Clinical Trial Details
— Status: Withdrawn
Administrative data
| NCT number |
NCT02250794 |
| Other study ID # |
14042807 |
| Secondary ID |
|
| Status |
Withdrawn |
| Phase |
Phase 4
|
| First received |
|
| Last updated |
|
| Start date |
October 2014 |
| Est. completion date |
May 2015 |
Study information
| Verified date |
October 2021 |
| Source |
Rush University Medical Center |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The purpose of this study is to test whether a combination of two pills commonly used to
treat outpatient diabetes called metformin and sitagliptin (januvia) could provide successful
control of blood sugar levels in patients with type 2 diabetes during hospitalization for the
treatment of a general medical condition. Both metformin and sitagliptin are currently
approved by the Food and Drug Administration for the treatment of type 2 diabetes, but little
experience exists for their use in hospitalized patients. The current standard practice is to
use insulin injections to control blood sugar in hospitalized patients with type 2 diabetes.
This study will compare the use of metformin tablets twice per day along with sitagliptin
tablets once per day with daily insulin injections in patients with type 2 diabetes during
hospitalization, and will study how well the blood sugar levels are controlled.
Description:
We propose a trial to evaluate whether in-hospital glycemic control, as measured by mean
daily glucose concentration and frequency of hypoglycemic events, is different between
treatment with metformin and sitagliptin combination and treatment with glargine insulin once
daily and rapid-acting insulin analog with meals in patients with type 2 diabetes.
Hyperglycemia is associated with increased mortality, prolonged hospitalization and increased
complications such as infection (1). Consensus guidelines recommend long-acting basal insulin
and meal-time bolus insulin therapy for inpatient blood glucose management. These basal bolus
regimens are labor intensive, require multiple injections each day, and can cause
hypoglycemia. A study at our institution of patients admitted to the hospital and treated
with our basal bolus insulin protocol found the incidence of hypoglycemia (blood glucose less
than 70 mg/dl) to be 20% of all patient stays (2). A strategy for inpatient blood glucose
management with less risk of hypoglycemia is needed.
We propose a trial of the use of two oral medications metformin and sitagliptin that lower
blood sugar without the risk of hypoglycemia. Metformin is first-line therapy for outpatient
management of type 2 diabetes. It has long-standing evidence of safety and efficacy. It
decreases hepatic glucose production and increases insulin-mediated glucose utilization in
the muscle and the liver. A Cochrane Review of 29 trials of metformin as monotherapy compared
with other oral agents, insulin, diet, or placebo showed a reduction in cardiovascular events
and all-cause mortality with metformin (3).
Sitagliptin is a Dipeptidyl-peptidase-4 (DPP-4) inhibitor approved by the FDA as monotherapy
or in combination with metformin for the treatment of type 2 diabetes. Metformin and
sitagliptin are active within 24 hours of initiation and do not cause hypoglycemia.
Sitagliptin works by slowing the inactivation of glucagon-like peptide-1 (GLP-1). GLP-1
stimulates glucose dependent secretion of endogenous insulin with meals.
A recent preliminary study supports the use of sitagliptin for inpatient glucose management.
This trial included 90 patients with type 2 diabetes admitted to general medicine and surgery
services. It randomized patients to one of three groups: sitagliptin alone, sitagliptin plus
long-acting insulin (glargine), or a basal bolus insulin regimen. The study selected for
patients with mild to moderate diabetes by including only patients with diabetes controlled
by diet alone, any combination of oral antidiabetic agents, or a total daily insulin dose ≤
0.4 units/kg prior to admission. Patients were eligible if their blood sugar was 140 - 400
mg/dl. Patients in all three groups received supplemental (correction) doses of rapid-acting
insulin before meals and bedtime for blood glucose >140 mg/dL. Glycemic control improved
similarly in all treatment groups, but 100% of the patients in the sitagliptin alone group
required one or more injections of rapid-acting insulin to correct hyperglycemia (4). This
result suggests that sitagliptin alone is insufficient therapy for treating hyperglycemia in
this population. We will recruit a similar population of patients, and we will add metformin
for improved blood sugar control. Our sitagliptin and metformin group will not receive
supplemental doses of rapid-acting insulin as the purpose of this trial is to evaluate a
regimen without the risk of hypoglycemia.
Metformin is safe in patients with adequate renal function. The current prescribing
information for metformin is that its use is permitted with a serum creatinine ≤ 1.4 mg/dL in
women and ≤ 1.5 mg/dL in men which is equivalent to a GFR ≥ 60 ml/min (5). It is excreted by
the kidneys and therefore can potentially accumulate in patients with renal failure.
Metformin works by inhibiting gluconeogenesis-a process that utilizes lactic acid to produce
glucose. Thus, with accumulation of this medication, it could predispose patients to lactic
acidosis. The incidence of lactic acidosis with metformin is extremely low. A systematic
review of 347 randomized trials and prospective cohort studies representing 70,490
patient-years of metformin use and 55,451 patient-years in the non-metformin group revealed
no cases of lactic acidosis. Almost half of the studies allowed inclusion of patients with a
serum creatinine above 1.5 mg/dL, and 97% of the studies allowed inclusion of patients with
at least one contraindication to metformin therapy (6). Another trial evaluated the risk of
lactic acidosis with metformin in 393 patients with renal insufficiency, with serum
creatinine levels of 1.5 to 2.5 mg/dl (mean level 1.8 mg/dl) and found no cases of lactic
acidosis over four years of the trial duration (7).
Most cases of lactic acidosis in patients taking metformin have been associated with shock or
other tissue hypoxia. Elevated lactate in these patients may not be related to metformin.
This is supported by the fact that lactic acidosis occurs as frequently in metformin users as
users of other anti-diabetes medications (8). Also, metformin levels do not correlate with
lactate levels or mortality suggesting that the underlying disease is more likely the cause
of the acidosis than metformin (9). However this theoretical concern for an exceedingly rare
complication has excluded metformin from use in hospitalized patients.
The recognition of the rarity of lactic acidosis among users of metformin with renal
insufficiency has changed recommendations to allow for its use in patients with mild to
moderate renal insufficiency. Current guidelines use an estimated GFR (eGFR) which is a more
accurate approximation of renal function than serum creatinine. The current recommendation of
the American Diabetes Association states that metformin can be used at full doses (2000
mg/day) as long as eGFR > 45 ml/min and serum creatinine is monitored. If the eGFR is <
45ml/min, then a maximal dose of 1000 mg/day is advised, with serum creatinine monitoring.
Metformin should not be used if the eGFR is < 30 ml/min (10).
The American College of Radiology has recently updated their guidelines for the use of
metformin in patients receiving IV contrast media (11). A prior guideline recommended holding
metformin for 4 days surrounding IV contrast administration to evaluate for contrast-induced
acute kidney injury. This guideline contributed to the practice of discontinuing metformin
during hospitalization due to the commonness of radiology studies using IV contrast. There is
no drug interaction between metformin and contrast media nor is there any effect of metformin
on renal function. Given the risk of contrast-induced acute kidney injury is very low in
patients with normal renal function and no co-morbidities, the revised (2013) American
College of Radiology guidelines recommend that metformin can be continued without the need to
evaluate renal function following contrast media. In the presence of co-morbidities that
increase the risk for developing acidosis (liver dysfunction, alcohol abuse, heart failure,
myocardial or peripheral muscle ischemia, sepsis or severe infection), the new guidelines
recommend holding metformin for two days after IV contrast administration. Our study will
only include patients without these co-morbidities and with normal renal function (eGFR > 60
ml/min). All subjects will have serum creatinine measured daily, and metformin will be
discontinued in the event of acute kidney injury.
Since metformin is safe and effective for glucose management in patients with type 2 diabetes
and normal renal function, we propose its continuation during hospitalization. This study
will include adult patients with type 2 diabetes currently treated with metformin alone or in
combination with other anti-diabetic agents including low dose insulin. All subjects will
have normal renal function (eGFR>60 ml/min) and no comorbidities that increase the risk for
acidosis. This prospective, randomized controlled trial will compare metformin and
sitagliptin (which cannot cause hypoglycemia) to usual insulin therapy, which is known to
cause hypoglycemia. This study has possible implications for improving the safety of therapy
for hospitalized patients with type 2 diabetes.
