Conditions: Type 2 Diabetes Mellitus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 22
Healthy volunteers: no

Brief summary:
In traditional step-up approach, the patients with poorly-controlled type 2 diabetes are instructed to take up to 4 insulin injections daily or multiple daily injections (MDI) as the most advanced therapy. However, a significant number of these patients continue to have poor diabetes control. The most common reason is the noncompliance with multiple injections and the patient's reluctance to accept insulin-induced weight gain. More recently, the algorithm in diabetes management has significantly changed to accommodate the newer generation of medications. Addition of the diabetes medications, that can induce weight loss such as oral Sodium-glucose Cotransporter-2 (SGLT2) Inhibitors and once-weekly glucagon-like peptide (GLP)-1 receptor agonists (GLP1 RA) injection, to a basal insulin is now recommended before the patient is advanced to MDI. This approach works very well in most patients since weight loss gives the patients an extra motivation to take medication regularly. Similarly, the patient does not require to take an insulin injection before each meal throughout the day in this approach.

Unfortunately, there are still a large number of patients with poor glycemic control who are still on MDI. Some of them were initiated on MDI before the availability of newer generations of medications. Some were started simply because the physician was not aware of or not the familiar with the new recommendations. Regardless of the reason, these patients are likely to remain on MDI despite chronic poor glycemic control since the physicians are understandably reluctant to step down the most advanced insulin therapy. In addition, there has been no data on the benefits and safety of the stepping-down approach from the most advanced insulin therapy to the more patient-friendly approach that is the combined use of oral SGLT2i and once-weekly GLP1 RA injection.

Detailed description:
A prospective, randomized, open-label, controlled, parallel-group trial is planned. This study is an interdepartmental collaborative study among the Department of Internal Medicine, Department of Family \& Community Medicine (UCSF Fresno), Sierra Vista Family Medicine Residency Program and Division of Endocrinology.

The study will be conducted at the following multiple locations in order to maximize the patient recruitment:

1. Internal medicine clinic at Derian Koligian ambulatory care center (ACC)
2. Family practice medicine clinic at ACC
3. Diabetes clinic at ACC
4. Internal medicine clinic at University Medicine Associates in East medical Plaza
5. Endocrine clinic at University Medicine Associates in East medical Plaza
6. Sierra Vista clinics

The patients will be recruited during the first 12 months of the study or until the predetermined sample size is reached, whichever comes first.

The patient's primary care provider will be informed of the enrollment in the study if the participant gives the permission to do so.

All participants in both group will need to make all 3 visits to UCSF Clinical Research Center over 16- week period.

(1) First visit: Once the site co-investigators identify the suitable and interested study patient, a trained research coordinator will contact the patient for the first visit. The patient will be seen at the UCSF Clinical Research Center by the research coordinator and a physician co-investigator.

During the first visit, all patients in both group will

* be given the information about the study.
* sign the consent form.
* be randomly assigned to either treatment (i.e. Step Down) or control (MDI) group by using A Randomization Plan from http://www.randomization.com.
* have the blood test for A1c, CMP, CBC, fasting lipid and measurements of body weight, height, blood pressure, and heart rate.
* complete both the Diabetes Medications Satisfaction (DM-SAT) Questionnaire form and the Brief Medication Questionnaire (BMQ).

Medication changes at first visit:

In treatment group,

1. All prandial insulin injections (Humalog, Novolog, Apidra, Novolin R or Humulin R), usually 3 times daily before meals, will be discontinued.
2. Basal insulin (NPH, Lantus, Levimir, Toujeo or Tresiba), usually once daily at bed time, will be continued at 80 % of the home dose. The dose will be gradually increased until the patient is back on the home dose (the dose that the patient has been taking at home prior to the enrollment) or fasting BG of 80-130mg/dl is achieved by using the self-titration regimen.
3. If the patient is on pre-mixed basal+prandial insulin 2-3 times daily, it will be discontinued and a basal insulin alone, (NPH, Lantus, Levemir, Toujeo or Tresiba), will be given at 40% of total daily dose of pre-mixed insulin. The dose will be gradually increased until fasting BG of 80-130mg/dl is achieved by using the self-titration regimen.
4. Metformin, that most patients are expected to be on, will be continued, but other non-insulin oral medications for diabetes will be discontinued. If the patient is not on metformin, then Metformin ER will be started at 500mg with a meal for 2 weeks as a routine care and then 1000mg daily as a maintenance dose if tolerated.
5. Both SGLT2i and GLP1 RA will be added to metformin and a basal insulin.

The patient will be trained on the injection technique of the once-weekly GLP1 RA, potential side effects, risk and benefits of all new medications in detail, hypoglycemia management and the self-titration regimen for the basal insulin.

In the control group, there will not be any change in MDI therapy, and the participants will continue to have the usual and standard care through the primary care provider. The participants should not receive SGLT2i and GLP1 RA during the study period.

(2) Second visit: At 4 weeks after the patient starts taking new medications, the patients will make the 2nd visit to the UCSF Clinical Research Center.

During the 2nd visit, the patient in the treatment group will

* be enquired about any side effect of the medications.
* be reviewed on insulin dose and the use of self-titration regimen for the basal insulin.
* have the blood test for A1c, CMP, CBC, fasting lipid and measurements of body weight, height, blood pressure, and heart rate.
* complete both the Diabetes Medications Satisfaction (DM-SAT) Questionnaire form and the Brief Medication Questionnaire (BMQ).

In the control group, there will not be any change in MDI therapy, and the participants will continue to have the usual and standard care through the primary care provider. The participants should not receive SGLT2i and GLP1 RA during the study period.

During the 2nd visit, the patient in the control group will

* have the blood test for A1c, CMP, CBC, fasting lipid and measurements of body weight, height, blood pressure, and heart rate.
* complete both the Diabetes Medications Satisfaction (DM-SAT) Questionnaire form and the Brief Medication Questionnaire (BMQ).

  (3) Third visit: The patients will make the 3rd or final visit to the UCSF Clinical Research Center at 12 weeks after 2nd visit or 16 weeks from the date of the start of both SGLT2i and a GLP1 RA.

During the 3rd visit, the patients in both groups will

* have the blood test for A1c, CMP, CBC, fasting lipid and measurements of body weight, height, blood pressure, and heart rate.
* complete both the Diabetes Medications Satisfaction (DM-SAT) Questionnaire form and the Brief Medication Questionnaire (BMQ).

The investigators will try to make a clinic appointment with primary care provider one month prior to the last visit to the research center for those who are in the treatment group if the patient gives the permission to do so. Therefore the primary care provider will be able to order the medications through the patient's health insurance plan if the patient wishes to remain on the study medications beyond the study period. Alternatively, the patients can go back on insulin therapy that was given prior to the study.

Monitoring of the treatment group:

The patients in both groups will monitor FPGs daily at minimum. The research coordinator will call all participants in both groups at weeks 1, 2, 8, and 12 to review fasting glucose measurements, ask for possible adverse events, incidents of hypoglycemia, and any change in medication.

All participants in both groups in both groups will be reviewed again at the UCSF Clinical Research Center at weeks #4 and #16 for both blood tests and physical examinations.

Outcome measurements:

The primary outcome is the change in A1c at the end of 16 weeks of study period and secondary outcomes are the changes in fasting blood glucose, weight, blood pressure, heart rate, fasting lipids, serum sodium and potassium, serum creatinine, liver enzymes, CBC, medication adherence scores and treatment satisfaction scores . These changes will be compared between the two independent groups, namely the treatment group and the control group, and also within the same group.

Blood test and questionnaire:

The following blood work will be drawn and analyzed at the community regional medical center at baseline (first visit), at 4 weeks and at the end of the study at 16 weeks:

1. A1c
2. Complete Blood Count (CBC) with differential
3. Complete metabolic panel (CMP)
4. Fasting lipid profile

Patient satisfaction with treatment in both groups will be measured by the validated the Diabetes Medications Satisfaction (DM-SAT) Questionnaire form.

Patient adherence will be determined by using the Brief Medication Questionnaire (BMQ).

SAMPLE SIZE AND ANALYSIS PLAN:

The investigators will attempt to recruit and consent 20 patients in each arm that was calculated to provide an 80% statistical power at a 0.05 alpha in this continuous endpoint, two independent sample study.

The calculation was based on the following:

A mean Hemoglobin A1c of 8.5±1% at the initiation of the study period. In the treatment group we anticipate a decline in Hemoglobin A1c of 12-15% by the end of the study period. The standard deviation for the mean A1c was derived from the literature.

The data will be analyzed by using SPSS software. Significance testing will be conducted at the two-sided 5% level. Continuous variables will be examined for normality and if assumption is met, differences in mean values will be tested using Student's t test an analysis of variance (ANOVA). If not normally distributed, non-parametric procedures will be used, including Wilcoxan rank Sum test. Categorical data will be analyzed using Fisher's exact test and Chi square analysis. Since before/after comparisons will also be performed on the same study patients we will utilize paired t tests and McNemar's chi-square test.

Arms:
arm 1: Interventions: All prandial insulin injections, usually 3 times daily before meals, will be discontinued. Basal insulin, usually once daily at bed time, will be continued at 80 % of the home dose. Albiglutide OR Dulaglutide AND Empagliflozin will be added to metformin and a basal insulin. arm 2: Interventions: There will not be any change in insulin therapy, and they will continue to have the usual and standard care through the primary care provider. They should not receive SGLT2i and GLP1 RA during the study period.

Interventions: intervention 1: GLP1 receptor agonist intervention 2: basal insulin intervention 3: SGLT2 inhibitor intervention 4: Metformin
Intervention descriptions: intervention 1: "Albiglutide or Dulaglutide" will be added to a basal insulin. intervention 2: The participant will continue with the basal insulin. intervention 3: "Empagliflozin" will be added to a basal insulin. intervention 4: The participant will continue with metformin.

Protocol document:
Prot_SAP_000.pdf: 
1 
 
Is the stepping-down approach a better option than multiple daily injections in patients with chronic 
poorly controlled diabetes on advanced insulin therapy? 
 
NCT02846233 
 
May 2, 2019 
 
 
 
 


2 
 
Study Protocol 
 
Is the stepping-down approach a better option than multiple daily injections in patients with chronic 
poorly controlled diabetes on advanced insulin therapy? 
 
Methods and Materials: 
 
This study is an interdepartmental collaborative study among the Department of Internal 
Medicine, Department of Family & Community Medicine (UCSF Fresno), Sierra Vista Family 
Medicine Residency Program and Division of Endocrinology. 
 
The study will be conducted at the following multiple locations in order to maximize the patient 
recruitment: 
(1) Internal medicine clinic at Derian Koligian ambulatory care center (ACC) 
(2) Family practice medicine clinic at ACC 
(3) Endocrine clinic at ACC 
(4) Internal medicine clinic at University Medicine Associates in East medical Plaza 
(5) Endocrine clinic at University Medicine Associates in East medical Plaza 
(6) Sierra Vista clinics 
 
The patients will be recruited during the first 12 months of the study or until the 
predetermined sample size is reached, whichever comes first. 
 
Inclusion criteria 
The patients with T2DM who met all of the following criteria were included in the study. 
(1) > 21 years of age 
(2) Body mass index (BMI) ≥30 kg/m2 
(3) On insulin at least 2 times daily comprising both a basal and a prandial insulin or a pre-mix 
insulin with or without other non-insulin medications for a least past 3 months 
(4) A1c >8% 
(5) eGFR >45% 
 
Exclusion criteria 
The patients with any of the following criteria were excluded. 
(1) Any patient who did not meet the above inclusion criteria. 
(2) Pregnancy 
(3) On a SGLT2i and a GLP1 RA or U-500 insulin at the time of enrollment. 
(4) T1DM 
(5) C-peptide below normal range if measured in the past. 
(6) A history of diabetes ketoacidosis 
(7) A history of recent and frequent (≥ 2 times within past 3 months) urinary tract infection or 
genito-urinary candidiasis requiring antibiotic and/or anti-fungal therapies within past 3 
months 
(8) A personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple 
Endocrine Neoplasia syndrome type 2 (MEN 2) 
(9) eGFR <45% 
(10) A history of acute pancreatitis 


3 
 
Design 
This is the prospective, randomized, open-label, controlled, parallel-group study. Patients will be 
allocated 1:1 to either intervention (i.e. Step-Down) or control (MDI) group by using block 
randomization with computer-generated random sequence from http://www.randomization.com. 
 
 
Procedures 
All participants in both groups will make a total of 3 visits over a 16- week period. The 2nd visit is at 
week 4 and 3rd visit at week 16 after initial visit. At each visit, all patients will have a blood test for 
A1c, CMP, CBC, fasting lipid and measurements of body weight, height, blood pressure, and heart 
rate, answered adverse reaction questions and completed the Diabetes Medications Satisfaction 
(DM-SAT) Questionnaire form. 
 
At first visit, the following changes will be made in intervention group: 
(1) All prandial insulin injections (Humalog, Novolog, Apidra, Novolin R or Humulin R) will be 
discontinued. 
(2) Basal insulin (NPH, Lantus, Levemir, Toujeo or Tresiba) will be continued at 80 % of  the 
home dose. The dose will be gradually increased until the patient is back on the home dose 
(the dose that the patient has been taking at home prior to the enrollment) or fasting BG of 80-
130mg/dl was achieved by using the self-titration regimen. (Attachement#1) 
(3) If the patient is on pre-mixed insulin  2-3 times daily,  it will be switched to a basal  insulin 
alone and Glargine was given at 40% of total daily  dose of pre-mixed insulin.  The dose will  
be gradually increased until fasting BG of 80-130mg/dl is achieved by using the self-titration 
regimen. (Attachement#1) 
(4) Metformin at home dose will be continued, but other non-insulin diabetes medications will be 
discontinued. If the patient is not on metformin, then Metformin ER will be started at 500mg 
daily with a meal for 2 weeks and then 1000mg daily as a maintenance dose if tolerated. 
(5) Both SGLT2i, Empagliflozin 10 mg or 12.5mg once daily, and GLP1 RA, Dulaglutide 0.75mg 
subcutaneously once weekly, will be added to metformin and a basal insulin. 
 
The patients will be trained on the injection technique of the once-weekly GLP1 RA and given 
information on potential side effects, risk and benefits of all new medications in detail, hypoglycemia 
management and the self-titration regimen for the basal insulin. 
In the control group, the patients will be advised to remain on MDI and to have the usual and 
standard care through the primary care provider.  They  will also  be  advised to gradually  increase 
the basal insulin until fasting BG of 80-130mg/dl is achieved by using the self-titration regimen as in 
the intervention group. (Attachement#1) 
The patients in both groups will be advised to monitor FPGs daily at minimum. 
A research coordinator will make a phone call to all participants in both groups at week 1, 2,  8, and 
12 to review fasting glucose measurements, ask for possible adverse events, incidents of 
hypoglycemia, and any change in medication. 
At each visit, the patients will be questioned for adverse events (nausea,  vomiting, diarrhea, 
headache, acute pancreatitis, bacterial or fungal genito-urinary tract infection, severe hypoglycemia 
with blood glucose <40,  mild hypoglycemia with BG 41-69, diabetes  ketoacidosis,  any 
hospitalization for hyper or hyper-glycaemia). 
At 2nd visit, Empagliflozin and GLP1 RA, Dulaglutide will be increased to maximum doses of 25mg 
and 1.5mg respectively if the patient tolerated the starting dose  and if  the additional  glycemic 
control is required. 
 
Outcome measurements 
The primary outcome is the change in A1c at the end of study period at week 16 and secondary 
outcomes are the changes in fasting blood glucose, weight, blood pressure, heart rate, fasting 


4 
 
lipids, serum sodium and potassium, serum creatinine, liver enzymes, CBC and Diabetes 
Medications Satisfaction (DM-SAT) scores at week 16. 
Treatment satisfaction will be measured using  the Diabetes  Medication Satisfaction Tool  (DM-SAT). 
4 The DM-SAT measures satisfaction  with the patient’s  diabetes  medications regimen. The 
instrument consists of 16 items which create 4 subscales (3 items for wellbeing, 3 items for medic al 
control, 5 items for lifestyle, and 5  items for convenience) and  a total  score. Responses  are 
summed and converted to a score from 0 to 100 for each subscale and overall, with higher scores 
representing more satisfaction. 
 
Statistical Analysis: 
 
We will attempt to recruit and consent 20 patients in each arm that was calculated to provide an 
80% statistical power at a 0.05 alpha in this continuous endpoint, two independent sample study. 
The calculation was based on the following: 
A mean Hemoglobin A1c of 8.5±1% at the initiation of the study period. In the treatment group we 
anticipate a decline in Hemoglobin A1c of 12-15% by the end of the study period. The standard 
deviation for the mean A1c was derived from the literature (Glucagon-Like Peptide 1 Receptor 
Agonist or Bolus Insulin With Optimized Basal Insulin in Type 2 Diabetes. Michaela Diamant Et al. 
Diabetes Care October 2014 vol. 37 no. 10. 2763-2773) 
 
The data will be analyzed by using SPSS or similar software. Significance testing  will be conducted 
at the two-sided 5% level. Continuous variables will be examined for normality and if assumption is 
met, differences in mean values will be tested using Student’s t test an analysis of variance 
(ANOVA). If not normally distributed, non-parametric procedures will be used, including  Wilcoxan 
rank Sum test. Categorical data will be analyzed using Fisher’s exact test and Chi square analysis. 
Since before/after comparisons will also be performed on the same study patients, we will utilize 
paired t tests and McNemar’s chi-square test.