Pharmacist Management of Diabetes Mellitus: A Randomized Controlled Trial.
Running Title: `Pharmacist Management of Diabetes Mellitus:
John P. Jameson, PharmD
Ferris State University
Grand Rapids Family Medicine Residency Program
Philip J. Baty, MD
Advantage Health Physician Network
Grand Rapids Family Medicine Residency Program
Corresponding author:
John Jameson, PharmD
Address: Suite 4000, Wege Center, 300 Lafayette SE, Grand Rapids, MI 40503
Phone: 616-685-6655
Fax: 512-366-9941
Email: John@ProfJameson.com
Word count: 2044
Number of tables and numbers of figures: 3 Tables
Abstract
Objective:
Various methods have been used to improve Hemoglobin A1c (A1c) control for patients.
However, a significant number of patients fail to achieve even moderate control of their A1c.
This study investigates the effect of pharmacist management of poorly controlled diabetes in a
community based primary care group.
Study Design
A randomized controlled trial of Pharmacist management of Diabetes compared with usual
medical care.
Methods:
Patients 18 years of age and over with A1c levels ≥9% were enrolled. Patients were randomly
assigned to either the intervention (n=52) or control group (n=51). Control control group
management included the use of registries and targeted patient outreach. The intervention group
experienced this plus medication management, patient education and case management by
a clinical pharmacist.
Results:
The non parametric data show a median A1c decrease of 1.5 % for the intervention group and
0.4% for the control group (p=0.06). A significantly greater number of patients in the
intervention group decreased their A1c by 1 percent or more, relative to the control group (67%
vs. 41%, respectively; p=0.02).
The majority of this benefit was seen for non-Caucasian
compared to Caucasians (56% vs. 22%, respectively; p=0.03). Males showed a significant
benefit as well, with an A1c decrease of 1.9 percent vs. 0.15% for females (p=0.02).
Conclusions:
Patients with poorly controlled diabetes improved A1c levels significantly when a pharmacist's
management was added to an aggressive organizational diabetes management program.
Clinically trained pharmacists can help primary care providers improve diabetes management,
especially with males and minority patients.
Keywords: Pharmacist, Diabetes Mellitus, Case Management, A1c
Introduction
Diabetes affects 23 million people in the United States. Minorities are disproportionately
affected. Adjusting for population age differences, 2004-2006 survey data indicate that 6.6% of
non-Hispanic whites, 7.5% of Asian Americans, 10.4% of Hispanic and 11.8% of non-Hispanic
blacks have Diabetes Mellitus (1). Diabetes care accounts for 19% of the total health care cost,
$174 billion dollars in 2007 (2). Among persons with diabetes, 21 to 43 percent have A1c levels
> 9% (3); evidence suggests attempting to achieve A1c levels below 7% will delay, ameliorate,
or even prevent the microvascular and neuropathic complications of diabetes (4,5) There is
conflicting evidence regarding trying to lower A1c below 7.0% (6). Current American Diabetes
Association guidelines recommend we use a goal of less than 7.0% for A1c control(7)
The medical literature demonstrates the use of clinical databases and case managers is
associated with an improvement in patient A1c levels (8-10). Case managers coordinate all
disease related care and education as well as support patient self management. Early studies
showing the value of nurse case managers were conducted in an era of fewer medications and
less aggressive management, with the vast majority of studies involving patients enrolled in
health plans notably Health Maintenance Organizations (HMO)(8) Patients in the nurse case
management group showed a significantly depressed A1c concentration by 0.6 to 1 percent
compared to the control group.
More recent studies have employed a model where pharmacists work in collaboration
with primary care physicians (11-16). Given the ever increasing options for treating diabetes,
pharmacists should be well positioned to evaluate the merits of each therapeutic option and to
provide patient education. Studies showing the benefit of pharmacists serving as case managers
have been small and often non-randomized. The few randomized controlled trials have been
done in large urban academic or diabetes referral centers. As an example, Choe et al. (10)
showed improved A1c and process outcome measures in a single university based ambulatory
Internal Medicine clinic for diabetic patients. We add to the literature a randomized study that
looks at pharmacist and primary care physician collaborative care in the treatment of poorly
controlled diabetic patients outside the academic and specialty care setting.
Research Design and Methods
Study design and setting
This is a 12-month prospective randomized controlled study. The primary outcome measure is
the change in A1c at the end of one year. Secondary outcomes were the percent of patients with
a 1 point decrease in A1c. This outcome was assessed in the population as a whole and as a
function of minority status.
The Research Committee and the Institutional Review Board of
Saint Mary’s Health Care, Grand Rapids, Michigan approved this trial.
The site for the study is the Advantage Health Physician Network (AHPN), which employs an
electronic registry that identifies all adults with Diabetes Mellitus. A total of 13 AHPN offices
participate, including three urban, nine suburban and one rural site. Clinical practice guidelines,
diabetes indicators and performance thresholds are tracked routinely and shared regularly with
providers and staff. Each office has specific personnel budgeted to support diabetes quality
related initiatives. The latest quality indicators for individual patients are available at each office
visit. In addition, there is phone and mail outreach to patients who are due for diabetes related
care. In 2007 there were 6,000 patients in the registry and 55% had an A1c less than 7% and
LDL less than 100.
Patients and Randomization
Diabetes patients 18 years of age or older with an A1c ≥ 9% or no office visits within twelve
months were contacted by a study nurse. The nurse saw the patient at their home and determined
eligibility. Patients were excluded if an endocrinologist was currently managing them or if they
were not expected to live for the duration of the study. Eligible patients were tested with a Bayer
DCA 2000 point of care A1c instrument and offered enrollment if their A1c was nine or greater.
The study nurse obtained IRB approved informed consent at this point from patients who agreed
to participate and attend all study visits.
Randomization to intervention or control group was done by the research nurse using
sequential envelopes containing computer generated group assignment. Envelopes were only
opened only after the subject was deemed eligible. Both groups received the aggressive outreach
described above. Those in the intervention group also met with the clinical pharmacist at their
respective primary care site for an assessment of adherence, barriers to optimizing blood glucose
levels, and current medication regimen. All intervention patients received individualized
education regarding diabetes self-management. The pharmacist followed the Management of
Hyperglycemia in Type 2 Diabetes Guidelines.(17) Primary care physicians approved any
changes in medication or therapy, though the pharmacist was given autonomy to adjust insulin
doses as needed. The number of subsequent visits was based on the need for further education
or monitoring therapeutic changes. Follow up visits were supplemented with phone calls as
needed for medication management. Patients were followed for 12 months post-enrollment. We
were not able to assess adverse events in the usual care group. There was only one severe
hypoglycemic event in the intervention group. Severe events were defined as requiring
assistance from another person.
Statistics
A power analysis indicated that at least 39 patients were needed in each group to show a
clinically significant decrease in A1c of 1.1 or greater (beta=0.20 and alpha=0.05). Chi Square
and Fishers Exact test were used where appropriate for nominal data. The Mann Whitney U test
was used for quantitative data. Significance was assessed at p<0.05. The statistical software
used was NCSS 2004 (Kaysville UT).
Results
Recruitment began in May of 2006 and final 1 year follow up for the last patient was in
December 2007. Among all AHPN patients with diabetes, 902 had an A1c ≥9% or had not been
seen by the primary care provider within the previous 12 months. Of these, 490 were
successfully contacted and invited to participate. Two hundred thirty five patients were
excluded; 191 (39%) declined participation and 44 (9%) were managed by a specialist. An
additional one hundred fifty two (31%) had an A1c less than nine at the time they saw the study
nurse. The remaining 104 patients were randomized, 52 to the control group and 52 to the
intervention group.
One patient in the control group was excluded as an outlier based upon a change in A1c
greater than three standard deviations from the mean change in A1c level. This patient was
hospitalized for 3 weeks for diabetes complications and subsequently decreased their A1c by
8.6%. Thus, the final analysis is based on 103 patients; 52 in the intervention group and 51 in
the control group. Baseline demographic data are presented in Table 1. Hemoglobin A1c was
the only significant difference between the groups at baseline.
The A1c changes were not normally distributed, so median values were used as the
measure of central tendency. Overall median reductions in the intervention group had a decrease
in A1c that was 1.1 percentage points greater than the control group. This difference
approached, but did not achieve statistical significance. Post hoc sub group analysis shows
males in the intervention group achieved a large, statistically significant improvement (-1.90 (0.05, -2.95)) versus the control group (-0.15 (0.98, -1.38)).
From the perspective of individual patient improvement, a statistically greater number of
patients in the intervention group achieved a 1-point or greater improvement in A1c. Twice as
many non-Caucasians and males (post hoc) in the intervention group exceeded the 1-point
improvement mark. No treatment effects using this measure were seen for females or
Caucasians. (Table 3)
This intervention required considerable effort. The pharmacist averaged six office visits
and three phone calls per patient over the course of a year. Office visits lasted between 30 and
60 minutes. Phone calls were 10 to 20 minutes in length. The pharmacist changed the regimen
to basal/bolus insulin in 15 (28%) patients and discontinued oral medications completely in 15
(28%) patients.
In the control group, only one patient was changed to basal bolus, oral
medications were discontinued in one patient and insulin was added in one patient.
Conclusions
This study was undertaken to ascertain the benefit of having a pharmacist work with
primary care physicians to reduce A1c levels among poorly controlled diabetic patients at
multiple community based clinics. It has been shown that greater benefits accrue when moving
from poor (A1c>9%) to moderate glycemic control compared to moving from moderate to
almost-normal glycemic control. Vijan et al.(18) shows that 80 percent of the reductions in
blindness and end-stage renal disease resulted from targeting fewer than 20 percent of patients
with the worst A1c control. Our overall findings of significantly improved A1c outcomes in the
intervention group are compatible with the findings of two recent comprehensive reviews of
Pharmacist management of diabetes (14,15). Our study further identified that the benefit was
primarily among non-Caucasian and male patients. To our knowledge, this subgroup
differentiation has not been previously identified.
Our finding of greater improvement for minorities with pharmacist intervention is
congruent with the findings of studies that were limited to specific ethnic groups. Studies in
non-Caucasians (10,19) showed much greater improvement over control than studies in
Caucasians (12,20). Not only do minorities have more poorly controlled diabetes, they have
more complications.(21-23) Mexican Americans and African Americans have at least a fourfold
greater incidence of kidney disease and Mexican Americans have 1.8 times more peripheral
vascular disease than non-Hispanic whites with diabetes (24). Given the disproportionate
prevalence of diabetes and diabetic complications in minorities, coupled with poorly controlled
A1c, case management with a clinical pharmacist can be of benefit to this population and is one
of the tools that is likely to have clinically meaningful results.
The intervention group showed more improvement despite having lower baseline A1c
levels than the controls. In men, approximately two people need to be treated by a pharmacy
case manager for one year to have one patient improve their A1c by at least one point. In
minorities it only takes three people to see and be managed by a pharmacist to have one of them
lower their A1c by one percent. The United Kingdom Prospective Diabetes Study (UKPDS 35)
shows that for Type 2 diabetics every decrease in A1c of 1.0 leads to a reduction of 21% in
death, 14% in myocardial infarction (MI) and 37% in microvascular complications (4) Thus,
men and minorities in the intervention group achieved changes that are likely to be clinically
significant.
The fact that basal bolus insulin was started in 28% of patients versus 2% in usual care
indicates a different approach to management of diabetes by the clinical pharmacist. In addition
to adding insulin, the pharmacist simplified the medication regimen by discontinuing oral
medications in 28% of patients versus 2% in usual care. The success of changing insulin doses
and withdrawing oral medication in the intervention group demonstrates the large educational
commitment required of both the clinician and the patient in the management of diabetes. The
average patient was in contact with the pharmacist for over 300 minutes during the one year
intervention.
Limitations associated with our study include the use of a single primary care group,
although this is mitigated by the use of diverse sites (e.g., urban, suburban, rural). This study
was not designed to prove if a clinical pharmacist is specifically required to obtain the benefits of
this case management approach. The time and cost does highlight the intense commitment it
takes to help patients overcome the inertia of not starting insulin. The subsidized nature of the
cost and pharmacist time in this study are threats to external validity. Finally, the only
pharmacist used in this study was clinically trained and experienced in patient care activities
such as medication management and motivational interviewing. Overall, this study should be
generalizable to similarly equipped primary care groups using an experienced clinical
pharmacist.
The doubling of the percentage of patients with significantly improved A1c levels in men
and minorities suggest that our current system is inadequate in these populations. Our
hypothesis, based on clinical observation, is that these two groups require more time spent, more
individualized education, and perhaps more proactive follow up. Future research should further
explore clinical pharmacist case management interventions in general and to elucidate the
apparent enhanced benefit we found in minorities and men.
Take Away Points
The population of patients with poorly controlled Diabetes represent an ongoing challenge.
Pharmacist management significantly increases the percentage of patients who improve their
A1c
This study suggests, but does not prove that males and non-whites are two groups that respond to
Pharmacist management more than to usual care.
Acknowledgments.
Financial Support for this study was provided by Advantage Health Physician Network, Doran
Foundation, Michigan Pharmacist Foundation, Priority Health, and Western Michigan Society of
Health System Pharmacists,
We would like to thank Susan Emelander, RN for her indispensible role patient enrollment and
follow up. We would like to thank GRMERC Research Department, Andrea Wendling M.D.
and Sister Rosita Schiller for manuscript review and suggestions.
Prior presentations: Michigan Family Medicine Research Day 2008, Brighton, Michigan
Disclosures: Dr. Jameson has no disclosures. Dr. Baty is a practicing clinician in the Advantage
Health Physician Network.
References
1. http://diabetes.niddk.nih.gov/dm/pubs/statistics/#race Accessed November 7th, 2008.
2. Diabetes Statistics, 2007. http://www.diabetes.niddk.nih.gov/dm/pubs/statistics/index.htm 14
July 2008
5. Saydah SH, Fradkin J , Cowie CC. Poor control of risk factors for vascular disease among
adults with previously diagnosed Diabetes. JAMA 2004;291(3):335-342.
6. Stratton IM, Adler AI, Neil AW, et. al. Association of glycemia with macrovascular and
microvascular complications of Type2 Diabetes (UKPDS 35) prospective observational study.
BMJ 2000;321:405-412
5. Diabetes Control and Complications Trial / Epidemiology of Diabetes Interventions and
Complications (DCCT/EDIC) Study Research Group. Intensive Diabetes treatment and
cardiovascular disease in patients with Type 1 Diabetes. N Engl J Med 353;(25):26432653.
6.
The Action to Control Cardiovascular Risk in Diabetes Study Group Effects of Intensive
Glucose Lowering in Type 2 Diabetes Volume 358:2545-2559 June 12, 2008 Number 24 p
2445-2459.
7. DIABETES CARE, VOLUME 32, SUPPLEMENT 1, JANUARY 2009 p S13-S49.
8. Norris SL, Nichols PJ and Caspersen CJ et. al. The effectiveness of disease and case
management for people with diabetes. A systematic review Am J. prev Med
2002;22(4S)15-38.
9. Renders CM, Valk GD, Franse LV, et. al. Long term effectiveness of a quality impact
program for patients with Type 2 Diabetes in general practice. Diabetes Care
2001;24(8)1365-1370
10. Weingerten SR, Henning JM, Adamgarav E et.al. Interventions Used in Disease
Management Programs for Patients with Chronic Illness-Which Ones Work? BMJ 2002;
325:925-932
11.
Choe HM, Mitrovich S, Dubay D, et al. Proactive case management of high-risk patients
with type 2 Diabetes Mellitus by a clinical pharmacist: a randomized controlled trial. Am J
Manag Care. 2005;11(4):253-260.
12. Leal S, Glover JJ, Herrier RN, Felix A. Improving quality of care in diabetes through a
comprehensive pharmacist-based disease management program. Diabetes Care.
2004;27:2983-2984.
13. Kiel PJ and McCord AD. Pharmacist Impact on Clinical outcomes in a Diabetes Disease
Management Program via Collaborative Practice. Ann Pharmacother 2005;39:1828-32.
14. Clifford RM, Batty KT, Davis WA, Davis TM. Effect of a pharmaceutical care program on
vascular risk factors in Type 2 Diabetes
15. Wubben DP, Vivian EM. Effects of a pharmacist outpatient interventions on adults with
Diabetes Mellitus: a systematic review. Pharmacotherapy 2008;28:412-436
16. Machado M, Bajcar J, Guzzo GC, Einarson TR. Sensitivity of patient outcomes to
pharmacist interventions. part I: systematic review and meta-analysis in Diabetes
management. Ann Pharmacother 2007;41:1569-82.
17 Nathan DM, Buse JB, Davidson MB, Management of hyperglycemia in type 2 diabetes: A
consensus algorithm for the initiation and adjustment of therapy: a consensus statement
from
the American Diabetes Association and the European Association for the Study of
Diabetes.
Diabetes Care. 2006 Aug;29(8):1963-72.
18. Vijan S, Hofer TP, Hayward RA. Estimated benefits of glycemic control in microvascular
complications in type 2 diabetes. Ann Intern Med. 2007;27(9):837-839.
19. Two Feathers J, Kieffer EC, Palmisano G et.al. Racial and ethnic approaches to community
health (REACH) Detroit Partnership: Improving Diabetes-related outcomes among African
American and Latino adults. Am J Pub Health 2005;95:1552-60
20. Guirguis LM, Johnson JA, Farris KB, Tsuyuki RT, Toth EL. A pilot study to evaluate the
impact of Pharmacists as Certified Diabetes Educators on the clinical and humanistic
outcomes of people with Diabetes. Canadian Journal of Diabetes Care 2001;25:266-76.
21. Jiang HJ, Andrews R, Stryer D, Friedman B. Racial/ethnic disparities in potentially
preventable readmissions: the case of Diabetes. Am J Public Health. 2005;95(9):1561-1567.
22. Kirk JK, Bell RA, Bertoni Ag, et al. Ethnic disparities: control of glycemia, blood pressure,
and LDL cholesterol among US adults with type 2 diabetes. Ann Pharmacother. 2005;
39(9):1489-1501.
23. Quandt SA, Bell RA, Snively BM, et al. Ethnic disparities in glycemic control among rural
older adults with type 2 diabetes. Ethn Dis. 2005;15(4):656-663.
24. Saydah S, Cowie C, Eberhardt MS, De Rekeneire N, Narayan KM. Race and ethnic
differences in glycemic control among adults with diagnosed diabetes in the United States.
Ethn Dis 2007;17(3):529-35.
Table 1. Baseline Characteristics of the Study Population*
Demographic
Pharmacist Usual
p value
Age*
49.3+10.8
49.7+10.9 ns **
Weight*
223+ 50
209.5+60
ns **
Sex (% male)
25 (48.9)
25 (49)
ns ***
Caucasian (% yes)
36 (69.2)
29 (56.8)
ns ***
Baseline hemoglobin A1c (%)
10.4 (1.2)
11.1(1.6)
0.016 **
Oral Medications (% yes)
29 (55.8)
23 (45.1)
ns ***
Insulin (% yes)
23 (44.2)
28 (54.9)
ns ***
Basal (% yes) (alone or w/ orals) 11 (21.1)
6 (11.8)
ns ***
Basal bolus (% yes)
17 (32.7)
17 (33.3)
ns ***
Private insurance (% yes)
29 (55.7)
36 (70.5)
ns ***
Medicare/Medicaid (% yes)
3 (5.8)
4 (7.9)
ns ***
None (% yes)
20 (38.4))
11 (21.6)
ns ***
Glycemic management
Insurance type
The only significant difference between groups at baseline was a lower
A1c at baseline in the intervention group.
* Mean (SD)
** unpaired Student t test
*** chi square
Table 2. Median Reduction in A1c by group
All Subjects
Median Reduction in A1c p value
Intervention group (n = 52) -1.5 (-0.03, -2.68)
Control group (n = 51)
0.06
-0.4 ( 0.50, -2.10)
Caucasian only
Intervention group (n = 36) -1.8 (-0.2, -2.7)
Control group (n = 29)
0.05
-1.2 (0.0, -2.5)
Non-Caucasian only
Intervention group (n = 16) -1.1 (0.1, -1.9)
Control group (n = 22)
0.07
-0.1 (1.4, -0.9)
Males
Intervention group (n = 25) -1.90 (-0.05, -2.95)
Control group (n = 26)
0.03*
-0.15 (0.98, -1.38)
There was a trend for greater improvement in the intervention group
Post hoc analysis shows a significantly greater improvement in men
in the intervention group
Data presented as Median (Interquartile Ranges) p values calculated by Mann Whitney U.
*Statistically Significant
Table 3 Subjects Who Achieved a One Point or Greater Decrease in A1c
All Subjects
Number (percent)
p value
Intervention group (n = 52)
35 (67.3)
0.02*
Control group (n = 51)
21 (41.1)
Caucasian only
Intervention group (n = 36)
25 (69)
Control group (n = 29)
16 (55)
0.23
Non-Caucasian only
Intervention group (n = 16)
9 (56.2)
Control group (n = 22)
5 (22.7)
0 .034*
Women Only
Intervention group (n=27)
16 (59.2)
Control group (n=26)
13 (50)
0.49
Men Only
Intervention group (n=25)
18 (72)
Control group (n=25)
7 (28)
0.002*
Statistically significant differences are found in the intervention group overall. Secondary
analysis shows significant improvement in both men and minority subgroups.
P values calculated by the chi square test
*Statistically Significant