The Effect Of Metformin On Microvascular Outcomes in Patients With Type 2 Diabetes: A Systematic Review And Meta-analysis

Abstract

1. Aims

Examine the efficacy of metformin compared to placebo or other glucose-lowering medications on microvascular outcomes in patients with Type 2 Diabetes Mellitus (T2DM).

2. Methods

MEDLINE, EMBASE, Web of Science, and Scopus were searched from database inception to March 2020. We included randomized clinical trials of patients with T2DM receiving metformin compared with another active glucose-lowering treatment or placebo in which a microvascular outcome was assessed. The risk of bias was assessed using the Cochrane Risk of Bias tool. Microvascular complications included kidney-related outcomes, retinopathy, and peripheral neuropathy. An inverse-weighted variance random-effect meta-analysis was performed to estimate drugs' effect on microvascular disease.

3. Results

Nineteen RCTs (n = 18,181) were included. Metformin increased the estimated glomerular filtration rate (eGFR) by a mean difference (MD) of 1.08 (95% CI 0.84 to 1.33 ml/min/1.73 m2 ) after 24 weeks. No effect was found on urinary albumin-creatinine ratio, serum creatinine, and end-stage kidney disease; Patient-important outcomes regarding kidney disease, retinal outcomes, peripheral neuropathy, or quality of life were not assessed by any of the included studies and could not be analyzed.

4. Conclusions

There is no evidence of the clinically significant beneficial effect of metformin therapy as compared to other glucose-lowering medications or placebo on the examined microvascular complications.

Keywords

Type 2 diabetes; Patient important outcomes; Microvascular; Metformin; Systematic review.

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Introduction

Historically, clinical practice guidelines have recommended metformin as the first-line glucose-lowering therapy, making it the most frequently prescribed medication for the treatment of type 2 diabetes mellitus (T2DM) [1–5]. The evidence for these recommendations emerges primarily from the United Kingdom Prospective Kidney Disease (UKPDS) 33 and 34 trials [6,7] as well as systematic reviews [8], which have demonstrated the efficacy of metformin in reducing glucose control parameters (i.e., hemoglobin A1c and/or fasting plasma glucose) and patient-important macrovascular outcomes including all-cause mortality. However, recent trials have demonstrated that sodium-glucose cotransporter-2 (SGLT2) inhibitor and glucagon-like peptide-1 (GLP-1) receptor agonist classes of medications have significant microvascular (specifically, kidney) and macrovascular benefits [9,10,19,11–18], making them preferred agents for diabetes management in the context of kidney disease and cardiovascular disease.

Microvascular complications affect 12–18% [20,21] of people with type 2 diabetes and are important causes of morbidity, impaired quality of life, and high costs of living among these patients [20,21]. There is scarce evidence about the effect of metformin on microvascular complications as few studies are available and have discrepant results, and most of these consider microvascular disease as secondary endpoints and do not rely on patient-important outcomes [22–27]

To address this important knowledge gap and establish the impact of metformin therapy on microvascular disease outcomes among adults with type 2 diabetes, we performed a systematic review and meta-analysis of studies that examined surrogate and patient-important microvascular endpoints.

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Methods

1. Study design

This review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) [28]. The review protocol was registered in Prospero (Centre for Reviews and Dissemination, University of York) as CRD42019120365.

2. Data sources and searches

The search strategy was performed by an experienced librarian (NA-V) with input from the principal investigator (RR-G). A comprehensive search was conducted in MEDLINE, EMBASE, Web of Science, and Scopus to find eligible studies. All databases were searched from inception to May 30, 2020. The reference lists from primary studies and narrative reviews were searched and experts in the field were consulted to obtain any additional references that might complement our initial search strategy.

3. Study selection

We included randomized clinical trials (RCTs) enrolling adults (18 years or older) with T2DM, with a sample size of at least 100 participants (to include large trials that could provide more precise results) receiving any dose of metformin compared with another active glucose-lowering treatment or placebo, in which a microvascular outcome was assessed. We excluded studies that enrolled participants < 18 years or with a diagnosis other than T2DM. There were no language restrictions. Two reviewers working independently and in duplicate screened all abstracts and full-text studies for eligibility using Distiller Systematic Review Software (Evidence Partners). A pilot review was performed before each phase, the chance-adjusted agreement was quantified using kappa statistics, and pilots were run in each phase until a kappa of at least 0.7 was reached. Upon retrieval of potentially eligible studies, full-text publications were evaluated in the second screening phase. Reviewers documented reasons for exclusions. Disagreements were resolved by consensus.

4. Data extraction and quality assessment

Data from the included studies were extracted independently and in duplicate by two reviewers. Disagreements were resolved by consensus and, if necessary, an expert was consulted. A standardized data extraction form was used. Extracted data included several participants, drug administration duration, baseline medication(s), comparator groups, duration of follow-up, and dosage. Microvascular outcomes were assessed for both surrogate and patient-important outcomes.

Kidney-related surrogate outcomes were the urinary albumin-to-creatinine ratio (UACR), estimated glomerular filtration rate(eGFR), and serum creatinine. Kidney-related patient-important outcomes were kidney-related death, adverse events (including elevated blood creatinine, reduction in glomerular filtration rate, and renal impairment), and advanced kidney disease defined as the need for continuous renal replacement therapy or kidney transplant, or chronic kidney disease stage 3 or greater.

Retinopathy-related surrogate outcomes were the onset of retinal neo-vascularization, cataract extraction, events reported as general retinopathy, retinal photocoagulation, and treatment with intravitreal agents. Retinopathy-related patient-important outcomes were diabetes-related blindness, vitreous hemorrhage, retinal detachment, severe macular edema, and retinal artery occlusion.

Neuropathic surrogate outcomes were changes from baseline in tendon reflex and electrophysiologic parameters. Neuropathic patient-important outcomes were diabetic foot ulcer, diabetic peripheral neuropathy, pain, numbness, sensory loss (touch or vibration), and quality of life related to neuropathy.

Reviewers working independently and in duplicate assessed the methodological quality of each study using the Cochrane risk-of-bias tool for randomized trials (RoB2) to identify the risk of bias affecting each trial [30]. Disagreements were resolved by consensus.

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5. Missing data and author contact

One author was contacted via e-mail to determine if they could provide the data used to calculate the geometric means presented in Lachin et al. [29]. However, the author could not provide this information. Therefore, geometric means were transformed into an approximation of algebraic means according to Higgins et al [30]. Data reported solely in figure form were extracted using the plot digitizer software version 4.3 [31].

6. Data synthesis and analysis

A narrative synthesis of the included studies was conducted, considering population characteristics, and when multiple groups were available, the most effective arm based on the studies’ primary outcome was chosen. When enough data were available (more than one study reporting on the outcome), a random effect meta-analysis was performed to estimate the drug’s effect on microvascular disease endpoints. To measure heterogeneity, a p-value of < 0.10 for the test of heterogeneity across trials and > 50% for the measure of inconsistency (I2 ) was considered as high heterogeneity [32]. The primary analysis used an inverse-weighted variance random-effect meta-analysis to account for the uncertainty in the location of the mean of different effects between studies. When events were evaluated, we used a modified Mantel-Haenszel meta-analysis with Peto’s method. Meta-analyses were performed using R (Version 4.0) [33].

7. Sensitivity analyses

To assess the robustness of the results, several pre-determined sensitivity analyses were performed. When inverse-weighted variance meta-analyses were presented, studies reporting mean changes were excluded due to their small standard deviation. When possible, sensitivity analyses excluding studies deemed to be at high risk of bias were performed. Finally, we performed an analysis limited to studies with the active treatment of 48 weeks or longer to assess the effect in the longest term.

Discussion

1. Main findings

Our study did not demonstrate a meaningful effect of metformin on any microvascular disease endpoint among patients with T2DM. This includes UACR, change in serum creatinine, the incidence of kidney failure, and incident/progressive peripheral artery disease. Data on patient-important outcomes, were scarce, limiting any valuable inferences. While our primary analysis suggested a higher eGFR with metformin use, a sensitivity analysis excluding studies reporting mean changes, found no such effect.

Our findings were consistent with previous studies reporting that the evidence in microvascular outcomes was low quality and inconclusive for other diabetes drug classes [22]. Maruthur et al. evaluated 52 RCTs and 13 observational studies of pharmacological treatment (glyburide, pioglitazone, dapagliflozin, or acarbose) in type 2 diabetes and concluded that evidence was insufficient and of low quality for evaluating their comparative effects on microvascular outcomes [8,23]. A contemporary reassessment of metformin’s comparative efficacy was necessary because none of the previous reviews focused solely on the effect of metformin; these studies usually compared metformin as an add-on to other drug classes.

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2. Kidney outcomes

We found that metformin increases the eGFR. However, when we excluded studies with short duration and high risk for bias, no statistically significant difference was seen. This may be explained by the weight of Aronson’s study [47]; specifically, the fact that it reported mean change values instead of means, narrowing its confidence interval, and giving it a more spurious weight in the meta-analysis.

The absence of consistent beneficial effects of metformin therapy on kidney-related outcomes must be considered in the context of emerging evidence demonstrating the efficacy of other glucose-lowering medication classes – specifically SGLT-2 inhibitors and GLP-1 receptor agonists [54,59–63].

3. Retinopathy

There was no impact of metformin therapy on the examined retinopathy endpoints. Thus, while evidence supports intensive glycemic control as a way of reducing the risk of retinopathy incidence and progression [6,64,65], none of the currently available studies suggest a preference for any therapeutic class over another. While sitagliptin has shown benefits compared with placebo on the reduction of retinal capillary flow [54] and the incidence of diabetic retinopathy and diabetic eye disease [66], retinal outcomes have rarely been reported thus the impact of different drug classes on the prevention or delay in progression of diabetic retinopathy in patients with T2DM remains unknown. [27,61,62,67,68].

4. Peripheral neuropathy

We found no statistically significant differences in peripheral neuropathy endpoints. However, peripheral neuropathy was inconsistently defined, with only one study using a formal diagnostic scale. Consequently, peripheral neuropathy needs to be consistently defined and evaluated in future trials [69].

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Conclusion

In adult patients with T2DM, there is no evidence of the clinically significant beneficial effect of metformin therapy as compared to other glucose-lowering medications or placebo on microvascular complications. Importantly, the majority of studies focused on surrogate rather than patient-important outcomes. These results can help patients and clinicians engage in shared decision-making about preferred choices for the pharmacologic management of T2DM.

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José Gerardo González-González a,b, Ricardo Cesar Solis a, Alejandro Díaz GonzálezColmenero a, Karina Raygoza-Cortez a, Pablo J. Moreno-Peña a, Alicia L. Sánchez a, Rozalin a G McCoy e,f , Naykky Singh Ospina h, Spyridoula Maraka c,d, Juan P Brito g, René RodriguezGutierrez a,b,g,

a Plataforma INVEST Medicina UANL-KER Unit Mayo Clinic (KER Unit Mexico), Universidad Autónoma de Nuevo León, Monterrey 64460, Mexico

b Endocrinology Division, Department of Internal Medicine, University Hospital “Dr. José E. González”, Universidad Autonoma de Nuevo León, Monterrey 64460, Mexico

c Division of Endocrinology and Metabolism, University of Arkansas for Medical Sciences, Little Rock, AR, USA

d Central Arkansas Veterans Healthcare System, Medicine Service, Little Rock, AR, USA

e Division of Community Internal Medicine, Department of Medicine, Mayo Clinic, Rochester, MN, USA

f Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Rochester, MN, USA

g Knowledge and Evaluation Research Unit, Mayo Clinic, Rochester, MN 55905, USA

h Division of Endocrinology, Department of Medicine, University of Florida, FL 32610, USA