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Beyond glycaemic control

In this chapter we have already discussed the trials that have inves-
tigated the degree to which T2DM treatments influence CV risk. Fifty
percent of people diabetes die from CV disease, primarily heart dis-
ease and stroke, so there’s intense interest in defining the degree to
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which specific drugs and combinations of drugs influence CV risk.

Since the 1990s, the options for OAD treatment have increased mark-
edly. The expanded selection has created a need for comparative
data on the risks and benefits of anti-diabetic drugs, particularly in light
of the greater cost of newer agents. A meta-analysis of forty clinical
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trials shows that metformin is associated with a 26% reduction in the
relative risk of CV mortality compared with SUs, TZDs, glinides and pla-
cebo. A meta-analysis is only as good as the studies it includes and
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the authors of this particular analysis conclude: “larger, long-term stud-
ies taken to hard endpoints and better reporting of CV events in short-
term studies will be required to draw firm conclusions about major clini-
cal benefits and risks related to OADs.” 82

It is increasingly evident that controlling weight, hypertension and dys-
lipidaemia is tantamount to reducing CVD outcomes in patients with
T2DM. Some emerging T2DM treatments, such as the SGLT-2 inhibitors,
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have been shown to reduce blood pressure and body weight (1–4 kg).
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As monotherapy or add-on to metformin over periods of 12–24 weeks,
dapagliflozin at a dose of 10 mg/day reduced systolic blood pressure
(3–5 mmHg) and diastolic blood pressure (~2 mmHg) with no apparent
change in heart rate. 74, 84, 85 These results are promising, but it remains to
be seen if these agents can sustain this level of blood pressure reduc-
tion in the long term. Sustained improvements in glycaemia and one of
the most important CV risk factors would represent a significant break-
through in the management of T2DM. Furthermore, SGLT-2 inhibitors
could offer a clinically meaningful treatment opportunity even in T1DM. 86

Certain T2DM therapies have also demonstrated their ability in improv-
ing dyslipidaemia. A meta-analysis shows that metformin significantly
reduces total and low-density lipoprotein (LDL) cholesterol, although
these reductions are rather small. In a study in T2DM patients, pioglita-
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zone improves levels of triglycerides, HDL cholesterol, LDL particle con-
centration, and LDL particle size. In 3-year open-label extension stud-
13
ies the incretin therapy exenatide was associated with a 12% decrease
in triglycerides, a 6% decrease in LDL and 24% increase in HDL. It has
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been postulated that the weight loss/weight neutrality of incretin thera-
pies contributes to lipid improvements. In a four week study the DPP-4
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inhibitor vildagliptin was shown to improve postprandial plasma tri-
glyceride levels. Large, long term studies are the only definitive way of
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elucidating the influence that T2DM treatments have on CV risk factors.

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