The n e w e ng l a n d j o u r na l of m e dic i n e

From the Cardiovascular Division, Vanderbilt University Medi- ablation versus escalation of antiarrhythmic drugs. N Engl J Med
cal Center, Nashville. 2016;​375:​111-21.
4. Cuculich PS, Schill MR, Kashani R, et al. Noninvasive cardiac
1. Poole JE, Johnson GW, Hellkamp AS, et al. Prognostic impor- radiation for ablation of ventricular tachycardia. N Engl J Med
tance of defibrillator shocks in patients with heart failure. N Engl 2017;​377:​2325-36.
J Med 2008;​359:​1009-17. 5. Leksell L. The stereotaxic method and radiosurgery of the
2. Connolly SJ, Dorian P, Roberts RS, et al. Comparison of brain. Acta Chir Scand 1951;​102:​316-9.
beta-blockers, amiodarone plus beta-blockers, or sotalol for 6. Loo BW Jr, Soltys SG, Wang L, et al. Stereotactic ablative
prevention of shocks from implantable cardioverter defibrilla- radiotherapy for the treatment of refractory cardiac ventricular
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165-71. DOI: 10.1056/NEJMe1713245
3. Sapp JL, Wells GA, Parkash R, et al. Ventricular tachycardia Copyright © 2017 Massachusetts Medical Society.

Adjunctive Treatments for Type 1 Diabetes

David M. Nathan, M.D.

The proliferation of new drug treatments for
type 2 diabetes in the United States in the past
15 years, with more than 17 drugs approved in
six new classes of antidiabetic drugs, has been
promoted by several factors. First, the recognition
of the importance of intensive glycemic control
to reduce the risk of long-term complications
has spurred development.1 Second, the epidemic
of type 2 diabetes has created an enormous mar-
ket with commensurate profits for the pharma-
ceutical industry. Finally, the relatively low bar
set by the Food and Drug Administration (FDA)
for the approval of new antidiabetic drugs —
specifically, the requirement to lower the glycated
hemoglobin level, a surrogate measurement, rath-
er than to show direct effects on long-term com-
plications — has accelerated new drug approvals.
The putative cardiovascular toxic effects associ-
ated with rosiglitazone forced the FDA in 2008 to
require postmarketing cardiovascular safety stud-
ies for all new antidiabetic drugs.2 It is of inter-
est that several drugs, including several sodium–
glucose cotransporter 2 (SGLT2) inhibitors, reduce
cardiovascular risk in patients with type 2 diabe-
tes who are at very high risk.3
In contrast, advances in treatments for type 1
diabetes have been aimed primarily at reducing
the glycated hemoglobin level by improving the
physiologic delivery of insulin with devices, such
as pumps aided by continuous glucose monitor-
ing; advances have also been aimed at developing
insulin analogues that can be used to mimic the
insulin profiles of nondiabetic patients. The data
obtained during the Diabetes Control and Com-
plications Trial (DCCT) and its long-term follow-
up showed that intensive therapy that resulted in
glycated hemoglobin levels of less than 7% during
the DCCT substantially reduced the long-term
morbidity and mortality associated with type 1
diabetes.4 The addition of other drugs to insulin
therapy has not gained traction, since recent
studies showed that metformin, glucagon-like
peptide 1 receptor agonists, and pramlintide had
little to no benefit with respect to the glycated
hemoglobin level to balance the attendant costs
and side effects.5-7 To date, only pramlintide, an
injectable agent that slows gastric emptying, has
been approved as adjunctive therapy for type 1
diabetes.
Garg and colleagues now report the results
of a placebo-controlled trial that evaluated the
effects of sotagliflozin, an SGLT1 and SGLT2
inhibitor that is not currently approved by the
FDA, in combination with insulin therapy for
the treatment of type 1 diabetes.8 The rationale
for this double-blind clinical trial, other than to
achieve regulatory approval, was to address the
inability of more than two thirds of people with
type 1 diabetes to achieve a glycated hemoglobin
level of less than 7%. The proportion of patients
achieving the composite primary end point (a gly-
cated hemoglobin level lower than 7% and no
episodes of ketoacidosis or severe hypoglycemia)
was significantly larger with sotagliflozin than
with placebo. The trial design favored the active
intervention, since the patients’ glycated hemo-
globin levels (the major marker used by clinicians
to adjust therapy) were masked to investigators,
which most likely inhibited adjustments in the
insulin regimens and may have prevented the
control group from receiving the best possible
treatment.

2390 n engl j med 377;24 nejm.org  December 14, 2017

The New England Journal of Medicine

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 Editorials
Despite the flaws in the design of this short-
term trial, are the results helpful in determining
whether practitioners should choose this adjunc-
tive therapy — should it be approved? If, as in the
trial, sotagliflozin were added to insulin thera-
py, the proportion of patients who would achieve
a glycated hemoglobin level of less than 7% with
no episodes of ketoacidosis or severe hypoglyce-
mia would be increased by 13 percentage points
(with less than one third of the patients treated
with sotagliflozin achieving the target glycated
hemoglobin level) and the glycated hemoglobin
level would be 0.46 percentage points (6%) below
the level among those who receive insulin alone.
The risk of microvascular complications rela-
tive to the glycated hemoglobin level is a con-
tinuum. The DCCT data showed that for every
10% decrease in the glycated hemoglobin level,
the risk of microvascular complications was re-
duced by approximately 35 to 40% over an aver-
age period of 6.5 years.9 Thus, if the 6% reduc-
tion in glycated hemoglobin level that was seen
in this short-term trial with sotagliflozin were
sustained for 6.5 years, the predicted reduction
in the risk of microvascular complications would
be approximately 20%. The accompanying risks
of ketoacidosis, dehydration, and genital mycotic
infections, which have immediate and potential­
ly serious clinical effects, would each be three to
six times as high as the risks with insulin alone.
Unfortunately, the results of this trial suggest
that the increased risk of ketoacidosis counter-
balances the increased likelihood of achieving a
glycated hemoglobin level of less than 7%. (The
rate of severe hypoglycemia in the whole sota-
gliflozin group was not significantly different
from the rate in the placebo group.)
There is little to suggest that the risk of keto-
acidosis would be mitigated over time. The eligi-
bility criteria used in the trial resulted in a study
population that had a relatively low risk of keto-
acidosis and severe hypoglycemia, and the inves-
tigators took steps to further reduce the risk of
ketoacidosis. A previous 18-week clinical trial of
the SGLT2 inhibitor canagliflozin showed similar
results: a modest reduction in the glycated hemo-
globin level in the canagliflozin group as com-
pared with the placebo group, and a 4 to 6%
prevalence of ketoacidosis in the canagliflozin
group as compared with 0% prevalence in the
placebo group.10 The critical information neces-
sary to judge the relative risks and benefits of
n engl j med 377;24 nejm.org  December 14, 2017
The New England Journal of Medicine
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Copyright © 2017 Massachusetts Medical Society. All rights reserved.
adjunctive therapy — specifically, the frequency
of ketoacidosis for every case of clinically sig-
nificant microvascular disease averted — cannot
be gleaned from such short-term studies.
The further development of automated insulin
delivery systems is likely to make adjunctive drug
therapies for type 1 diabetes unnecessary. Im-
proved automated delivery systems should be able
to lower the glycated hemoglobin level while re-
sulting in fewer episodes of hypoglycemia than
those seen with adjunctive therapies and requiring
less effort from the patient. Any added benefits of
adjunctive therapies for type 1 diabetes must be
carefully balanced against their added risks and
costs. Physicians and patients should beware.
Disclosure forms provided by the author are available with the
full text of this editorial at NEJM.org.
From the Diabetes Center, Massachusetts General Hospital,
and Harvard Medical School, Boston.
This editorial was published on September 13, 2017, at NEJM.org.
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DOI: 10.1056/NEJMe1711296
Copyright © 2017 Massachusetts Medical Society.
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