by inhibiting collateral
  circulation).
• There is evidence that they can speed up the
  decline of endogenous insulin secretion.

11
Sulfonylureas

• First generation (bigger dose needed)
• Chlorpropamide, tolbutamide.
• Second generation (smaller dose needed)
• Glibenclamide, glipizide.
• Third generation (putative extra benefits)
• Glimiperide
• Side effects weight gain, hypoglycemia,
  photosensitive skin rash, cross reactivity with
  sulfonamides, fluid retention, others

They mainly differ in terms of the dose required
and whether they are long-acting (chlorpropamide
and glibenclamide) or short-acting (tolbutamide
and glipizide).
12
Alvarsson, M, Sundkvist, G, Lager, I, et al.
Beneficial effects of insulin versus
sulphonylurea on insulin secretion and metabolic
control in recently diagnosed type 2 diabetic
patients. Diabetes Care 2003 262231.

• When 39 recently diagnosed Swedish type 2
  diabetic patients (all of whom were islet cell
  antibody negative) were randomly assigned to
  glyburide or twice daily insulin, stimulated
  C-peptide levels decreased by 0.12 nmol/L in the
  glyburide group after one year, but increased by
  0.14 nmol/L in the insulin-treated group
  (plt0.02).
• HbA1c decreased by about 1.0 percent in both
  groups during the first year, but deteriorated in
  year two in the glyburide but not the insulin
  group.

13
Meglitinides

• Repaglinide (Prandin)
• Nateglinide (Starlix)
• They are pharmacologically different from
  sulfa-drugs and so can be used in patients who
  are allergic to sulfonamides.
• They are short-acting insulin stimulators with
  little merit beyond the above.
• Side effects hypoglycemia, weight gain,

14
Gut-enzyme inhibitors

• Alpha-glucosidase inhibitors (Acarbose and
  miglitol) decrease post-prandial hyperglycemia.
• Only modestly successful in lowering HbA1c
• Side effects (flatulence) can be a BIG problem.
• Lipase inhibitors (Orlistat) prevent absoption of
  fat and so can reduce calorie intake and
  facilitate weight loss.
• As with all other drugs to help weight loss their
  effect is relatively short-lasting.
• Side effects include unpleasant smelling fatty
  stools, reduced absorption of fat soluble
  vitamins,

15
When are glitazones a good idea?

• There is suggestive evidence that EARLY use of
  glitazones may preserve beta-cell function (DPP,
  TRIPOD, PIPOD, and others).
• There are hints and indirect data that TZD use
  MAY improve CVD outcomes.
• Weight gain and fluid retention are a BIG
  problem.
• We are anxiously awaiting the results of the
  large RCTs with hard outcomes
• PROACTIVE
• CHICAGO
• PERISCOPE

16
TZDs and Weight Gain-1 Weight gain is dose
dependent. This study compares 6 months of
treatment with different TZDs at different
doses. Arnoff, S, et al. Diabetes Care 23
1067, 2000.
17
Progressive weight gain among a cohort of type 2
diabetic patients using pioglitazone 45 mg over a
36 month period (presented at ADA, 2002)
TZDs and Weight gain-2
Wt. kg
0
6
12
18
24
30
36
Months
18
Shadid, S, Jensen, MD. Effects of pioglitazone
versus diet and exercise on metabolic health and
fat distribution in upper body obesity.
Diabetes Care 2003 26 3148.
TZDs and Weight gain-3

• Among 39 centrally obese insulin resistant
  nondiabetic subjects assigned to either diet and
  exercise or to 30mg of pioglitazone for 20 weeks
  insulin sensitivity improved in both groups
  (though was more substantial among those doing
  diet and exercise). Those doing diet and
  exercise lost a mean of 11.8 kg while the
  pioglitazone group gained 2.7 kg. Both groups
  showed a decrease in the waist-to-hip ratio but
  in the pioglitazone group this was only due to a
  preferential increase in lower body fat
  deposition. Only diet and exercise was
  associated with a decrease in intra-abdominal fat

19
C Delea, TE, Edelsberg, JS, Hagiwara, M, Oster,
G, Phillips, LS. Use of thiazolidiniediones and
risk of heart failure in people with type 2
diabetes. Diabetes Care 2003 262983
TZDs and Fluid Retention and Heart Failure-1

• A large retrospective cohort study comparing
  5,441 type 2 diabetic patients using
  thiazolideinediones with 28,103 randomly selected
  type 2 patients using other oral hypoglycemic
  agents found that use of thiazolideinediones was
  associated with an 8.2 percent incidence of heart
  failure over a 40 month period compared with 5.3
  percent in non-thiazolidinedione users (hazard
  ratio 1.7, p lt0.001).

20
Nesto, RW, Bell, D, Bonow, RO, et al.
Thiazolidinedione use, fluid retention, and
congestive heart failure a consensus statement
from the American Heart Association and American
Diabetes Association. Circulation 2003 1082941.
TZDs and Fluid Retention and Heart Failure-2

• The fluid retention induced by thiazolidinediones
  appears to be relatively resistant to diuretics
  but responds promptly to withdrawal of therapy.
  The mechanisms responsible for both the fluid
  retention and lack of response to diuretics are
  not known.
• Thiazolidinediones should not be given to
  patients with New York Heart Association (NYHA)
  class III or IV HF .
• The initial dose should be low (eg, 2 to 4 mg
  rosiglitazone daily or 15 mg pioglitazone daily)
  in patients with one or more risk factors of HF,
  asymptomatic left ventricular dysfunction, or
  NYHA class I or II HF. Patients should be
  observed for weight gain or edema. Dose
  escalation should be performed gradually while
  reassessing the patient for signs of HF.
• If weight gain and edema develop in a patient
  taking a thiazolidinedione, a careful assessment
  for evidence of HF should be made.

21
PROACTIVE PROspective pioglitAzone Clinical
Trial In MacroVascular Events

• Double-blind RCT of 5,000 type 2 DM pats at high
  risk for macrovascular disease.
• Add pioglitazone or placebo to existing therapy.
• POEMs all cause mortality, nonfatal MI, acute
  coronary syndrome, PTCA or CABG/stents, stroke,
  leg amputation, PVD surgery.
• Results expected in 2007.

22
CHICAGO A study evaluating Carotid intima-media
tHICkness (CIMT) in Atherosclerosis using
pioGlitazOne

• 400 patients with type 2 diabetes randomized to
  either having pioglitazone or glimepiride added
  to existing therapy.
• Compare the effects on rate of progression of
  atherosclerosis using CIMT and electron-beam
  tomography (EBT).
• Results expected in 2007.

23
PERISCOPE Pioglitazone Effect on Regression of
Intravascular Sonographic Coronary Obstruction
Prospective Evaluation.

• 600 patients with type 2 diabetes randomized to
  either having pioglitazone or glimepiride added
  to existing therapy.
• Compare the effects on rate of progression of
  atherosclerosis using intravascular ultrasound
  (IVUS).
• Results expected in 2007.

24
So lets go back

• If BI MF is not enoughthen what?

25

• Add sulfonylurea?
• Add a glitazone?
• Add daytime NPH?
• Add pre-meal sliding scale aspart or lispro.
• Less weight gain
• Less hypoglycemia
• Lower HbA1c
• More logical and flexible (but also more work)

26
How to add daytime insulin

• Once the FBG is in target, if the HbA1c is still
  over 7.0 it is a good idea to check BGs before
  lunch, dinner and bedtime. If the BG rises
  steadily throughout the day this indicates that
  they no longer make enough endogenous insulin
  (assuming the person is doing the best they can
  with diet and exercise) . What I do then is to
  stop the glyburide (if they are on it) but
  continue the metformin (assuming no
  contraindications to metformin).

27
There are several options for adding daytime
insulin

• 1) Add a dose of NPH before breakfast. As a
  "rule of thumb" start at about half their bedtime
  dose. So if the person is already taking 60
  units of NPH at bedtime and now has a FBG under
  130 mg/dl add another 30 units of NPH at
  breakfast. The problem with daytime NPH is that
  it tends to cause weight gain and can make people
  hungry and sometimes hypoglycemic in the middle
  of the day.
• 2) Take a sliding scale dose of insulin aspart
  (Novolog) before lunch and dinner. (See next
  slide on sliding scales)
• 3) A variation of 1) and 2) is to add some NPH
  before breakfast and sliding scale Novolog before
  the evening meal.

28
Philosophy of pre-meal dosing of fast-acting
insulin

• If the meal contains a lot of carbohydrate you
  need a bigger dose of insulin.
• If the blood glucose is already high before you
  start to eat you need a bigger dose of insulin.
• Picking a pre-meal base dose of insulin.
• Consistent Carbohydrate Profile plus fixed base
• (e.g. 30g,15g, 40g, 15g, 60g, 15gwith
  2U,2U,4U)
• Carbohydrate-to-Insulin ratio
• (e.g. 1U per 15 grams, or 1 per 10g, 2 per
  15g, etc.)

29
Pre-meal sliding scales

• Base dose, if BG is 70-150 mg/dl.
• Add 1 unit for every 50 mg/dl over 150mg/dl.
• So if a person has a fixed base dose of 6 units
  for their evening meal but has a BG of 235 mg/dl
  they would add 2 units (for a total of 8U).

Notes Pick base dose using a fixed amount or
using C/I ratio. A slim motivated athlete
might have a pre-meal target of 70-120 mg/dl and
add 0.5U for every 20 mg/dl above this. Heavier
and more insulin-resistant individuals will need
a larger base dose and larger increments in the
sliding scale.
30
Why not use Lantus in type 2 diabetes?
Smooooth, peakless insulin delivery all day with
just one shot
31
The value of adding bedtime basal insulin
Glargine (Lantus) over NPH insulin in
insulin-naïve patients with type 2 diabetes on
oral agents. Rosenstock, J, Riddle, MC, and the
HOE901/4002 Study Group.

• 756 type 2 insulin-naive diabetic patients with
  inadequate control on oral agents alone.
• Random addition of Lantus or NPH at bedtime,
  titrated weekly until FBG lt100 mg/dl and HbA1c
  lt7.0.
• 24 weeks of follow-up.

Presented at the ADA Scientific Meetings, June
2002
32
ResultsRosenstock, J, Riddle, MC, et al. ADA,
2002
Conclusions Lantus required a bigger dose of
insulin and gave slightly less nocturnal
hypoglycemia.
33
Lantus is now on the GHC formulary, and can be
used IF patient

• Has type 1 diabetes.
• Is motivated and is doing MDI with pre-meal
  adjustments with fast-acting insulin.
• Is being followed by people who understand and
  can support intensive insulin therapy.
• Is experiencing significant hypoglycemia that is
  preventing him/her reaching his/her HbA1c target.

34
Comparison of insulin pharmacokinetics.