Running Head: METFORMIN AND INSULIN IN T1DM

In adolescents with type one diabetes mellitus, does combination therapy with metformin and

insulin correlate to a decrease in the daily insulin requirement in comparison to using exclusively

insulin for management?

University of New Hampshire

Mary Heald and Megan Crump

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Background & Rationale

In recent years, the trend of obesity in type one diabetes mellitus has increased

significantly, which is historically atypical for this population (Libman et al., 2015). The onset of

puberty increases glycemic requirements and additionally obesity can further increase these

needs as a result of insulin resistance. Frequent increases of insulin dosages correlates with

ineffective management of the disease (Tatsuhiko, Shigeo, Misao, Kensuke, 2005). Therefore,

interventions set to improve long-term management of glycemic levels have the potential to

decrease the incidence of possible future cardiovascular and microvascular complications.

Nurses are responsible for understanding the implications of prescribed, new interventions for

optimal patient safety. Understanding the methodology between metformin and insulin within

this population is essential for educating and assisting adolescents, giving them different options

for treatment.

The majority of studies that implement metformin therapy in the type one diabetes

population focus on adults, however the selected studies chose to examine young adults,

specifically. In the pubescent years, the abundant hormone secretion generates increased insulin

requirements in response to exacerbated insulin receptor resistance (Nadeau et al., 2015).

Although individuals with type one diabetes cannot produce their own insulin, during profound

growth, individuals could benefit greatly from a drug that increases insulin sensitivity. The need

for more insulin, to compensate for rapid growth during puberty, correlates with an escalation in

BMI. High BMIs leads to an increased risk for diabetes complications in later years. Metformin,

a biguanide oral medication, causes a reduction in glucose secretion by the liver, maximizes

absorption within the GI tract, while increasing insulin receptor sensitivity. Although it is more

commonly used in type two diabetes mellitus, it can be effective in type one, as the mechanism
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of action is not to increase insulin production, but to increase the effectiveness of the injected

insulin. Liu and Yang (2015) suggest an overall decrease in the daily insulin requirements based

on adjunctive therapy with metformin for patients in this population.

Search Methods

Databases accessible through the University of New Hampshire provided a multiplicity

of articles associated with the research topic. The EBSCOhost search engine, provided by the

Cumulative Index to Nursing & Allied Health Literature (CINHAL) database, yielded 17 results

utilizing key phrases such as, type 1 diabetes, adolescents, and metformin. The date range

was set from 2006 to 2016 in order to incorporate only current information and the search was

limited to English only. All three of the selected studies emerged from the CINHAL database,

although the biomedical database, EMBASE was utilized as well. The same terms were

searched, but with the addition of daily insulin, as this is the outcome measure that was to be

assessed. After close analysis, three articles were selected based on relevance and quality, two

double-blind randomized-controlled trials and one systematic review/meta-analysis.

Critical Appraisal of the Evidence

First Study

A study by Nadeau et al. (2015) examined the effects of metformin therapy on a

population of patients with type one diabetes mellitus in comparison to a placebo group. Unlike

other experiments on the topic, this trial utilized a double-blinded approach, ensuring that not

only the researchers, but also the participants were unaware of the designated treatment plan, a

marked strength of the study. A total of 74 patients living in Colorado, ages 13 to 20, were

randomized and instructed to take either metformin or a placebo pill; the placebo pill was

indistinguishable from the authentic metformin tablet. Researchers chose a considerably low
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universal dose of metformin for the treatment group, 1,000 milligrams daily, taking into

consideration the risk of hypoglycemic episodes with higher doses.

The implementation of a standardized scale validated that all participants were actively

going through puberty during the experimental phase; puberty is commonly a period of

heightened insulin resistance. Baseline physical characteristics between groups did not differ

significantly. Exclusion criteria included renal impairment, as evidenced by increased creatinine

levels, a diagnosis of hypertension, poor control of diabetes in the past, and significant

preexisting retinopathy. Metabolic parameters were measured at follow up visits conducted at six

week intervals, for a duration of six months and clients were instructed to record blood glucose

levels frequently throughout the day. Providers titrated insulin dosages as needed throughout the

experimental phase and any changes were noted for further analysis. Both patients with a normal

BMI and overweight patients who received metformin exhibited a marked decrease in daily

insulin needs at follow up appointments, along with decreased BMI and body measurements.

In order to prioritize patient safety, researchers chose a dose of metformin that was under

the suggested daily dose. Participants had few adverse side effects, and complied with the

medication regimen throughout the study. Thus, subsequent trials on this population should

consider increased dosages; higher doses yielded more positive results on glycemic control in

similar studies. Increased insulin sensitivity in patients taking metformin was assumed due to a

reduction in insulin requirements. And so, more accurate measurements of variables, including

hormone levels, glucose variability, and fat distribution must be implemented in later studies to

prove the correlation between insulin sensitivity and requirements.

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Second Study

Liu and Yang (2016) selected five double-blind randomized controlled trials after a

review of 25 pertinent articles available through PubMed and EMBASE. The inclusion criteria

was specific to full-text english literature, participants ages 20 years or younger, with a diagnosis

within ten years. A systematic review and subsequent meta analysis was conducted in order to

observe any alterations in the daily amount of insulin required in adolescents with type one

diabetes mellitus when management additionally involved metformin. The metformin doses

ranged from 1,000 to 2,000 milligrams each day. Researchers compared data between the

treatment group and the control group to evaluate the effectiveness of the biguanide medication.

The control group was comprised of individuals who were randomly selected to receive both

insulin and a placebo pill, which resembled metformin. Among the five articles, the duration of

implementation ranged from three to nine months, depending on the study.

After analyzing the results of the 301 total participants, researchers divided the

population into groups based on physical characteristics, such as weight and body mass index

(BMI). Three of the groups were representative of average sized individuals, while the other two

groups were considered overweight. Researchers considered these differences when examining

and formulating conclusions. Regardless of body size, a considerable decrease in daily insulin

requirements was seen within the treatment group in comparison to those in the placebo group.

Organizing the subjects based on physique allowed for further analysis of potential outliers, a

key strength of the study. In relation to decreases in insulin requirements, the data was consistent

between overweight individuals and those with an average BMI. Therefore, the research suggests

that benefits encompass a variety of body types. In general, a meta-analysis is a high quality
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source in the field of research, providing a compilation of relevant, current, and credible

randomized controlled trials, another strength to the study.

Insulin resistance directly correlates with an increasing amount of insulin required,

generally influencing glycemic control. Overall, this study showed a decrease in insulin demands

when managing the disease with both insulin and metformin. It is unknown whether this

information is applicable in terms of preventing future health complications. Researchers were

limited to studies with small sample sizes and short experiment lengths. Research suggests that

extension of the study, in both length and size, may allow for evaluation of possible long-term

physiological effects in regards to usage of both metformin and insulin.

Third Study

Libman et al., (2015) utilized a double-blind randomized-controlled trial in order to

evaluate the usage of metformin in combination with insulin specific to overweight adolescents

with type one diabetes mellitus. Although this study analyzed a multiplicity of outcome

measures, the one pertinent to the current research question is the alterations of insulin

requirements after the introduction of metformin. The population was generated through a

computerized randomization of 140 participants, spanning 26 different youth clinics that had a

focus in endocrinology. The subjects ages ranged from 12-19 years, with a BMI at or above the

85th percentile, all of which required similar average daily insulin doses. After selecting the

population, individuals were organized into control and treatments groups through electronic

randomization methods as well. 71 individuals were placed within the treatment group while a

total of 69 represented the control group.

Over a six month period, participants were instructed to take the pill at scheduled times

throughout the day. The control group unknowingly managed symptoms with a mock version of
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the metformin tablet, while the treatment group received a maximum of 2,000 milligrams of the

medication daily. Over a 26-week period, scheduled telephone and face to face meetings were

arranged for as needed alterations of medication and insulin dosages as the study progressed.

Close monitoring was also executed to uphold the client's safety, as negative side effects were a

possibility, such as hypoglycemic events and GI problems. Aside from the use of randomization,

frequency of monitoring the progress was a strength specific to this study, ensuring authentic

data. Potential risks were noted during data analysis specific to the negative impacts on the GI

tract. Otherwise, results concluded an overall decrease of insulin requirements by 25% in many

individuals within the treatment group. Although the evidence reveals marked improvement in

insulin requirements, researchers do not recommend implementation. It is limiting that the

provider made individual adjustments to the medication based on the individual, as this does not

represent a standardized method, leaving room for error when analyzing insulin requirements as

an outcome measure.

Evidence Synthesis

Collectively, the aforementioned articles argue that when metformin is introduced into a

regimen for management in adolescents with type one diabetes, insulin needs decline. Each of

the three articles evaluated a variety of outcome measures, but the category of insulin

requirements showed marked changes, universally. The first (Nadeu et al., 2015) and second

study (Liu & Yang, 2015) analyzed individuals of normal and high BMI, but the third study

(Libman et al., 2015) focused exclusively on overweight patients. Though the population differed

slightly in this respect, the same effect was present among various body types, suggesting wide-

ranging benefits during the period of heightened growth that occurs in puberty. Nadeau et al.

(2016) reports an absence of GI effects with the 1,000 mg of metformin and recommend that
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trials utilize higher doses. Conversely the study by Libman et al. in 2015 reported significant GI

adverse effects with the typical therapeutic dose in type two diabetes, 2,000 milligrams. The

negative GI symptoms led the researchers to conclude that in general, the administration of

metformin is inadvisable regardless of its effects on decreasing insulin resistance. All studies

recognized the risk of developing complications with diabetes such as cardiovascular

abnormalities, nephropathy, and retinopathy. They also considered the recent spike in BMI and

obesity seen in this particular population, which causes a faster onset of comorbidities and

exaggerates the need to provide strategies regarding optimal diabetes management. Reducing

insulin resistance correlates with a decrease in weight therefore averting or delaying the onset of

the previously stated disease processes (Libman et al., 2015).

Clinical Recommendations

No significant adverse effects were present in participants when doses below 1,000 mg

were incorporated, suggesting that it is safe to use this dose as adjunctive therapy with insulin in

adolescents with type one diabetes. Patients should be offered metformin therapy and educated

about its use, the potential benefits and how to monitor for any side effects. It is important for

nurses to be aware of these potential side effects when assessing the patient and interpreting safe

doses, as they may be responsible for administration in a hospital setting. Liu and Yang (2016)

suggest increasing the sample size and extending experiments. Longer studies, that include

multiple follow up visits, could result in more pronounced changes in insulin requirements and

metabolic parameters. The longer follow up periods would provide more insight into whether or

not metformin directly correlates with decreased onset of issues like retinopathy and CVD.
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References

Libman, I. M., Miller, K. M., DiMeglio, L. A., Bethin, K. E., Katz, M. L., Shah, A., & ... T1D

Exchange Clinic Network Metformin RCT Study, G. (2015). Effect of Metformin Added

to Insulin on Glycemic Control Among Overweight/Obese Adolescents With Type 1

Diabetes: A Randomized Clinical Trial. JAMA: Journal Of The American Medical

Association, 314(21), 2241-2250. doi:10.1001/jama.2015.

Liu, W., & Yang, X. (2016). The Effect of Metformin on Adolescents with Type 1 Diabetes: A

Systematic Review and Meta-Analysis of Randomized Controlled Trials. International

Journal Of Endocrinology, 1-12. doi:10.1155/2016/3854071

Nadeau, K. J., Chow, K., Alam, S., Lindquist, K., Campbell, S., McFann, K., & ... Walravens, P.

(2015). Effects of low dose metformin in adolescents with type I diabetes mellitus: a

randomized, double-blinded placebo-controlled study. Pediatric Diabetes, 16(3), 196-

203. doi:10.1111/pedi.12140

Tatsuhiko, U., Shigeo, M., Misao, O., & Kensuke, H. (2005). Usefulness of the addition of

metformin to insulin in pediatric patients with type 1 diabetes mellitus. Pediatrics

International, 47(4), 430-433. doi:10.1111/j.1442-200x.2005.02075.x16174