A Real-World Approach to Insulin Therapy in Primary Care Practice

P R A C T I C A L               P O I N T E R S

             A Real-World Approach to Insulin Therapy
                     in Primary Care Practice
Irl B. Hirsch, MD; Richard M. Bergenstal, MD; Christopher G. Parkin, MS; Eugene Wright, Jr., MD; and John B. Buse, MD, PhD

                                              Because of these factors, providers may      However, subjects who had been inten-

        ype 2 diabetes is a progressive
        disease characterized by relent-      delay in making the necessary transition     sively treated during the DCCT showed
        less deterioration of pancreatic -   from oral agents to insulin. Indeed,         significant decreases in risk for
cell function.1 With the increasing inci-     recent evidence suggests that the hemo-      nephropathy and retinopathy compared
dence of type 2 diabetes, especially          globin A1c (A1C) result that triggers glu-   with subjects from the conventional
among younger individuals who will            cose-lowering action is ≥ 9%.3 This is       treatment arm. In other words, the bene-
live longer with their disease, more          unfortunate because numerous studies         fits of 6.5 years of intensive treatment
patients will develop severe insulin defi-    have shown that excellent glycemic con-      during the DCCT have extended well
ciency and require insulin replacement.       trol can be achieved with insulin therapy    beyond the time of intensive therapy.
Because primary care providers see the        in patients with type 2 diabetes.4–7
vast majority of patients with type 2 dia-    Moreover, there is an increasing body of     Insulin May Have a Protective
betes, they may soon find themselves          evidence showing that early and effec-       Quality
overwhelmed with insulin-requiring            tive intervention with insulin is more       Insulin therapy may actually protect
patients.                                     important than had been previously           against endothelial damage.
    This article provides some practical      believed.8–10                                Observational and interventional evi-
guidelines for initiating insulin therapy                                                  dence consistently indicates that
in primary care practice. It is important     Early and Aggressive Intervention            glycemic control with insulin therapy in
to remember, however, that these are          Matters                                      the hospital setting can improve clinical
general guidelines and that management        Insulin is considered the most effective     outcomes.14–17 Malmberg et al.14 demon-
should be individualized for each             treatment for lowering extremely high        strated that the unfavorable long-term
patient.                                      glucose. This is important because inhi-     prognosis for myocardial infarction
                                              bition of glucotoxicity may be beneficial    could be improved by insulin treatment.
WHY INSULIN THERAPY?                          in preserving functional -cell mass.1       In that study, diabetic patients who
Some primary care providers may be            Oral agents do not work as quickly or        received insulin infusion immediately
apprehensive about using insulin in           lower glucose enough to effectively          within 24 hours of myocardial infarc-
patients with type 2 diabetes. Wallace        address glucotoxicity in many patients.      tion, followed by multidose subcuta-
and Matthews2 have gone so far as to          For example, patients treated with sul-      neous insulin treatment for at least 3
suggest that patients and providers have      fonylureas show a decrease in fasting        months, showed a significantly lower
often “colluded in implicit and unspoken      glucose of only 60–70 mg/dl; the A1C         mortality rate (19%) at 1 year compared
contracts to continue oral agents for as      value will decrease by 1.5–2.0 percent-      with subjects who received standard
long as possible.”                            age points.11,12                             treatment (26%), which generally
     Concerns about hypoglycemia and               New data from the Epidemiology of       included sulfonylurea therapy.
patient willingness and/or ability to         Diabetes Interventions and Complica-
inject insulin are good reasons why           tions (EDIC) study highlight the impor-      New Insulin Analogs More Closely
many providers may approach insulin           tance of early intervention to aggressive-   Match Normal Physiology
therapy with caution. Compounding this        ly lower glucose.8 The EDIC study is an      New insulin analogs (rapid and long act-
reluctance is the perception that insulin     ongoing effort that follows the cohort       ing) closely match normal physiolo-
therapy is too complex to manage in a         from the Diabetes Control and Compli-        gy.18–20 Rapid-acting insulin analogs,
busy primary care practice; prescribing       cations Trial (DCCT).13 In the EDIC          such as insulin aspart and insulin lispro,
information provided by manufacturers         study, glycemic levels no longer differed    produce higher serum insulin levels ear-
has been somewhat vague regarding ini-        substantially between the two original       lier and have a shorter duration of action
tial dosing and titration.                    DCCT treatment groups at 7 years.            than regular human insulin. This results

78                                                                                           Volume 23, Number 2, 2005 • CLINICAL DIABETES
P R A C T I C A L             P O I N T E R S

in lower postprandial glucose excursions        in patients with type 2 diabetes much        should be put on insulin therapy, it is
and shorter durations of postprandial           earlier and much more aggressively.          helpful to look to the guidelines for
hyperglycemia, with significantly                                                            glycemic control. The American Dia-
reduced incidence of severe hypo-               Patients Will Eventually Need Insulin        betes Association (ADA)36 and American
glycemia in patients with type 2 dia-           Therapy                                      College of Endocrinology (ACE)37 pub-
betes.18,19 Additionally, studies that have     As stated earlier, type 2 diabetes is a      lish goals for A1C, postprandial glucose,
looked at the effects of rapid-acting           progressive disease in which -cell          and fasting/preprandial glucose (Table
insulin analogs combined with interme-          function deteriorates. Findings from the     1). Most patients who are unable to
diate-acting insulins (free-mixed and           U.K. Prospective Diabetes Study              achieve these goals using oral agents are
premixed preparations) in patients with         (UKPDS) showed that deterioration in         candidates for insulin therapy. Table 2
type 2 diabetes have shown improved             -cell function occurred in the diet-only    lists the more commonly used insulins,
postprandial glucose control with               treatment group as well as in patients       along with information about their peak
reduced hypoglycemia.21–23                      treated with sulfonylureas or metformin,     activity.
                                                suggesting that neither of these agents           The key to making this determina-
New Evidence Links Glucose                      slowed the rate of decline.30 The            tion is timely (preferably weekly) titra-
Excursions to Cardiovascular Risk               UKPDS also showed that even basal            tion of dosages until either glucose tar-
Reducing postprandial glucose excur-            insulin (ultralente) did not slow -cell     gets are met or maximum effective
sions is particularly important in light of     deterioration.30 Another study found that    dosages fail to achieve target levels. For
new data that show a relationship               ~ 30% of patients initially treated with a   example, weekly titration of sulfony-
between postprandial hyperglycemia and          sulfonylurea drug have a poor response;      lurea dosages, in combination with dai-
atherosclerotic risk. A recent study from       the remaining 70% experience a failure       ly fasting glucose data (provided by the
Esposito et al.10 demonstrated that             rate of ~ 4–5% per year.31 It is, there-     patient), will show whether monothera-
reduction of postprandial hyperglycemia         fore, reasonable to conclude that most       py with sulfonylurea can provide ade-
in patients with type 2 diabetes is asso-       patients with type 2 diabetes will even-     quate glycemic control. If not, the addi-
ciated with carotid intima-media thick-         tually need exogenous insulin.               tion and timely titration of a second
ness (CIMT) regression; CIMT is a clin-             Unfortunately, insulin therapy too       agent (metformin or a thiazolidine-
ical marker for atherosclerosis. Recent         often is used as a “punishment” for          dione) over the next 2 months, along
data from Ceriello et al.9 showed that          above-target hyperglycemia. A better         with continued blood glucose monitor-
postprandial hyperglycemia is accompa-          approach would be to explain to patients     ing, will show whether combination
nied by endothelial dysfunction in              early in the course of their disease,        oral therapy can provide adequate
patients with type 2 diabetes and that          instead of at the end, the natural history   glycemic control. If not, insulin therapy
rapid-acting insulin at mealtime                of insulin deficiency in type 2 diabetes.2   is clearly warranted and should be
improved endothelial function. Earlier                                                       promptly initiated (Figure 1).
reports from Ceriello et al.24 suggest that     WHO SHOULD BE STARTED ON                          Although it may be tempting to add
postprandial hyperglycemia and hyper-           INSULIN?                                     a third oral agent, clinicians must consid-
triglyceridemia induce endothelial dys-         Initiating therapy with oral agents is a     er the added cost and potential side
function through oxidative stress. Other        reasonable approach to take with most        effects associated with triple oral thera-
studies support the link between post-          patients, the exception being patients       py. A recent study by Schwartz et al.38
prandial glucose excursions and athero-         with extreme hyperglycemia (fasting          showed that a regimen of premixed
sclerotic risk.25–28                            plasma glucose > 250 mg/dl).32 These         insulin in combination with metformin
     Chiasson et al.29 showed that              patients require insulin, even basal-bolus   was as effective as but much less expen-
addressing postprandial hyperglycemia           insulin therapy, to lower glucose levels.
using an -glucosidase inhibitor actually       Otherwise, starting with oral therapy can     Table 1. Goals for Glycemic
delayed progression from impaired glu-          be very effective, especially in patients     Control
cose tolerance to type 2 diabetes and was       with a short duration of diabetes and,                               ADA         ACE
associated with a significant reduction in      thus, relatively adequate -cell function.    A1C (%)
P R A C T I C A L                   P O I N T E R S

 Table 2. Onset, Peak, and Duration of Insulins

 Insulin*                              Onset                        Peak                             Effective duration
 Rapid-acting                          5–15 minutes                 30–90 minutes                    < 5 hours
 Short-acting                          30–60 minutes                2–3 hours                        5–8 hours
 Intermediate (basal)                  2–4 hours                    4–10 hours                       10–16 hours
 Long-acting (basal)                   2–4 hours†                   No peak                          20–24 hours
  75% NPL/25% lispro                   5–15 minutes                 Dual                             10–16 hours
  70% APS/30% aspart                   5–15 minutes                 Dual                             10–16 hours
  70% NPH/30% regular/NPH              30–60 minutes                Dual                             10–16 hours
 *Assumes  0.1–0.2 units/kg/injection. Onset and duration may vary significantly by injection site.
 †Time to steady state.
 Adapted from DeWitt DE, Hirsch IB: Outpatient insulin therapy in type 1 and type 2 diabetes mellitus: scientific review. JAMA
 289:2254–2264, 2003

                                                                                                   and complexity out of initiating insulin
                                                                                                   therapy in patients with type 2 diabetes.
                                                                                                   Figure 1 provides an algorithm for tran-
                                                                                                   sition from oral therapy to insulin.

                                                                                                   Match the Regimen to the Patient
                                                                                                   A basal-bolus regimen—glargine with
                                                                                                   rapid-acting insulin analogs at each
                                                                                                   meal—is the ideal regimen in terms of
                                                                                                   physiological action and overall
                                                                                                   glycemic control. However, many
                                                                                                   patients are reluctant to start with a
                                                                                                   basal-bolus insulin regimen.
                                                                                                   Furthermore, basal-bolus insulin man-
                                                                                                   agement requires not only motivation of
                                                                                                   both patient and provider, but also com-
                                                                                                   prehensive training in carbohydrate
                                                                                                   counting (or some method of
                                                                                                   food/insulin matching) and insulin
                                                                                                   adjustment. Therefore, it is important to
                                                                                                   match the insulin regimen to the individ-
                                                                                                   ual needs, concerns, and capabilities of
                                                                                                   each patient.
Figure 1. Algorithm for initiating insulin therapy.                                                    Patients who are reluctant to do
                                                                                                   basal-bolus management initially often
sive than triple oral therapy; a high per-       HOW TO START PATIENTS ON                          make the transition to multiple daily
centage of subjects (16.3%) from the             INSULIN                                           injection (MDI) regimens after gaining
triple oral agent treatment group did not        Starting patients on insulin does not             confidence in their ability to safely and
complete the regimen because of a lack           have to be difficult. This section presents       effectively use insulin through less inten-
of efficacy or side effects.                     an approach that takes the uncertainty            sive regimens. Table 3 presents common

80                                                                                                   Volume 23, Number 2, 2005 • CLINICAL DIABETES
P R A C T I C A L                P O I N T E R S

 Table 3. Patient-Based Insulin Regimens                                                     analog premixed insulin is an option if
                                                                                             the patient eats small lunches or misses
 Basal-Only Insulin                                                                          lunch regularly. Although no definitive
    A1C:          > 7.5–10%                                                                  studies have looked at this issue, the
    Medication: Oral medications adequately control postprandial glucose excursions          authors agree that for individuals eating
    Pattern:      High fasting glucose with minimal glucose rise during the day              large lunches (e.g., > 40% of their total
    Diet history: Small, regular meals (large meals will result in postprandial hyper-       daily calories), a better premix insulin
                  glycemia)                                                                  would be 70% NPH/30% regular insulin.
    Lifestyle:    Reluctance to do MDI, requires oral agents                                 The problem with this regimen, however,
    Monitoring: Fasting
                                                                                             is that the lunchtime meal needs to be
 Once- or Twice-Daily Premixed Insulin                                                       consumed at about the same time each
   Rapid-Acting Analog/Intermediate-Acting                                                   day to avoid hypoglycemia.
   A1C:          > 7.5%                                                                           Basal-bolus insulin therapy may be
   Medication: Oral agent failure (maximum tolerated dosages, contraindications, cost        required for patients with glucose toxici-
                                                                                             ty (fasting plasma glucose > 250
   Pattern:      Any fasting glucose; glucose rises during the day
                                                                                             mg/dl).42 Basal-bolus insulin therapy can
   Diet History: Large suppers/small lunches
   Lifestyle:    Consistent daily routine, reluctance to do MDI                              be continued or modified after glucose
   Monitoring: Fasting and presupper (if insulin is administered twice daily)                returns to near-normal levels. Addition-
                                                                                             ally, basal-bolus insulin management
                                                                                             should be presented as the next option if
     A1C:          > 7.5%
                                                                                             patients are unable to achieve targets
     Medication: Oral agent failure (maximum tolerated dosages, contraindications, cost
                   issues)                                                                   with a premixed insulin regimen. This
     Pattern:      Any fasting glucose; glucose rises during the day                         will be the rule for patients with more
     Diet history: Isocaloric meals or larger lunches                                        severe insulin deficiency.
     Lifestyle:    Consistent daily routine, reluctance to do MDI
     Monitoring: Fasting and presupper (if insulin is administered twice daily)              Start Low and Titrate Steadily
 Basal-Bolus (MDI)                                                                           A common starting dose for insulin ther-
    A1C:          > 7.5%                                                                     apy in patients with type 2 diabetes is
    Pattern:      Regimen can be matched to any pattern to achieve glycemic control          0.15 units/kg body wt/day;42 however,
    Diet history: Regimen can be matched to any diet to achieve glycemic control             because > 90% of patients with type 2
    Lifestyle:    Erratic schedule, motivated to achieve tight glycemic control              diabetes are insulin resistant,43 signifi-
    Monitoring: Frequent blood glucose monitoring (minimum before meals and bedtime)         cantly higher doses are often required to
                                                                                             achieve glycemic targets.39-41,44
insulin regimens based on patient clini-         daily premixed therapy. In one study,           The Treat-to-Target study44 used a
cal status and lifestyle characteristics.        there was a slight increase in overall      starting dose of 10 units/day with
    Although regimens for once-daily             hypoglycemia with no increase in noc-       glargine or human NPH at bedtime;
glargine and once-daily and twice-dai-           turnal hypoglycemia,39 whereas another      mean daily dosages at end point adjusted
ly premixed insulin are listed, it is            study showed no difference in overall       for body weight were 0.48 units/kg for
important to note that recent studies            hypoglycemia with less nocturnal hypo-      glargine and 0.42 units/kg for NPH in
comparing once-daily regimens to                 glycemia in the premix group.40 A third     those patients who were maintained on
twice-daily regimens have demonstrat-            study showed similar findings regarding     one or two oral agents throughout the
ed significant differences between the           overall hypoglycemia.41 In short, no        study. This is equivalent to ~ 40
two approaches.39–41                             definitive differences in hypoglycemia      units/day in an average 200-lb patient. A
    One study showed that twice-daily            were consistently seen in these studies.    study of premixed insulin in patients on
premixed insulin (25% lispro/75% NPL)                When postprandial glucose is not        oral agents initiated insulin therapy with
provided lower A1C levels compared               adequately controlled by combination        a dose of 6 units/day; however, the aver-
with once-daily glargine when patients           therapy using basal insulin and oral        age dosage at 28 weeks was > 75
were randomized to one or the other              agents, a twice-daily regimen using a       units/day (0.85 units/kg/day), with no
insulin regimen in addition to existing          premixed insulin preparation (prebreak-     major hypoglycemic episodes reported.41
metformin therapy39 Results also showed          fast, presupper) is preferred. Clinicians       The differences in average dosages
a smaller rise in postprandial glucose           can start patients on once-daily injec-     at end point reported in these studies
levels and a higher proportion of patients       tions at the evening meal and add the       resulted from differences in baseline
achieving an A1C of ≤ 7.0% on twice-             second injection as needed. Rapid-acting    A1C levels, durations of diabetes, and

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P R A C T I C A L                 P O I N T E R S

overall levels of insulin resistance in the   persist for months (or years, in some cas-         ticularly those who are self-adjusting
study subjects. Nevertheless, these stud-     es). A major obstacle to timely insulin            their insulin dosages.
ies show 10 units/injection to be a safe      adjustment is primarily the logistics of               If patients are not at goal after 3–6
starting dose for once-daily and twice-       communicating with the patient. Table 6            months of therapy or if recurrent hypo-
daily insulin regimens (Table 4).             presents some options for patient follow-          glycemia limits titration, consider chang-
     It is important to note that although    up that may expedite achieving glycemic            ing the regimen. Table 7 presents strate-
glargine can be taken at any time during      targets on timely basis. Diabetes educa-           gies for making this transition.
the day, it should be injected at the same    tion is a crucial aspect of patient care               When assessing the need to change
time every day. Patients should docu-         and is recommended for all patients, par-          regimens, it is important to understand
ment all results from self-monitoring of
blood glucose (SMBG) and insulin dos-          Table 4. Starting Dosages
es in their logbooks when starting or
                                               1  Premix           10 units (presupper)
adjusting insulin. Glucose meter down-
                                               2  Premix           10 units (prebreakfast), 10 units (presupper)
loading is another excellent tool for          1  Basal            10 units (bedtime)
review of SMBG data.45                         MDI                  Individualized*

Monitor and Adjust Therapy Until               *Patients with type 2 diabetes seldom start insulin on an MDI regimen. Dosages should be
                                               based on the current insulin regimen. Additionally, consider referral to a certified diabetes
Targets are Achieved
                                               education program for training in carbohydrate counting and insulin adjustment.
Although insulin is the most effective
treatment for lowering glucose, a recent
national study showed that only half of        Table 5. Dosage Titration for Once-Daily or Twice-Daily Insulin Regimens
patients with type 2 diabetes who are
treated with insulin achieve an A1C            Most Values (during last 3–7 days)                  Dosage Change
< 7%.46 To be successful, insulin therapy      < 80 mg/dl                                          –2 units
requires timely and appropriate titration      80–109 mg/dl                                        No change
of dosages. Table 5 presents a titration       110–139 mg/dl                                       +2 units
                                               140–179 mg/dl                                       +4 units
schedule that can be used with once-
                                               ≥ 180 mg/dl                                         +6 units
daily and twice-daily regimens to make
safe and timely insulin adjustments.           Adjust prebreakfast dose based on presupper/evening value.
    Working with this schedule, patients       Adjust presupper (premixed)/bedtime (basal) dose based on prebreakfast/morning value.
measure blood glucose once or twice            DO NOT increase dose if hypoglycemia (< 70 mg/dl) or symptoms are present.
daily (prebreakfast, presupper) depend-
ing on their regimen. Based on these           Table 6. Options for Patient Follow-Up
blood glucose data reported by the
patient, the clinician can then make step-     1. Patient visit
wise adjustments in response to the aver-         • First month: Patient visits physician once per week.
age glucose values. Prebreakfast dosage           • Thereafter until glycemic targets are achieved: Patient visits physician or sends blood
adjustments are based on presupper glu-             glucose monitoring data weekly to physician via phone, fax, or e-mail. Physician/nurse
                                                    responds with instructions for dosage adjustment.
cose results, whereas presupper dosage
adjustments are based on prebreakfast          2. Phone, fax, e-mail
glucose values.                                   • First month: Patient sends blood glucose monitoring data weekly to physician via
    For example, in a patient on 10 units           phone, fax, or e-mail. Physician/nurse responds with instructions for dosage adjust-
of premixed insulin twice daily who                 ment.
reports prebreakfast glucose values rang-         • Thereafter until glycemic targets are achieved: Patient continues to send blood glucose
                                                    monitoring data weekly. Physician/nurse (by protocol) responds with instructions for
ing from 148 to 175 mg/dl over the past
                                                    dosage adjustment.
3–7 days, the appropriate adjustment
would be an additional 4 units of insulin      3. Patient self-adjustment
before supper.                                    • First month: Patient monitors blood glucose, adjusts insulin dosage as needed, and
    Another key aspect of insulin titra-            sends monitoring and dosage adjustment data weekly to physician via phone, fax, or e-
tion is timely adjustment. As with oral             mail. Physician/nurse (by protocol) responds with instructions for dosage adjustment.
                                                  • Thereafter until glycemic targets are achieved: Patient continues to send blood glucose
therapy, clinicians often wait too long to
                                                    monitoring and insulin adjustment data to physician weekly. Physician/nurse (by pro-
make adjustments in insulin dosages,
                                                    tocol) responds with instructions for dosage adjustment.
allowing excessive glycemic exposure to

82                                                                                                 Volume 23, Number 2, 2005 • CLINICAL DIABETES
P R A C T I C A L                    P O I N T E R S

 Table 7. Transition From One Regimen to Another                                                    issue. Figure 3A illustrates how address-
                                                                                                    ing fasting glucose can initially lower
 Current 1  Basal → New 2  Premix                                                                 fasting levels and even improve post-
 • Divide total daily dose in half. Give prebreakfast and presupper premix insulin. The new         prandial excursions by reducing gluco-
   regimen should be started 18–24 hours after last basal dose was given.                           toxicity and thus improving -cell func-
 • Titrate to goal based on SMBG data and diet history. The largest meal requires a larger          tion. However, once fasting glucose
   proportion of insulin.                                                                           levels are normalized, increasing the
 • Reduce total dose by 20% if there is recurrent hypoglycemia.                                     basal dosage will not adequately address
 Current 1  Premix → New 2  Premix                                                                the remaining postprandial hyper-
 • Divide total daily dose in half. Give prebreakfast and presupper.                                glycemia (Figure 3B). Therefore, a regi-
 • Titrate to goal based on SMBG data and diet history. The largest meal requires a larger          men that addresses both fasting and post-
   proportion of insulin.                                                                           prandial hyperglycemia is needed
 • Reduce total dose by 20% if there is recurrent hypoglycemia.                                     (Figure 3C).
 Current 1  Basal Only → Add Rapid-Acting Insulin at Largest Meal*
 • Give 10% of total daily dose as rapid-acting analog at largest meal.                             CONCLUSION
 • Reduce basal dose by 10%.                                                                        Insulin therapy in the treatment of type
                                                                                                    2 diabetes offers significant advantages
 Current 2  Premix → MDI†
                                                                                                    in efficacy and outcomes. However,
 • Divide total daily dose in half.
                                                                                                    unfounded fear of hypoglycemia and
 • Initial basal insulin dose = total daily dose/2  80%.
 • Initial prandial insulin dose = half of total daily dose  percentage of estimated calories      uncertainties regarding initial dosage
   for each meal                                                                                    and titration have been key obstacles for
                                                                                                    many providers when making the deci-
 *   This regimen serves as a transition to MDI therapy.                                            sion to initiate insulin treatment in their
     Example: Patient is currently on 60 units total daily dose of premix insulin (30 units twice
                                                                                                    patients with type 2 diabetes.
     daily) and eats ~ 20% of total daily calories at breakfast, 20% at lunch, and 60% at supper.
                                                                                                        Given the progressive nature and
     The new regimen would be 24 units of basal insulin with 6 units of rapid-acting insulin at
     breakfast, 6 units at lunch, and 18 units at supper.                                           increasing incidence of type 2 diabetes,
                                                                                                    more patients will be faced with severe
and consider the impact of fasting glu-                                                             insulin deficiencies in their lifetimes. It
cose and postprandial glucose on overall                                                            is hoped that the information and recom-
glycemic control. Monnier et al.47
recently published findings that showed
a variable relationship between fasting
and glucose based on current A1C lev-
els. As shown in Figure 2, the report
revealed that the relative contribution of
fasting glucose to overall glycemia is
~ 70% in patients with an A1C of
> 10.2%; the contribution of fasting glu-
cose decreases as A1C levels decrease.
     Knowing the relative contribution of
fasting and postprandial glucose to A1C
allows clinicians to make more informed
decisions about therapy. For example, if
a patient’s A1C is at 7.5%, adjustment
should focus on lowering postprandial
glucose; adding basal insulin will not
directly address postprandial hyper-
glycemia. Although the addition of basal
insulin will improve the overall A1C, as
shown in the Treat-to-Target study,44 it
will not lower the degree of postprandial
                                                     Figure 2. Relative contribution of fasting and postprandial glucose to A1C.
excursions. Only meal plan modification
                                                     Adapted from Monnier et al.47
or prandial insulin will address this

CLINICAL DIABETES • Volume 23, Number 2, 2005                                                                                                83
P R A C T I C A L               P O I N T E R S

                                                                                    mendations provided in this article will
                                                                                    help primary care providers become
                                                                                    more effective in their management of
                                                                                    patients with type 2 diabetes.


                                                                                    The authors gratefully acknowledge
                                                                                    support from Eli Lilly in funding the
                                                                                    expenses related to developing this

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glycemia.                                                                           fonylurea: a double-blind placebo-controlled

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study of NIDDM patients. Diabetes Care                          Ceriello A, Taboga C, Tonutti L, Quagliaro            Malone JK, Kerr LF, Campaigne BN, Sach-
19:1194–1199, 1996                                       L, Piconi L, Bais B, Da Ros R, Motz E: Evidence       son RA, Holcombe JH, for the Lispro Mixture-
                                                         for an independent and cumulative effect of post-     Glargine Study Group: Combined therapy with
       Blaum CS, Velez L, Hiss RG, Halter JB:            prandial hypertriglyceridemia and hyperglycemia       insulin lispro mix 75/25 plus metformin or
Characteristics related to poor glycemic control         on endothelial dysfunction and oxidative stress       insulin glargine plus metformin: a 16 week, ran-
in NIDDM patients in community practice. Dia-            generation effects of short- and long-term simvas-    domized, open label, cross-over study in patients
betes Care 20:7–11, 1997                                 tatin treatment. Circulation 106:1211–1218, 2002      with type 2 diabetes beginning insulin therapy.
    13                                                                                                         Clin Ther 26:2034–2044, 2004
       The DCCT Research Group: The effect of                25
                                                                Temelkova-Kurktschiev TS, Koehler C,
intensive treatment of diabetes on the develop-          Henkel D, Leonhardt W, Fuecker K, Hanefeld M:             40
                                                                                                                      Malone JK, Bai S, Campaigne BN,
ment and progression of long-term complications          Postchallenge plasma glucose and glycemic             Reviriego J, Augendre-Ferrante B: Twice-daily
in insulin-dependent diabetes mellitus. N Engl J         spikes are more strongly associated with athero-      pre-mixed insulin rather than basal insulin thera-
Med 329:977–986, 1993                                    sclerosis than fasting glucose or HbA1c level.        py alone results in better overall glycaemic con-
    14                                                   Diabetes Care 23:1830–1834, 2000                      trol in patients with type 2 diabetes. Diabet Med
       Malmberg K, Norhammar A, Wedel H,                                                                       2005. In press
Ryden L: Glycometabolic state at admission:                  26
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ally treated patients with diabetes mellitus and         prandial plasma glucose is an independent risk        twice-daily biphasic insulin aspart 70/30 (BIAsp
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from the Diabetes and Insulin-Glucose Infusion           ness in non-diabetic individuals. Atherosclerosis     patients with type 2 DM on oral antidiabetic
in Acute Myocardial Infarction (DIGAMI) study.           144:229–235,1999                                      agents. Diabetes 53 (Suppl. 2):602-P, 2004
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                                                                Shaw JE, Hodge AM, de Courten M, Chit-                Mayfield JA, White RD: Insulin therapy for
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Verwaest C, Bruyninckx F, Schetz M, Vlasselaers          glycaemia confirmed as a risk factor for mortali-     replacement of beta-cell function. Am Fam Physi-
D, Ferdinande P, Lauwers P, Bouillon R: Inten-           ty. Diabetologia 42:1050–1054, 1999                   cian 70:489–500, 2004
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Engl J Med 345:1359–1367, 2001                                  Balkau B, Shipley M, Jarrett RJ, Pyorala K,           Haffner SM, D’Agostino R Jr, Mykkanen L,
                                                         Pyorala M, Forhan A, Eschwege E: High blood           Tracy R, Howard B, Rewers M, Selby J, Savage
      Furnary AP, Zerr KJ, Grunkemeier GL,               glucose concentration is a risk factor for mortali-   PJ, Saad MF: Insulin sensitivity in subjects with
Starr A: Continuous intravenous insulin infusion         ty in middle-aged non-diabetic men. Diabetes          type 2 diabetes: relationship to cardiovascular
reduces the incidence of deep sternal wound              Care 21:360–367, 1998                                 risk factors: the Insulin Resistance Atherosclero-
infection in diabetic patients after cardiac surgical                                                          sis Study. Diabetes Care 22:562–568, 1999
procedures. Ann Thorac Surg 67:352–360, [dis-                   Chiasson JL, Josse RG, Gomis R, Hanefeld
cussion 360–362], 1999                                   M, Karasik A, Laakso M, the STOP-NIDDM                       Riddle MC, Rosenstock J, Gerich J, the
                                                         Trail Research Group: Acarbose for prevention of      Insulin Glargine 4002 Study Investigators: The
       Lazar HL, Chipkin SR, Fitzgerald CA, Bao          type 2 diabetes mellitus: the STOP-NIDDM ran-         Treat-to-Target Trial: randomized addition of
Y, Cabral H, Apstein CS: Tight glycemic control          domised trial. Lancet 359:2072–2077, 2002             glargine or human NPH insulin to oral therapy of
in diabetic coronary artery bypass graft patients                                                              type 2 diabetic patients. Diabetes Care
improves perioperative outcomes and decreases                   Turner RC, Cull CA, Frighi V, Holman RR:       26:3080–3086, 2003
recurrent ischemic events. Circulation                   Glycemic control with diet, sulfonylurea, met-
109:1497–1502, 2004                                      formin, or insulin in patients with type 2 diabetes         Hirsch IB: Blood glucose monitoring tech-
                                                         mellitus: progressive requirement for multiple        nology: translating data into practice. Endocr
      Rosenfalck AM, Thorsby P, Kjems L, Birke-          therapies (UKPDS 49). JAMA 281:2005–2012,             Pract 10:67–76, 2004
land K, Dejgaard A, Hanssen KF, Madsbad S:               1999                                                      46
Improved postprandial glycaemic control with                                                                          Koro CE, Bowlin SJ, Bourgeois N, Fedder
insulin aspart in type 2 diabetic patients treated            Groop LC: Sulfonylureas in NIDDM. Dia-           DO: Glycemic control from 1988 to 2000 among
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      Anderson JH Jr, Brunelle RL, Keohane P,                   DeFronzo RA: Pharmacologic therapy for
Koivisto VA, Trautmann ME, Vignati L,                    type 2 diabetes mellitus. Ann Intern Med                     Monnier L, Lapinski H, Colette C: Contri-
DiMarchi R: Mealtime treatment with insulin              131:281–303, 1999                                     butions of fasting and postprandial plasma glu-
analog improves postprandial hyperglycemia and               33
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hypoglycemia in patients with non-insulin-                      Nathan DM: Initial management of               glycemia of type 2 diabetic patients: variations
dependent diabetes mellitus. Arch Intern Med             glycemia in type 2 diabetes mellitus. N Engl J        with increasing levels of HbA1c. Diabetes Care
157:1249–1255, 1997                                      Med 347:1342–1349, 2002                               26:881–885, 2003
       Rosenstock J, Schwartz SL, Clark CM Jr,                  Hayward RA, Manning WG, Kaplan SH,
Park GD, Donley DW, Edwards MB: Basal                    Wagner EH, Greenfield S: Starting insulin thera-
insulin therapy in type 2 diabetes: 28-week com-         py in patients with type 2 diabetes: effectiveness,
                                                         complications, and resource utilization. JAMA         Irl B. Hirsch, MD, is a professor of med-
parison of insulin glargine (HOE 901) and NPH
insulin. Diabetes Care 24:631–636, 2001                  278:1663–1669, 1997                                   icine in the Division of Metabolism,
      Jacobon L, Sogaard B, Riis A: Pharmacoki-
                                                               UKPDS Study Group: UKPDS 28: a ran-             Endocrinology, and Nutrition at the Uni-
netics and pharmacodynamics of a premixed for-           domized trial of efficacy of early addition of met-   versity of Washington Medical Center in
mulation of soluble and protamine-retarded               formin in sulfonylurea-treated type 2 diabetes.
insulin aspart. Eur J Clin Pharmacol 56:399–403,         Diabetes Care 21:87–92, 1998                          Seattle. Richard M. Bergenstal, MD, is
2000                                                         36
                                                                American Diabetes Association: Standards       executive director of the International
     Roach P, Trautmann ME, Anderson JH, the             of medical care in diabetes. Diabetes Care 28         Diabetes Center and a clinical professor
Mix25 Study Group: Improved postprandial                 (Suppl. 1):S4–S36, 2005                               at the University of Minnesota, both in
glycemia during treatment with an intermediate-              37
                                                                American Association of Clinical Endocri-      Minneapolis. Christopher G. Parkin,
acting insulin mixture, Mix25 (Abstract). Dia-           nologists: Medical guidelines for the manage-
betologia 41 (Suppl. 1):A244, 1998                                                                             MS, is a medical writer and consultant
                                                         ment of diabetes mellitus. Endocr Pract 8 (Suppl.
       Roach P, Trautmann M, Arora V, Sun B,             1):40–82, 2002                                        to professional medical organizations
Anderson JH Jr, and the Mix50 Study Group:
Improved postprandial blood glucose control and
                                                                Schwartz S, Sievers R, Strange P, Lyness       and healthcare companies and president
                                                         WH, Hollander P: Insulin 70/30 mix plus met-
reduced nocturnal hypoglycemia during treatment          formin versus triple oral therapy in the treatment    of CGParkin Communications in
with two novel insulin lispro-protamine formula-
tions, insulin lispro mix25 and insulin lispro           of type 2 diabetes after failure of two oral drugs:   Carmel, Ind., Eugene E. Wright, Jr., MD,
                                                         efficacy, safety, and cost analysis. Diabetes Care
mix50. Clin Ther 21:523–534, 1999                        26:2238–2243, 2003                                    is medical director of Primary Care and

CLINICAL DIABETES • Volume 23, Number 2, 2005                                                                                                                  85
P R A C T I C A L              P O I N T E R S

Specialty Practices of Cape Fear Valley     support from Mannkind Corporation.          Pharmaceuticals.
Health System in Fayetteville, N.C. John        Dr. Bergenstal has served on advi-          The University of North Carolina
B. Buse, MD, PhD, is an associate pro-      sory panels for, received consulting fees   has received honoraria related to Dr.
fessor at the University of North Caroli-   or honoraria from, and received             Buse’s speaking engagements for Abbott,
na School of Medicine in Chapel Hill,       research support from Eli Lilly, Novo       Pfizer, and Eli Lilly; grant support relat-
where he is the division chief of General   Nordisk, and Sanofi-Aventis Pharma-         ed to his research activities from Bristol-
Medicine and director of the Diabetes       ceuticals.                                  Myers Squibb, Novartis Pharmaceuti-
Care Center. He is also an associate edi-       Mr. Parkin has received consulting      cals, and Pfizer; and consulting fees
tor of Clinical Diabetes.                   fees from Abbott Diabetes Care, Bayer       related to his formal advisory activities
                                            Diagnostics, Eli Lilly, EMD Pharma-         from Amylin Pharmaceuticals, BD
Notes of disclosure: Dr. Hirsch has         ceuticals, Roche Diagnostics, and           Research Laboratories, Eli Lilly, Merck,
received consulting fees or honoraria for   Sanofi-Aventis Pharmaceuticals.             and Bristol-Myers Squibb.
speaking engagements from Eli Lilly,            Dr. Wright has served on advisory           All of these companies manufacture
Novo Nordisk, and Sanofi-Aventis Phar-      panels and received consulting fees or      pharmaceutical products for the treat-
maceuticals. He also receives research      honoraria from Eli Lilly and Amylin         ment of diabetes.

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