1) METFORMIN: CHANGING THE TREATMENT ALGORITHM FOR TYPE 2 DIABETES
Submitting InstitutionAston University
Unit of AssessmentAllied Health Professions, Dentistry, Nursing and Pharmacy
Summary Impact TypeTechnological
Research Subject Area(s)
Medical and Health Sciences: Cardiorespiratory Medicine and Haematology, Clinical Sciences, Pharmacology and Pharmaceutical Sciences
Summary of the impact
Metformin is now the most prescribed medication for type 2 diabetes
worldwide. Pre - 1990 it received trivial use and was on the verge of
withdrawal. Research at Aston (1993 - 1996) generated a new appreciation
of its mechanisms of action and therapeutic potential. Aston research was
reinforced with a concerted education programme for healthcare
professionals, including high-profile reviews and treatment guidelines. We
claim impact on health & welfare and health practitioners as Aston
research has provided a foundation for improved care of type 2 diabetes
patients on a global scale.
Background: Research at Aston (1993 - 1996) revealed new
mechanisms of action of metformin relating to efficacy and safety,
providing the impetus for clinical research and renewed therapeutic
application (S3.1). Although metformin had been introduced as a diabetes
therapy in the 1950s, it was little used and all but discontinued in the
1980s, condemned by class association with other biguanides that caused
Research insights/findings: The Aston research established that
the major concern about metformin, namely lactate production, was mostly
of intestinal (not hepatic) origin and was mostly attributed to misuse
that could be avoided by judicious respect for contraindications and
exclusion criteria. The work identified multiple actions of metformin,
opening avenues of investigation into insulin-dependent and
insulin-independent mechanisms that form the basis of our present
appreciation of this drug (S3.1; S3.2).
Underpinning research: Building on earlier work, research at Aston
involved development and application of a novel simultaneous multi-site
blood and tissue sampling technique in small rodents together with isotope
distribution studies which were used to identify the origin and disposal
of nutrients and metabolites during exposure to metformin. This work was
conducted from 1993 - 1996 by Professor Cliff Bailey (then Senior Lecturer
and later Professor, 1973 - date) with Carol Wilcock (Research Fellow 1990 - 1993),
Paul Nicklin (Research Fellow, 1992 - 1995), Tony Page (visiting
Research Fellow, 1990 - 1994) and Kurt Mynett (Research Assistant, 1993 - 1995).
The work established that metformin was accumulated in the walls of
the intestine where it promoted the conversion of glucose to lactate (S3.3 - 3.6).
The lactate was then cycled back to glucose in liver and other
tissues for storage as glycogen and use in energy metabolism, contributing
to lower blood glucose concentrations while increasing energy expenditure.
This in turn provided an explanation for the origin of risk for
hyper-lactataemia and the lack of weight gain with this agent. Additional
studies distinguished insulin-dependent and insulin-independent effects of
metformin to reduce hepatic glucose output and increase peripheral glucose
disposal. Overall these studies gave rise to a new appreciation of the
anti-diabetic capability and application of metformin.
Research grant support for this research was difficult to obtain in the
1990s because research into pharmaceuticals was considered to reside
within commercial organisations: also metformin was considered to be
defunct. This research represents an early, and against the trend,
collaboration between academic and commercial bodies and provides an
example of what has now become a model of collaborative enterprise. To
initiate and persevere with this research at Aston therefore required
special commitment, and initial investment by the University to generate
References to the research
1. Bailey CJ et al., (eds) Metformin: the gold standard.
Scientific handbook. Wiley, Chichester, 2007, 288pp. ISBN
978-0-470-72644-0. Copy available on request.
2. Bailey CJ, Turner RC. Metformin. New Engl J Med 334,
574-579,1996 doi: 10.1056/NEJM199602293340906, citations 1065.
3. Wilcock C, Bailey CJ. Accumulation of metformin by tissues of
the normal and diabetic mouse. Xenobiotica 24, 49-57, 1994. doi:
10.3109/00498259409043220, citations 100.
4. Bailey CJ, Mynett KJ. Insulin requirement for the
anti-hyperglycaemic effect of metformin. Brit J Pharmacol 111, 793-796,
1994. PMC1910090, citations 4.
5. Bailey CJ, Mynett KJ, Page T. Importance of the intestine as a
site of metformin-stimulated glucose utilization. Brit J. Pharmacol 112,
671-675, 1994. PMC1910373, citations 32.
6. Nicklin P, Keates AC, Page T, Bailey CJ. Transfer of metformin
across monolayers of human intestinal Caco-2 cells and across rat
intestine. Int J Pharmaceutics,128, 155-162, 1996.
doi:10.1016/0378-5173(95)04259-8, citations 15.
Refs 1 and 2 verify the historical context and global clinical impact of
research described in section 2. Refs 3-6 provide peer-reviewed examples
of the quality of laboratory research that generated a new appreciation of
the anti-diabetic mechanisms and therapeutic potential of metformin as
described in section 2.
Details of the impact
Research described in section 2 made a major impact on the revival and
application of metformin as the primary pharmacological treatment for type
2 diabetes worldwide. The research findings prompted clinical studies that
gave confidence and understanding for use of this drug, The work has
received particular recognition through the UK Prospective Diabetes Study
(S3.1; S5.1) and in recent treatment guidelines (S3.1; S5.2).
The impact of the research at Aston may be traced from its use to inform
the regulatory assessment process for the introduction of metformin into
the USA (1995), when Professor Bailey was accorded the unusual privilege
of being the expert witness to the US Food and Drug Administration (FDA)
for the evaluation of metformin and advisor for the design and evaluation
of the phase 3 clinical trials. The trial design became the standard for
new diabetes therapies trials throughout the last decade (S5.3). Having
authored the expert report on metformin to the European Medicines Agency
(EMA), which placed into context the implications of Aston research as
part of the periodic reassessment of approved drugs, Professor Bailey was
elected to serve on the EMA Committee for Human Medicinal Products
Healthcare Professional Working Group and Scientific Advisory Group from
Through the regulatory process, the research on metformin at Aston has
informed clinical practice. This has been translated into patient care via
the development of treatment algorithms. For example, metformin has been
adopted as first line treatment in the 2012 consensus guideline from the
American Diabetes Association and the European Diabetes Association for
the Study of Diabetes (S5.2). The guideline, which is now accepted
internationally, repositioned metformin as the preferred first-line
treatment for type 2 diabetes, citing work authored by Professor Bailey as
part of the justification for this decision (S5.2; S5.5). Metformin has
recently become the most prescribed medicinal product for the treatment of
diabetes in North America and Europe (S3.1), and the 9th most
prescribed drug in the USA in 2010, accounting for 48.3 million
prescriptions in that year (S5.6). The predominance of metformin is also
acknowledged in the current NICE guideline for England and Wales
(published in 2008) and in the Scottish guideline (published in 2010),
with reference to work described above from Aston (S5.7; S5.8). Metformin
is also listed as preferred initial drug therapy for type 2 diabetes by
most other national and international guidelines, for example the Diabetes
Australia guideline published in 2009 (S5.9) and the diabetes guidelines
for Latin America (S5.10).
Related research at Aston has also been instrumental in the development
of other medicines for diabetes and obesity. Use of the techniques devised
and applied to the study of metformin has provided metabolic information
that was pivotal for the development of the anti-obesity agent
sibutramine, and Professor Bailey is one of the named inventors on one of
the patents (Bailey CJ, Jones RB, and Jackson HC. Use of sibutramine
analogues to prevent the development of diabetes. WO 98/11884).
In summary, metformin has risen from a drug destined for withdrawal in
the 1980s to the most prescribed medication for type-2 diabetes worldwide.
We can claim a substantial contribution to this through early research
studies at Aston University (e.g. S3.3 - S3.6), along with follow-through
education (e.g. S3.1; S3.2). The impact on health and prevention of
diabetes complications is recognised with the prime positioning of
metformin in treatment algorithms and guidelines (S5.3; S5.5; S5.7; S5.8),
and the use of the drug by about half of all patients with type 2 diabetes
in the West (about 30 million patients with a commercial value of $1.6
billion in 2003) (S3.1; S5.2; S5.5; S5.6; S5.6; S5.7; S5.8; S5.9; S5.10).
As a post-script, metformin is now being investigated for potential use
in the treatment of vascular disease, polycystic ovary syndrome and
cancer. It may yet have more benefits to give, since being saved from
Sources to corroborate the impact
- Holman RR et al. 10-year follow-up of intensive glucose control in
type 2 diabetes. N Engl J Med 2008; 359:1577-89.
- Inzucchi SE et al, Management of hyperglycaemia in type 2 diabetes: a
patient-centred approach. Position statement of the American Diabetes
association (ADA) and European Association for the Study of Diabetes
(EASD). Diabetologia 2012; 55: 1577-96 and simultaneously Diabetes Care
- Guidance for Industry Diabetes Mellitus: Developing Drugs and
Therapeutic Biologics for Treatment and Prevention. U.S. Department of
Health and Human Services, Food and Drug Administration, Center for Drug
Evaluation and Research (CDER), February 2008. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071624.pdf
- European Medicines Agency. EMEA/CHMP Working Group with Healthcare
Professionals Organisations (HCP WG), February 2009.
- American Standards of Medical Care in Diabetes. Diabetes Care 2012,
35, Suppl 1, S1-63. http://care.diabetesjournals.org/content/35/Supplement_1/S11.full
- IMS Health USA, National Prescription Audit, Dec 2010
- NICE clinical guideline 66. The management of type 2 diabetes. 2008.
- SIGN guideline 116. The management of diabetes, 2010.
- National Evidence based guideline for blood glucose control in type 2
diabetes. Diabetes Australia Guideline Development Consortium, 2009.
- Gurzman JR et al. Treatment of type 2 diabetes in Latin America: a
consensus statement by the medical associations of 17 Latin American
countries. Rev Panam Salud Publica 2010, 28, 463-71.