As compared with glibenclamide, metformin was associated with
a 46% (p < 0.001) relative reduction in the risk of monotherapy
failure. However, the durability of glycaemic control with metformin was
not as great as with rosiglitazone (63% less monotherapy failure than
glibenclamide and 32% less than metformin; p < 0.001 for both).
Optimal glucose control, as measured by the time mean HbA1c was
maintained at <7% (53.0 mmol/mol), was highest with rosiglitazone (57
months) intermediate for metformin (45 months) and lowest for
glibenclamide (33 months) (Kahn et al., 2006). This landmark study once
again illustrated the progressive nature of type 2 diabetes, as was
initially reported by the UK Prospective Diabetes Study (UKPDS) in 2008.
It also serves as a reminder that metformin, though seemingly better in
attenuating this progression than insulin secretagogues, does not
appear to substantially preserve beta cell function. This could also be
considered as one conclusion of the Diabetes Prevention Program (DPP),
which found that the transition from impaired glucose tolerance to type 2
diabetes was, attenuated the most with lifestyle change, which had
nearly twice as potent an effect as metformin (Knowler et al., 2012).
2.3.2 METFORMIN USE IN COMBINATION THERAPY
Metformin
is also efficacious when used in various combination regimens. Such
progressive therapy is now almost the rule in the management of type 2
diabetes because of the aforementioned decline in beta cell secretory
capacity characterising this disease. As a result of its unique
mechanism of action and lack of association with hypoglycaemia as an
adverse effect, the drug pairs well with all other glucose lowering
medications. As noted, all type 2 diabetes drug development programmes
incorporate extensive investigations of such joint therapies. Indeed,
the most common agent incorporated into single-tablet fixed-dose
combination formulations is metformin. In earlier studies involving
sulfonylureas, thiazolidinediones and insulin, the efficacy of metformin
was tested when added to these background therapies. However, as the
biguanide’s popularity as first-line therapy became established, studies
involving more of the recently developed agents have tested their
efficacy when added to a background of metformin therapy
2.3.3 ADVERSE EFFECTS OF METFORMIN
Gastrointestinal
effects: The most common side effects of metformin are GI in nature:
diarrhoea, nausea and/or abdominal discomfort. They are usually mild,
transient and dose-related, but can occur in up to 50% of patients
taking the medication. About 5% of individuals cannot tolerate the drug,
even at low doses (Bouchoucha et al., 2011). Symptoms can be mitigated
by gradual titration or reduction in dose (Davidson and Peters, 2017).
These side effects may relate to drug accumulation in the enterocytes of
the small intestine. Slow-release formulations (extended-release
metformin [metformin XR]) are associated with fewer GI symptoms
(McCreight et al., 2016). Lactic acidosis a much rarer but more
concerning adverse consequence of biguanide therapy is lactic acidosis.
In the 1970s, use of an earlier member of this class, phenformin was
discontinued because of this association. A potentially lethal side
effect, lactic acidosis has been ascribed to the promotion of anaerobic
metabolism through interference with mitochondrial respiration,
resulting in increased lactate generation. This is particularly the case
when drug levels climb into the toxic range (> 5.0 mg/l [therapeutic
levels, 0.5–2.0 mg/l]) (DeFronzo et al., 2016), owing to decreased
renal clearance, such as in advanced chronic kidney disease or acute
kidney injury. Recognition of this risk substantially delayed the
approval of metformin in the USA in the early 1990s (Bailey and Turner,
2016). Metformin associated lactic acidosis (MALA) is actually rare,
with an estimated incidence of 3–10 per 100,000 person-years. Richy et
al., (2014) Of note, the risk of developing lactic acidosis from
metformin has been calculated to be 20 times less frequent than with
phenformin (Chan et al., 2009). Other risk factors for MALA include
states that result in increased lactate production, such as sepsis,
cardiogenic shock and alcoholism.
The US Food and Drug Administration
(FDA) originally recommended against the use of metformin in
individuals with renal impairment (i.e. serum creatinine ≥114 μmol/l in
men, ≥ 107 μmol/l in women), or those over age 80 years with abnormal
creatinine clearance, to minimise the likelihood of developing lactic
acidosis. However, subsequent investigations have strongly suggested
that the risk of lactic acidosis is extremely small and likely no
different in users of metformin vs other glucose-lowering agents. In
line with this, in an often-cited meta-analysis involving prospective
and retrospective studies, the risk of MALA with metformin was found to
be negligible. In fact, in most circumstances, so long as the estimated
GFR (eGFR) was >30 ml min−1 [1.73 m]−2, circulating drug levels
remained within the safe range (Inzucchi et al., 2014).
