REVIEW

Metabolic Control in Type 1 Diabetes: Is AdjunctiveTherapy the Way Forward?

Harriet Warnes . Rebecca Helliwell . Sam Matthew Pearson .

Ramzi A. Ajjan

Received: July 12, 2018 / Published online: September 12, 2018� The Author(s) 2018

ABSTRACT

Despite advances in insulin therapies, patientswith type 1 diabetes (T1DM) have a shorter lifespan due to hyperglycaemia-induced vasculardisease and hypoglycaemic complications sec-ondary to insulin therapy. Restricting therapyfor T1DM to insulin replacement is perhaps anover-simplistic approach, and we focus in thiswork on reviewing the role of adjuvant therapyin this population. Current data suggest thatadding metformin to insulin therapy in T1DMtemporarily lowers HbA1c and reduces weightand insulin requirements, but this treatmentfails to show a longer-term glycaemic benefit.Agents in the sodium glucose co-transporter-2inhibitor (SGLT-2) class demonstrate the great-est promise in correcting hyperglycaemia, but

there are safety concerns in relation to the riskof diabetic ketoacidosis. Glucagon-like peptide-1 agonists (GLP-1) show a modest effect onglycaemia, if any, but significantly reduceweight, which may make them suitable for usein overweight T1DM patients. Treatment withpramlintide is not widely available worldwide,although there is evidence to indicate that thisagent reduces both HbA1c and weight in T1DM.A criticism of adjuvant studies is the heavyreliance on HbA1c as the primary endpointwhile generally ignoring other glycaemicparameters. Moreover, vascular risk markers andmeasures of insulin resistance—important con-siderations in individuals with a longer T1DMduration—are yet to be fully investigated fol-lowing adjuvant therapies. Finally, studies todate have made the assumption that T1DMpatients are a homogeneous group of individu-als who respond similarly to adjuvant therapies,which is unlikely to be the case. Future longer-term adjuvant studies investigating differentglycaemic parameters, surrogate vascular mark-ers and harder clinical outcomes will refine ourunderstanding of the roles of such therapies invarious subgroups of T1DM patients.

Keywords: DPP-4 inhibitors; GLP-1 analogues;Hypoglycaemia agents; Metformin; Pramlintide;SGLT2 inhibitors; Type 1 diabetes (T1DM)

Enhanced Digital Features To view enhanced digitalfeatures for this article go to https://doi.org/10.6084/m9.figshare.6979601.

H. Warnes � R. Helliwell � S. M. Pearson � R. A. AjjanSchool of Medical Sciences, The University of Leeds,Leeds, UK

S. M. Pearson � R. A. AjjanDepartment of Diabetes and Endocrinology, TheLeeds Teaching Hospitals NHS Trust, Leeds, UK

R. A. Ajjan (&)The Leeds Institute of Cardiovascular and MetabolicMedicine, Leeds, UKe-mail: r.ajjan@leeds.ac.uk

Diabetes Ther (2018) 9:1831–1851

https://doi.org/10.1007/s13300-018-0496-z

INTRODUCTION

It has long been known that type 1 diabetesmellitus (T1DM) is associated with an increasedincidence of adverse vascular events, and thatthese cardiovascular events occur at a youngerage than in the nondiabetic population [1].Despite advances in therapy, the rate of endorgan damage in T1DM remains high, andmortality is significantly increased compared toindividuals without diabetes. The NationalInstitute for Health and Care Excellence (NICE)in the United Kingdom recommends thatpatients should aim to achieve a glycated hae-moglobin (HbA1c) below 48 mmol/mol unlessthey are troubled by recurrent hypoglycaemia,in which case individualised targets should beagreed on a patient-by-patient basis [2]. Simi-larly, the American Diabetes Association rec-ommends HbA1c\ 7% (53 mmol/mol) inT1DM patients, with a lower level of 6.5%(48 mmol/mol) in selected individuals [3]. Thecurrent standard treatment predominantlyinvolves intensive insulin regimes that aim tolower HbA1c in order to reduce the risk ofmicrovascular disease and limit long-termmacrovascular complications [4, 5].

A key aim in these patients is the reductionof macrovascular events, but the relationshipbetween glycaemic control and vascular occlu-sive disease is far more complex than initiallyenvisaged. The DCCT-EDIC trial has shown thatlowering HbA1c reduces the long-term risk ofmyocardial infarction [6]. However, intensivelytreating glycaemia predisposes to hypogly-caemia, which in itself increases the risk ofvascular events [7]. Mechanisms for hypogly-caemia-induced vascular damage include theinduction of an inflammatory and prothrom-botic milieu due to low glucose levels [8]. Tofurther complicate matters, large fluctuations inglucose control, typically seen in individualswith inadequate insulin dosing, are alsothought to be associated with vascular damagethrough increased oxidative stress and anenhanced inflammatory response [9]. Ourunderstanding of the mechanistic pathwayslinking glucose variability with increased car-diovascular risk is incomplete and causality has

yet to be fully proven, but the evidence behindthis being a contributory factor in the devel-opment of cardiovascular disease (CVD) isgrowing [10].

In addition to the detrimental effects ofhypoglycaemia, the weight gain associated withinsulin treatment predisposes to insulin resis-tance, which promotes vascular damagethrough the induction of endothelial dysfunc-tion and predisposition to an inflammatory andprothrombotic environment [11]. This explainsthe failure of some HbA1c-focussed studies inT1DM to demonstrate significant associationsbetween this glycaemic marker and adversevascular events, instead suggesting that insulinresistance may play a stronger role in thedevelopment of these complications [12, 13].

Weight gain has been implicated inincreased insulin resistance, and this is a well-established mechanism underlying the patho-genesis of type 2 diabetes mellitus (T2DM) [14].Therefore, T1DM patients who are overweightcan develop insulin resistance, giving rise to the‘double diabetes’ (DD) phenotype. The defini-tion of DD is yet to be formalised and is cur-rently used as a loose term to describeoverweight T1DM patients, particularly in thepresence of increased insulin requirements.Previous work has shown that patients withT1DM are particularly prone to weight gain,with one large prospective study demonstratinga sevenfold increase in the rate of obesity inT1DM over a follow-up period of 18 years ascompared with the general population [15].Other studies have confirmed the increasedprevalence of obesity in T1DM [16], raising thequestion as to whether adjuvant medicationsshould be considered in these patients to reduceweight irrespective of changes in markers ofglycaemic control. Moreover, evidence suggeststhat overweight T1DM patients are at higherrisk of vascular complications compared withtheir lean counterparts [17], further highlight-ing the need for alternative, non-insulin-basedtherapies in these individuals.

The current review assesses the role of adju-vant non-insulin-based therapies in T1DM inrelation to improving glycaemia, controllingweight and modulating the risk of vascularcomplications of diabetes. We have conducted a

1832 Diabetes Ther (2018) 9:1831–1851

PubMed search of articles using the terms ‘type1 diabetes’ and ‘metformin’, ‘sodium glucoseco-transporter-2 inhibitors (SGLT2)’ (and eachmember of this family), ‘glucagon like peptide-1agonists (GLP-1)’ (and each member of thisfamily), ‘amylin’ (and ‘pramlintide’) and‘dipeptidyl peptidae-4 inhibitors (DPP4)’ (andeach member of the family) up to June 2018,and attempted to summarise the major trials foreach class.

This article is based on previously conductedclinical trials and does not contain unpublishedwork with human participants or animals per-formed by any of the authors.

METFORMIN

Metformin, a biguanide agent, has been used forthe treatment of T2DM for over half a century.Its exact mode of action is not entirely clear, butit is believed to inhibit production of hepaticglucose, reduce intestinal glucose absorptionand improve glucose uptake and utilisation[18]. The use of metformin in T1DM has beenrepeatedly suggested, with some studies—butnot all—showing improved glycaemic control,assessed as a reduction in HbA1c.

One of the largest studies is the recent ran-domised controlled REMOVAL trial, whichinvolved 428 T1DM patients. The study inves-tigated the role of metformin in modulatingcarotid intima media thickness (cIMT) in thoseabove the age of 40 years with multiple cardio-vascular risk factors [19]. Metformin had nosignificant effect on cIMT, although a decreasein HbA1c 3 months after the introduction ofmetformin (- 0.24%, p = 0.0001) was demon-strated, which was not sustained at study end(3 years). A much smaller trial involving 15T1DM patients with an average body massindex (BMI) of 31.3 kg/m2 reported a decrease inHbA1c of 0.8% (p\ 0.005) after 16 weeks ofmetformin treatment compared to placebo [20].Similarly, a significant reduction in HbA1c of(0.6%) (DCCT-aligned) was observed in a trial of114 patients over 6 months compared to pla-cebo (? 0.2%) (DCCT-aligned) (p\ 0.001) [21].No significant difference in HbA1c was reportedin trials with durations of 24 weeks to 1 year,

involving 24–100 overweight patients withHbA1c[ 7% [22–24]. Similarly, a recent meta-analysis of 13 trials did not identify enoughevidence to suggest HbA1c is significantly low-ered by adjuvant metformin [25].

While the effects of metformin on glycaemiaappear to be short term and unsustained, areduction in daily insulin dose has been repor-ted in several trials when metformin was addedto standard therapy. In a 16-week trial involving15 overweight patients, a significant decrease ininsulin dose by 10 units/day was reported [20].Similarly, a 24-week trial involving 24 over-weight patients reported a significant reductionin daily insulin dose of 8.8 units/day [22].Another larger trial with a duration of 1 year,comprising 100 T1DM patients with poor gly-caemic control (HbA1c[8.5%) and an averageBMI of 26.2 kg/m2, reported a decrease of 5.7units/day in insulin dose compared with pla-cebo [24]. Moreover, a trial of 114 patients over6 months also identified a reduction of0.04 units/kg compared to placebo (0.02 units/kg, p = 0.004) [21]. Additional small trialsreported nonsignificant decreases in the totaldaily insulin dose [23]. Taken together, thesedata suggest a general reduction in insulin doseafter the introduction of metformin, but long-term studies are lacking. REMOVAL was one ofthe longest and largest studies of the use ofmetformin in T1DM, and this showed an initialreduction in total daily insulin requirementwhich was not sustained at 3 years [19].

Multiple studies involving overweightpatients provide evidence of significant weightloss associated with metformin use for up to3 years [19, 21–24]. A recent meta-analysis of 13trials identified the same outcome, with areduction in BMI of - 1.14 kg/m2 (- 2.05 to- 0.24, p = 0.01) [25]. Others failed to corrobo-rate these findings, although these were gener-ally small studies conducted over 8–16 weeksand involving no more than 24 patients each[20, 26]. A recent retrospective study of 181patients who were taking metformin or stan-dard therapy found no significant difference inweight over 10 years of follow-up [27]. Of note,the groups were not evenly matched, with thosetaking metformin having a significantlyincreased BMI compared to those not taking

Diabetes Ther (2018) 9:1831–1851 1833

metformin at study onset (29.8 vs 28.6 kg/m2;p\0.01). Confounders such as diet and physi-cal exercise were not included in analysis. Theretrospective design of the study and the factthat the groups were not evenly matched atstudy onset make it challenging to draw con-clusions about the ability of metformin toreduce weight in those with T1DM over longertime periods.

Metformin is not known to cause hypogly-caemia as it does not stimulate endogenousinsulin secretion; however, in insulin-treatedpatients it can theoretically increase the risk oflow glucose levels [18]. A meta-analysis of 13trials involving 1,183 patients identified anincreased hypoglycaemic risk with adjuvantmetformin (1.23, CI 1.00–1.52, p = 0.05) [25].The REMOVAL trial involving 387 patientsreported 0.16 severe hypoglycaemic events perpatient per year, which was similar to the con-trol arm [19]. Another trial uncovered 58 eventsof severe hypoglycaemia in 49 patients over a1-year period [24] in metformin-treated T1DMpatients, but this was not significantly differentfrom the placebo group (p = 0.261). Finally,another trial identified no statistical differencebetween 114 patients taking adjuvant met-formin and the placebo group (p = 0.2) [21].

Overall, metformin reduces HbA1c initially,but this effect does not appear to be sustained.Also, metformin reduces daily insulin doses, butagain this reduction is not seen over longerperiods of follow-up. Metformin-related weightloss is perhaps more sustained, but long-termconclusive data are lacking. Metformin does notappear to increase the rate of severe hypogly-caemic events, although the role of this agent incontributing to milder hypoglycaemia isunclear and will require continuous glucosemonitoring studies.

A summary of the main studies of metforminin T1DM is provided in Table 1.

SGLT2 INHIBITORS

Sodium glucose co-transporter type 2 mediatesthe reabsorption of glucose in the renal tubule,so inhibiting this co-transporter results in gly-cosuria and reduces blood glucose levels [28].

Moreover, this is associated with weight lossand reduced blood pressure, further helpingindividuals with T2DM and the metabolic syn-drome. It should be noted that SGLT2 inhibitorsare currently only licenced for use in individualswith T2DM; their use in T1DM patients is lim-ited to research studies, or they may be appliedby specialists outside licensed indications.

Small-scale and short-duration studies haveshown that SGLT2 inhibitors can be effective atreducing HbA1c in T1DM. One study enrolled75 participants with HbA1c between 58 and91 mmol/mol and BMI between 18.5 and 35 kg/m2. Individuals were randomly assigned in a1:1:1:1 fashion to empagliflozin 2.5 mg, 10 mg,25 mg or placebo for 28 days in addition to theirstandard multiple daily injection (MDI) insulinregimens [29]. At 28 days there was a significantdifference in HbA1c between those on empa-gliflozin and the placebo group (a differencethat showed a dose-dependent response).Another study (albeit single-armed) looked atthe introduction of 25 mg empagliflozin tostandard insulin therapy in 40 participants withT1DM [30]. The study was intended as a proof ofconcept and found a significant reduction inHbA1c from baseline (8.0 ± 0.9% to7.6 ± 0.9%; p\ 0.0001), associated with signif-icant decreases in weight, waist circumferenceand total daily insulin dose. Similarly, dapagli-flozin at 10 mg/day significantly reduced HbA1cfrom baseline in 12 overweight patients withpoorly controlled T1DM over a 24-week studyperiod (9.18 ± 1.02% to 8.05 ± 1.09%;p = 0.0156) [31]. Sotagliflozin (a dual SGLT1and SGLT2 inhibitor) also caused a significantreduction in HbA1c in 33 patients with T1DMwho had an average BMI of 26.6 kg/m2

(- 0.55%, p = 0.002) [32]. Additionally, a recentRCT involving 1402 patients with an averageHbA1c of 8.26% reported there was a signifi-cantly greater reduction in HbA1c with sotagli-flozin compared to placebo after 24 weeks oftreatment (- 0.79%, - 0.33% respectively,p\0.001) [33].

A recent RCT involving 351 patients on MDIor CSII insulin therapy trialled the addition of100 or 300 mg canagliflozin as adjuvant ther-apy. All patients had T1DM, and the range ofBMI for the group was 21–35 kg/m2. At the

1834 Diabetes Ther (2018) 9:1831–1851

Table1

Summaryof

themaintrialsinvestigatingtheuseof

metform

inin

type

1diabetes

Khanet

al.[20]

Lun

det

al.[24]

Jacobsen

etal.[22]

Pitocco

etal.[23]

Petrieet

al.(REMOVAL

trial)[19]

Zaw

adaet

al.

[21]

Year

2006

2008

2009

2013

2017

2018

Studydesign

Double-blind,

placebo-

controlled,

crossoverRCT

Double-blind,

placebo-

controlledRCT

Double-blind,

placebo-

controlledRCT

Double-blind,

placebo-

controlledRCT

Double-blind,

placebo-

controlledRCT

Randomized

controltrial

Noof

participants

15100

2442

428

114

Lengthof

follow-up

16weeks

12months

24weeks

6months

3years

6months

Changein

HbA

1c-

0.8%

(p\

0.05)

0.13%(95%

CI-

0.19

to0.44%)(p

=0.43)

-0.5±

0.3%

(p=0.26)

0.17%

(p=0.505)

-0.13

(95%

CI-

0.22

to-

0.037)

(p=0.006)

-0.6%

compared

to0.2%

incontrolgroup

(pB

0.001)

Changein

totaldaily

insulin

dose

-10

units

(pB

0.05)

-5.7un

its(p

B0.01)

-8.8un

its(p

=0.04)

-0.027un

its(p

=0.489)

-0.005un

its/kg

(p=0.545)

Changein

weight(kg)

-1.74

(95%

CI-

3.32

to-

0.17)(p

=0.030)

-3.8(p

=0.02)

-2.27

(95%

CI-

3.99

to-

0.54)(p

=0.012)

-1.17

(95%

CI-

1.66

to-

0.69)(p

B0.0001)

Reduction

inBMI:

-0.6kg/m

2in

metform

ingroup

comparedto

0.2%

kg/m

2in

controlgroup

Adverse

events

reported

Nosignificant

difference

inratesof

hypoglycaemia

reported.N

oepisodes

ofDKA

reported

ineither

group

Nosignificant

difference

inratesof

hypoglycaemiabetween

groups.S

mallbut

significant

increase

inserum

potassium

levels

inthemetform

ingroup

Significant

increase

inratesof

hypoglycaemiain

the

metform

ingroup,

most

markedduring

thefirst

8weeks

ofthestudy

(0.7

±0.9vs

0.3±

0.5

events/patient/w

eek,

p=0.005).T

hree

episodes

ofgastrointestinalside

effects

notedin

themetform

ingroup

Noside

effectsof

metform

inreported,

andno

difference

inratesof

hypoglycaemia

betweengroups.N

oepisodes

ofsevere

hypoglycaemiain

either

group

Nosignificant

difference

inratesof

hypoglycaemia

betweengroups,and

nodifference

inratesof

severe

hypoglycaemia.S

ignificant

increase

inthedropoutrate

inmetform

ingroup.

Increase

ingastrointestinal

side

effectsinthemetform

ingroup(16%

vs3%

),but

significancenotreported

Significantlyfewer

episodes

ofsevere

hypoglycaemia

inthe

metform

ingroup(1

vs8

events,p

B

0.001)

Diabetes Ther (2018) 9:1831–1851 1835

study endpoint, 18 weeks, those taking cana-gliflozin at either dose presented a significantreduction in HbA1c compared to placebo. Thiswas not accompanied by weight gain in eithergroup [34]. Other findings of the study werethat there were similar rates of hypoglycaemiaacross the groups, and that there was anincreased numerical rate in female genitalmycotic infections in those taking 300 mgcanagliflozin compared to placebo (21.2% vs5.6%). A further important finding was anincrease in diabetic ketoacidosis (DKA) in thosetaking canagliflozin compared to placebo (4.3%,6.0%, 0% for 100 mg, 300 mg and placebo,respectively).

An additional recent RCT of 833 patientswith T1DM and poor glycaemic control (HbA1c61–97 mmol/mol) studied adjuvant dapagli-flozin at 5 mg/day and 10 mg/day [35]. Adju-vant dapagliflozin was associated with asignificantly decreased HbA1c versus placebo at5 mg/day and 10 mg/day (- 0.42%, p\ 0.0001;- 0.45%, p\ 0.0001, respectively). This effectwas established at week 4 and maintained forthe study duration of 24 weeks. Moreover, areduction in body weight of - 2.96%(p\ 0.001) at 5 mg/day and - 3.72%(p\ 0.0001) at 10 mg/day was observed. Thiseffect was established by week 8 and maintainedthroughout the study. More genital infectionswere reported in the study group compared tothe placebo group (11% for 5 mg/day, 12% for10 mg/day vs 3% for placebo), but a statisticalanalysis was not reported. Similar rates ofhypoglycaemia were observed among the trialgroups. Moreover, there was no statisticallysignificant difference in definite DKA betweenthe three study arms (1% for 5 mg/day, 2% for10 mg/day and 1% for placebo).

Whilst SGLT2 inhibitors are known to reduceglycaemia, they may also be useful as weightloss medications. A trial of sotagliflozin, acombined SGLT1 and SGLT2 inhibitor,observed a significant reduction in body weightof 33 patients with an average starting BMI of26.6 kg/m2 (- 1.7 kg, p\ 0.01) [32]. Similarly,an RCT involving 1402 patients with an averagebaseline BMI of 28.29 kg/m2 reported a signifi-cant difference in weight loss between thesotagliflozin and control groups (- 2.98 kg,

p\0.001), with an average loss of 2.21 kg in thesotagliflozin group and an average weight gainof 0.77 kg in the control group [32]. Addition-ally, a trial of 40 patients with various startingBMIs (18.5–35 kg/m2) identified a 3.5% reduc-tion in body weight after 8 weeks of 25 mgempagliflozin, although this was not a placebo-controlled trial [30]. A trial of 100 mg and300 mg canagliflozin in patients with BMI21–35 kg/m2 did show a weight reduction, butits significance was undetermined (- 3.1% and- 5.1%, respectively) [34]. Therefore, furtherresearch is required to determine whether thepotent weight-loss effects of SGLT2 inhibitorsobserved in patients with T2DM translate to theT1DM population, as this may highlight a newtarget group for these agents [36].

Due to the mechanism of action of SGLT2inhibitors, hypoglycaemia is not common inthose with T2DM [37]. A meta-analysis of trialslooking at the use of SGLT2 inhibitors in thosewith type 1 DM did not find a significantlydifferent rate of hypoglycaemia compared toplacebo [38].

Changes in insulin requirements have beenreported in some trials investigating the addi-tion of SGLT2 inhibitors to insulin monother-apy in type 1 diabetes. One large trial with 1402participants which studied the addition ofsotagliflozin (a dual SGLT1 and SGLT2 inhi-bitor) found significant reductions in placebo-corrected total daily insulin dose, bolus insulindose and basal insulin dose (- 9.7%, - 12.3%and - 9.9%, respectively, p B 0.001 for all) [33].A recent meta-analysis reported reductions inboth bolus and basal insulin doses when aSGLT2 inhibitor was added to insulinmonotherapy (- 3.6 units/day, 95% CI - 2.0 to- 5.3, and - 4.2 units/day, 95% CI - 2.2 to- 6.3, respectively) [39]. There is therefore goodevidence that adding a SGLT2 inhibitor reducesthe insulin requirement in those with type 1diabetes, and there appears to be reduction inboth basal and bolus insulin doses for those onmultiple daily injection regimens.

A systematic review and meta-analysis oftrials using SGLT2 inhibitors in addition toinsulin in T1DM found significant improve-ments in fasting glucose, HbA1c, weight andtotal daily insulin dose in those treated with

1836 Diabetes Ther (2018) 9:1831–1851

these medications [38]. However, the systematicreview also highlighted an increased incidenceof diabetic ketoacidosis (DKA) in patients takingadjuvant SGLT2 inhibitors versus placebo,identifying 16 cases of DKA in 581 patients. Thereview did note that the studies reported bothmild hyperglycaemic and normoglycaemic DKAas well as typical DKA. Rates of other adverseevents such as hypoglycaemia were not differ-ent from placebo. This provides evidence thatthis drug class is beneficial in those with type 1diabetes, but the number of trials that met thesearch criteria (n = 10) was small. A subsequentsystematic review and meta-analysis including14 trials published similar results [39]. Signifi-cant reductions in HbA1c were documented at0.4% [95% confidence interval (CI) 0.35, 0.46;p\0.001], as well as significant reductions inweight, systolic blood pressure, and total dailyinsulin dose, accompanied by a reduction inglucose variability assessed using continuousglucose monitoring (CGM). Note that theauthors also reported significant increases inDKA and genital tract infections when com-pared to placebo (OR 3.38 and 3.44,respectively).

The EMPA-REG study pointed to a significantdecrease in mortality from cardiovascular causesin T2DM patients taking empagliflozin com-pared to placebo [40]. A meta-analysis of studieslooking at cardiovascular outcomes in thosetaking SGLT2 inhibitors and suffering fromT2DM highlighted significant reductions in all-cause mortality as well as mortality from car-diovascular causes [41]. Direct comparisonsbetween these study groups of T2DM and T1DMpatients cannot be drawn, but nevertheless, thisdrug class shows promising results in reducingadverse cardiovascular outcomes in those withimpaired glucose metabolism.

In summary, there is early evidence to sup-port the use of SGLT2 inhibitors as an adjuvanttherapy in patients with T1DM, as there is anobserved reduction in HbA1c without anincreased risk of severe hypoglycaemia. How-ever, future studies are required with morecomprehensive glycaemic assessment usingcontinuous glucose monitoring, which willhelp to fully establish the glycaemic benefits ofthis class of drugs. Moreover, outcome studies

are required to ascertain the role of these drugsin reducing microvascular and macrovascularcomplications in T1DM, as well as to furtheranswer specific concerns with regards to rates ofDKA and genital tract infections in patientstaking this class of medication.

A summary of the main studies of the use ofSGLT2 inhibitors in T1DM is provided inTable 2.

GLP-1 RECEPTOR AGONISTS

The key effects of GLP-1 receptor agonists arethat they slow gastric emptying (thus reducingappetite), enhance pancreatic insulin secretionand suppress pancreatic glucagon secretion.These effects work to maintain glucose home-ostasis in patients with T2DM [42]. Studiesregarding gastric emptying in type 1 diabeteswith GLP-1 analogues are relatively scarce, butthere is some evidence to suggest that this effectis not observed in this group [43].

Despite the predicted beneficial glycaemiceffects of GLP-1 receptor agonists in T2DM, anumber of recent clinical studies have generallyfailed to show an impact of GLP-1 analogues onHbA1c when used in addition to insulin therapyin T1DM [44–47]. However, a retrospectivestudy of exenatide involving a limited numberof patients (n = 11) reported a significantreduction in HbA1c from baseline (7.7%) to3 months of treatment (7.1%) (p = 0.013) [48].Note that all of the patients studied in this ret-rospective analysis were treated with continu-ous subcutaneous insulin infusion (CSII). A6-month trial of exenatide in 13 patients withHbA1c\ 8.4% found a significant decrease inpostprandial plasma glucose compared to pla-cebo, suggesting a potential reduction in gly-caemic variability [47]. Moreover, the bolusinsulin dose was significantly reduced by GLP-1receptor agonists in a number of studies[44, 46–48].

Therefore, there is significant interstudyvariability in the results obtained with this classof drugs in terms of their ability to improveglycaemic control in T1DM. A meta-analysis of7 studies (n = 206 participants) has shown amodest HbA1c reduction caused by the use of

Diabetes Ther (2018) 9:1831–1851 1837

Table2

Summaryof

themainfin

dingsof

trialsinvestigatingtheuseof

sodium

glucoseco-transporter

type

2inhibitorsin

type

1diabetes

Perkins

etal.[30]

Pieberet

al.[29]

Tam

ezet

al.

[31]

Sand

set

al.[32]

Garget

al.[33]

Dando

naet

al.(D

EPIC

Ttrial)[35]

Year

2014

2015

2015

2015

2017

2017

Studydesign

Single-arm

,proof

ofconcept

study

Placebo-controlledRCT

withvariabledosing

Single-arm

,proofof

concept

study

Placebo-controlledRCT

Placebo-controlledRCT

Placebo-controlledRCT

Agent investigated

Empagliflozin

Empagliflozin

Dapagliflozin

Sotagliflozin

Sotagliflozin

Dapagliflozin

No.

ofparticipants

4075

1233

1402

833

Durationof

study

8weeks

28days

24weeks

29days

24weeks

24weeks

Changein

HbA

1c(%

)comparedto

placebo

-0.4(p

B0.0001)

2.5mgem

pagliflozin

-0.35

(-0.62,-

0.09),

p=0.01

10mgem

pagliflozin

-0.38

(-0.62,-

0.10),

p=0.008

25mgem

pagliflozin

-0.49

(-0.75,-

0.22),

p\

0.001

-0.55%

(p=0.002)

-0.49

(p=0.002)

-0.46

(p\

0.001)

5mgdapagliflozin

-0.48

(p\

0.0001)

10mgdapagliflozin

-0.46

(p\

0.0001)

Changein

total

daily

insulin

dose

(units

unlessstated

otherwise)

-8.9(p\

0.0001)

2.5mgem

pagliflozin

-0.07

(-0.14,0

.05),

p=0.044

10mgem

pagliflozin

-0.09

(-0.16,0

.00),

p=0.013

25mgem

pagliflozin

-0.08

(-0.15,-

0.01),

p=0.023

Not

reported

-14.6%

(p=0.029)

-5.3(p\

0.001)

5mgdapagliflozin

-6.79

(p\

0�0001)

10mgdapagliflozin

-7.24

(p\

0�0001)

1838 Diabetes Ther (2018) 9:1831–1851

Table2

continued

Perkins

etal.[30]

Pieberet

al.[29]

Tam

ezet

al.

[31]

Sand

set

al.[32]

Garget

al.[33]

Dando

naet

al.(D

EPIC

Ttrial)[35]

Changein

weight(kg)

-2.6(p\

0.0001)

2.5mgem

pagliflozin

-1.5(-

2.4,

-0.7),

p\

0.001

10mgem

pagliflozin

-1.8(-

2.7,

-0.9),

pB

0.001

25mgem

pagliflozin

-1.9(-

2.7,

-1.0),

pB

0.001

Not

reported

-2.2(p

=0.005)

-2.98

(p\

0.001)

5mgdapagliflozin

-2.29

(p\

0�0001)

10mgdapagliflozin

-2.98

(p\

0�0001)

Adverse

events

reported

Improvem

entin

ratesof

symptom

atic

hypoglycaemiareported

2episodes

ofDKA,b

utas

aresultof

insulin

pump

failure

andgastrointestinal

upsetleadingto

withdrawal

from

trial

Nosignificant

increase

inratesof

hypoglycaemia

reported

between

groups

Noepisodes

ofDKA

reported

inanygroup

Nosignificant

adverse

events

reported

Rates

ofhypoglycaemiaam

ong

groups

notnu

mericallytested,

butadecrease

inhypoglycaemiceventswas

observed

inboth

groups

2episodes

ofDKAin

the

sotagliflozin

group,

butwas

foun

dto

bepump-relatedby

thestudyteam

Increasedratesof

DKA

inthesotagliflozin

group

(8.6%

vs2.4%

),but

statisticalsignificancenot

commentedon

Num

ericalincrease

inrates

ofhypoglycaemiain

the

sotagliflozin

group,

but

statisticalsignificancenot

commentedon

Nosignificant

differencesin

ratesof

hypoglycaemiaor

DKA

betweeneither

ofthedapagliflozin

groups

andplacebo

Diabetes Ther (2018) 9:1831–1851 1839

GLP-1 analogues in T1DM (- 0.21%, p\0.03),which was associated with a reduction in thetotal daily weight-adjusted bolus insulin dose(- 0.06 l/kg, 95% CI - 0.1 to 0.02, p\0.001),whereas the total daily insulin was not signifi-cantly lower than in the placebo group [49].

In general, GLP-1 analogues have shownpromise in their ability to reduce the weight ofT1DM patients. Studies reported weight lossesof between 4.2 and 6.8 kg compared to placeboover 12–52 weeks in healthy-weight and over-weight patients [44–48].

A study analysing additional measures ofbody fat in overweight patients found adecrease in waist circumference of 3.3 cm(p = 0.002) and a decrease in total adipose tissue(measured by computed tomography) of 61 cm2

compared to placebo (p = 0.0001) [45]. Addi-tionally, a 6-month retrospective study of exe-natide in overweight patients withHbA1c\ 8.4% measured insulin sensitivityusing the hyperinsulinaemic-euglycaemicclamp method and reported an increase ininsulin sensitivity of 1.94 mg/m2/min per lU/mL (p = - 0.0039) [47]. A 24-week RCT ofliraglutide in overweight patients withHbA1c\ 8.5%, however, found no significantdifference in insulin sensitivity [45]. Possibleexplanations for this discrepancy in outcomemay be related to differences in study designand patient population, the limited number ofsubjects enrolled, or it may represent a genuinedifference between the two agents studied.

Many trials involving GLP-1 receptor ago-nists have reported no significant difference inincidence or rate of hypoglycaemic events[45, 46, 48], although one study involving 40overweight T1DM patients has shown adecrease in hypoglycaemic events (incidencerate ratio 0.82, 95% CI 0.74–0.90) with GLP-1analogue therapy [44].

The largest RCTs published on this topic arethe ADJUNCT ONE and ADJUNCT TWO stud-ies. ADJUNCT ONE recruited 1398 adults withT1DM to receive liraglutide (at varying doses) orplacebo in a 3:1 randomisation with insulinbeing adjusted in a treat-to-target manner over52 weeks [50]. Despite the treat-to-target design,there was a numerical decrease in HbA1c acrossall three doses of liraglutide at 52 weeks

(0.6 mg/1.2 mg/1.8 mg daily), but only thereduction seen with the 1.2 mg daily dose wasstatistically significant vs placebo (-0.15%, 95%CI -0.27 to -0.03, p = 0.0164). A statisticallysignificant reduction in weight was observedacross all liraglutide doses, and total dailyinsulin dose was also reduced in the 1.8 and1.2 mg liraglutide groups vs placebo. Of con-cern, rates of symptomatic hypoglycaemia wereincreased in all liraglutide groups vs placebo,and there was a significant increase in hyper-glycaemia with ketosis in those treated with1.8 mg liraglutide daily in addition to insulin.ADJUNCT TWO ran for 26 weeks and recruited835 subjects [51]. Similarly to ADJUNCT ONE,participants were randomised to liraglutide0.6 mg/1.2 mg/1.8 mg daily or placebo in a 3:1manner. In contrast to the aforementionedstudy, changes in insulin dosing were capped. Astatistically significant reduction in HbA1c wasobserved for all liragutide groups vs placebo,coupled with reductions in weight and insulinrequirements. However, rates of symptomatichypoglycaemia were increased in the liraglutide1.2 mg group (21.3 vs. 16.6 events/patient/year;p = 0.03), and rates of hyperglycaemia withketosis ([1.5 mmol/L) were increased in thosetreated with 1.8 m/day of liraglutide (0.5 vs. 0.1events/patient/year in liraglutide and placebogroups, respectively; p = 0.01).

Pancreatitis is a feared consequence of GLP-1RAs in T2DM. Rates of this event have variedamong studies in T2DM patients, but none ofthe studies reviewed for this article reportedpancreatitis as an adverse event. Long-termfollow-up studies will be required to ensuresafety in T1DM.

A summary of the main studies of GLP-1analogues in T1DM is provided in Table 3.

PRAMLINTIDE

Amylin is a polypeptide co-secreted from pan-creatic b-cells [52]. Having first been identifiedin 1987, there has been a great deal of researchinto this hormone and its effects on metabo-lism, particularly in the first decade of thetwenty-first century. Due to autoimmunedestruction of pancreatic beta cells in type 1

1840 Diabetes Ther (2018) 9:1831–1851

Table3

Summaryof

themainfin

dingsof

trialsinvestigatingtheuseof

glucagon-like

peptide-1analoguesin

type

1diabetes

Sarkar

etal.[47]

Trainaet

al.

[48]

Frandsen

etal.

[46]

Dejgaardet

al.

[44]

Methieu

etal.

(ADJU

NCT

ONE)[50]

Ahren

etal.

(ADJU

NCT

TWO)[51]

Dub

eet

al.[45]

Weihaoet

al.

[49]

Year

2014

2014

2015

2016

2016

2016

2018

2017

Studydesign

Crossover

RCT

Retrospective

analysis

Placebo-

controlled

RCT

Placebo-

controlled

RCT

Placebo-

controlled

RCT

Placebo-controlled

RCT

Crossover,p

lacebo-

controlledRCT

System

aticreview

andmeta-

analysis

Agent investigated

Exenatide

Exenatide

Liraglutide

Liraglutide

Liraglutide

Liraglutide

Liraglutide

Liraglutide

and

exenatide

No.

ofparticipants

1311,allof

whom

weretreated

withCSII

40100

1398

835

15206

Durationof

study

12months

(6monthson

exenatide,

6monthsoff)

3months

12weeks

24weeks

52weeks

26weeks

24weeks

foreach

arm

ofcrossover

NA

Changein

HbA

1c-

0.1%

(p=0.39)

-0.6%

(p=0.013)

Nodifference

[-0.2%

(-0.5,

0.1%

),p[

0.1]

Estim

ated

treatm

ent

difference

vsplacebo

1.8mgliraglutide

-0.20%

[95%

CI-

0.32;

-0.07]

1.2mgliraglutide

-0.15%

[95%

CI-

0.27;

-0.03]

0.6mgliraglutide

-0.09%

[95%

CI-

0.21;

0.03]

Estim

ated

treatm

ent

difference

vsplacebo

1.8mgliraglutide

–0.35%

[95%

CI

–0.50;

–0.20],

pB

0.0001

1.2mgliraglutide

–0.23%

[95%

CI

–0.38;

–0.08],

p=0.0021

0.6mgliraglutide

–0.24%

[95%

CI

–0.39;

–0.10],

p=0.0011

-0.09%

(p[

0.1)

-0.21

(-0.40,

0.02),p=0.03

Diabetes Ther (2018) 9:1831–1851 1841

Table3

continued

Sarkar

etal.[47]

Trainaet

al.

[48]

Frandsen

etal.

[46]

Dejgaardet

al.

[44]

Methieu

etal.

(ADJU

NCT

ONE)[50]

Ahren

etal.

(ADJU

NCT

TWO)[51]

Dub

eet

al.[45]

Weihaoet

al.

[49]

Changein

totaldaily

insulin

dose

(units)

Average

of0.54

units/kg/day

±0.13

whilst

incontrol6months

(offexenatide).

Average

of0.47

units/kg/day

whilst

onexenatide.

Statistical

difference

betweengroups

ofp=0.007

-13%

(p=0.011)

Not

reported

-5�8(-

10�7,

-0�8),

p=0�0227

Expressed

asestimated

treatm

ent

ratios

1.8mgliraglutide

0.92

[95%

CI

0.88;0.96]

1.2mgliraglutide

0.95

[95%

CI

0.91;0.99]

0.6mgliraglutide

1.00

[95%

CI

0.96;1.04]

Expressed

asestimated

treatm

entratio

1.8mgliraglutide

0.90

[95%

CI

0.86;0.93],

pB

0.0001

1.2mgliraglutide

0.93

[95%

CI

0.90;0.96],pB

0.0001

0.6mg

liraglutide

0.95

[95%

CI0.92;

0.99],p=0.0075

-6.72

(p[

0.1)

Reduction

inweight-

adjusted

insulin

dose

-0.11

(-0.23,

0.00),p=0.05

Changein

weight(kg

unless

stated

otherwise)

-4.2kg

(p=0.0003)

-3.7%

(p=0.008)

-4.3(-

5.7,

-2.8),p

\0.001)

-6�8(-

12�2,

-1�4),

p=0�0145

1.8mgliraglutide

-4.9kg

[95%

CI-

5.7;

-4.2]

1.2mgliraglutide

-3.6kg

[95%

CI-

4.3;

-2.8]

0.6mgliraglutide

-2.2kg

[95%

CI-

2.9;

-1.5]

1.8mgliraglutide

–5.1kg

1.2mgliraglutide

–4.0kg

0.6mgliraglutide

–2.5kg;

AllpB

0.0.0001

vsplacebo.

-4.83

(p=0.0001)

-3.53

(-4.86,

2.19),p\

0.05

1842 Diabetes Ther (2018) 9:1831–1851

Table3

continued

Sarkar

etal.[47]

Trainaet

al.

[48]

Frandsen

etal.

[46]

Dejgaardet

al.

[44]

Methieu

etal.

(ADJU

NCT

ONE)[50]

Ahren

etal.

(ADJU

NCT

TWO)[51]

Dub

eet

al.[45]

Weihaoet

al.

[49]

Adverse

events

reported

Nonereported

Nonsignificant

increasein

rate

of hypoglycaemia.

Nosignificant

adverseevents

reported

Gastrointestinal

side

effectsin

both

groups

(statistical

difference

between

groups

not

reported)

Five

participants

required

atemporary

dose

reduction

inliraglutide

group,andone

participant

hada

maxim

umtolerateddose

of0.9mg/day

Increase

inheart

rate

foun

din

theliraglutide

group(7.5

BPM

,95%

CI

2.8–

12.2,

p=0.0019)

Increased

numberof

gastrointestinal

upsetsin

liraglutide

group,

but

significancenot

reported

Rates

ofsymptom

atic

hypoglycaemia

increased

acrossall

groups

Significant

increase

inrate

of hyperglycaem

iawithketosisin

the1.8mg

liraglutide

group(event

rate

ratio2.22

[95%

CI1.13;

4.34])

Significantlyhigher

rate

ofsymptom

atic

hypoglycaemia

inthe1.2mg

liraglutide

group

vsplacebo

(estim

ated

rate

ratio1.31

[95%

CI1.03;1.68],

p=0.0289)

Increasedrate

ofhyperglycaem

iawithketosis

([1.5mmol/L)

inthe1.8mg

liraglutide

group

vsplacebo

(estim

ated

rate

ratio3.96

[95%

CI1.49;10.55],

p=0.0059)

93%

ofparticipants

experienced

nausea

atsome

pointin

the

study.Nonehad

todiscontinu

eparticipation,

and

oneparticipant

hadamaxim

umtolerateddose

ofliraglutide

of1.2mgdaily

Concluded

that

combination

therapywith

GLP-1RAand

insulin

didnot

causeincreased

rate

ofhypoglycaemic

events

Com

mentedthat

gastrointestinal

upsetwas

common,b

utmost

participants

couldtolerate

theseeffects

Diabetes Ther (2018) 9:1831–1851 1843

diabetes, those who suffer with the conditionare rendered unable to produce this hormone inaddition to insulin.

The role of amylin in satiety has becomeclearer recently, and it appears to have impor-tant roles in making the individual ‘‘feel full’’,thus controlling meal sizes, which may bepartly related to the control of glucagon secre-tion following food consumption [53, 54]. Inlight of this, the role of amylin as adjuvanttherapy in patients with type 1 diabetes hasbeen explored, particularly in those who areoverweight. An amylin analogue, pramlintide,is approved for use in the treatment of type 1and type 2 diabetes in the United States,although it is not widely used worldwide.

The effect of pramlintide on HbA1c has beenstudied in a number of clinical trials involvingpatients with type 1 diabetes (Table 4). An earlystudy found no significant decrease in HbA1c inthose treated with pramlintide vs placebo, butinsulin doses had been reduced prior to com-mencing therapy, which may have affected theresults [55]. Further studies 26 and 52 weeks induration found reductions in HbA1c withpramlintide vs placebo [56, 57]. A study52 weeks in duration that included 480 patientswith type 1 diabetes showed a significantdecrease of 0.27% in HbA1c upon comparingthe pramlintide group with the placebo group[58]. An open-label extension of this study for aperiod of 1 year confirmed persistent improve-ments in HbA1c with continued use. Of note,the rate of those reaching a target HbA1cof\7% was also increased in the pramlintidegroup.

Due to the pharmacodynamics of pramlin-tide, it could be expected that a reduction inweight would be observed in those using it inconjunction with insulin therapy. Indeed, onestudy found a significant decrease in weightcompared to placebo over a 29-week study per-iod (- 1.3 ± 0.3 kg vs 1.4 ± 0.3 kg;p =\0.0001) [55], with similar results beingseen over a 26-week study period in anotherstudy (- 1.6 kg placebo-adjusted, p\ 0.001)[56]. Further work over a 52-week period con-firmed a decrease in weight with pramlintide[57]. Another study in adolescents (aged 13–17years) found significant decreases in weight over

a 4-week period for pramlintide use vs placebo,indicating that these effects are applicable to awide-ranging population [59]. Overall, there isgood evidence that pramlintide reduces weightin those with type 1 diabetes.

The effects of pramlintide on insulin dosinghave also been extensively evaluated. One studyfound a decrease in total daily insulin dose of12% when pramlintide was used in conjunctionwith insulin therapy for 29 weeks. This wascompared to an increase in 1% in those in theplacebo arm of the study, although the signifi-cance was not reported [55]. A study in adoles-cents reported a significant decrease in totaldaily insulin dose, which was attributed todecreases in mealtime insulin requirements butno change in basal insulin dose [59]. A study52 weeks in duration showed a small increase intotal daily insulin dose in those treated withpramlintide, but this was significantly lowerthan the increase seen in those in the placeboarm of the trial (2.3% vs 10.3%, p = 0.0176 fordifference between groups) [58].

A decrease in postprandial hyperglycaemiahas been hypothesised as a benefit of the use ofpramlintide therapy in type 1 diabetes. Onestudy found a decrease in mealtime insulinrequirements in the pramlintide group of 28%in the first 4 weeks, but this did not alter for therest of the study, and basal insulin requirementswere unchanged [57]. This is likely due to asignificant decrease in postprandial glucose inthe pramlintide group as compared to baseline,which was not observed in the placebo group.Another study, which assessed the effect ofpramlintide in those using closed-loop insulinsystems, found significant blunting of post-meal glucose levels and prolongation of time tomaximum glucose level compared to baselineafter 3–4 weeks of pramlintide use [60]. Fur-thermore, a crossover study involving twelvepatients with type 1 diabetes found a significantreduction in postprandial hyperglycaemia whenpramlintide was used [61]. Other studies haveconfirmed decreases in postprandial glucoselevels [59, 62].

Hypoglycaemia has been evaluated in anumber of studies looking at the adjuvant use ofpramlintide in type 1 diabetes. One study foundno change in overall rates of hypoglycaemia

1844 Diabetes Ther (2018) 9:1831–1851

Table4

Summaryof

themainfin

dingsupon

investigatingtheuseof

pram

lintide

intype

1diabetes

Whiteho

useet

al.[58]

Ratneret

al.[57]

Ratneret

al.[56]

Edelm

anet

al.[55]

Kishiyamaet

al.[59]

Year

2002

2004

2005

2006

2009

Studydesign

Double-blinded,

placebo-controlled

RCT.A

t20

weeks,p

articipantsin

thepram

lintide

groupwere

rand

omized

toeither30

mcg

QDSor

60mcg

QDS.Open-labelfollow-up

for1yearfollowingstudycompletion

Double-blinded,

placebo-

controlledRCT

Pooled

analysisof

subgroupsfrom

threeprevious

RCTsin

those

withHbA

1c7–

8.5%

Double-blinded,

placebo-

controlledRCT

Nonblinded,

placebo-controlled

RCTin

adolescents(aged

13–1

7)

Agent investigated

Pram

lintide

Pram

lintide

Pram

lintide

Pram

lintide

Pram

lintide

No.

ofparticipants

480

651

477

296

10

Durationof

study

52weeks

(and

1year

open-labelfollow-

up)

52weeks

26weeks

29weeks

4weeks

Changein

Hba1c

-0.39%

inpram

lintide

groupvs

-0.12%

instandard

groupat

52weeks

(p=

0.0071

fordifference

betweengroups).Increasedratesof

participantsachievingHbA

1Cgoalof

\7%

inpram

lintide

group

(p=0.01)

At52

weeks,those

who

werenaıveto

itsuseshow

edsimilarreductions

at104weeks

comparedto

theplacebo-

controlledgroup.

Those

who

continuedon

pram

lintide

from

52to

104weeks

show

edcontinued

improvem

entin

HbA

1c

-0.29%

(p=0.011)

for

pram

lintide

60mcg

TDS

-0.34%

(p=0.01)for

pram

lintide

60mcg

QDS

Significant

reductionvs

placeboconfi

rmed

forboth

dosing

regimens

-0.3%

(placebo-

corrected

difference

pB

0.0009

vsbaselin

e)

Nosignificant

difference

betweengroups

Not

stated

Changein

totaldaily

insulin

dose

(units)

2.3%

increase

inpram

lintide

groupand

10.3%

increase

inplacebogroupat

week52

(p=0.0176

fordifference

betweengroups)

-12%

inpram

lintide

group

vs1%

increase

inplacebo

group.

Significancenot

commentedon

-13.1

±10.1

inpram

lintide

groupvs

10.6

±4.1in

placebo

group(p

=0.02)

Changein

weight(in

kgun

less

stated

otherwise)

Significant

reductionin

body

weightin

thepram

lintide

groupvs

placebo

Significant

reductionin

weight

forboth

pram

lintide

groups

(60mcg

TDSandQDS)

vsplacebo

-1.6(placebo-

corrected

difference.

pB

0.0009

vsbaselin

e)

-1.3±

0.3vs

1.4±

0.3

(pB

0.0001)

-0.8±

0.98

vs0.88

±0.81

(p=0.02)

Diabetes Ther (2018) 9:1831–1851 1845

compared to placebo, but noted a significantincrease in the rate of severe hypoglycaemia(event rate/patient year 0.57 ± 0.09 vs0.30 ± 0.06; p\ 0.05) [55]. Further studies havenot shown increased rates of severe hypogly-caemia [56, 58, 59]. Additionally, one studyfound an increased rate of hypoglycaemia whencommencing pramlintide (first 4 weeks ofstudy), but this reduced to a rate comparablewith that in the placebo group after this period[57]. Results are therefore somewhat conflicting,but on balance it would appear that pramlintideis not associated with an increased risk ofhypoglycaemia if insulin dosing is adjustedcarefully (as done routinely in clinical trials)when the patient is started on this medication.

In summary, pramlintide appears to havepositive effects on HbA1c and weight. Effects ontotal daily insulin dosing are less clear-cut, butat worst it does not appear to be inferior toplacebo in this regard. The evidence of areduction in postprandial hyperglycaemia inthis class is strong and, with careful adjustmentof the insulin dosing, it does not appear to beassociated with an increased risk of severehypoglycaemia.

Of note, the majority of patients with type 1diabetes are treated with multiple daily injec-tions of insulin, and the addition of a furtherthree or four subcutaneous injections daily islikely a deterrent for many.

DPP-4 INHIBITORS

The use of DPP-4 inhibitors is now widespreadfor the treatment of type 2 diabetes, with manycontributory factors leading to their popularity.Their neutral effect on weight, ease of oraladministration and good tolerability are someof the factors cited as reasons for high rates ofprescription. However, when investigating theiruse in type 1 diabetes, it is apparent that thereare relatively few well-run randomized con-trolled trials.

A meta-analysis looking at this topic waspublished early in 2018 [63]. Only five trials metthe inclusion criteria, which included a total of253 patients. When one study was excluded dueto a lack of HbA1c data, this glycaemic marker

Table4

continued

Whiteho

useet

al.[58]

Ratneret

al.[57]

Ratneret

al.[56]

Edelm

anet

al.[55]

Kishiyamaet

al.[59]

Adverse

events

reported

Nauseaandanorexiamorethan

twofold

morecommon

inpram

lintide

group,

buteffectsweremild.N

odifference

indropoutrate

betweengroups

Significant

increase

intherate

ofsevere

hypoglycaemiain

thefirst4weeks

ofpram

lintide

use.Following

this,rates

weresimilarin

all

groups

Increasedratesof

nausea,

anorexiaandvomiting,

although

thesewereoften

transientanddidnotaffect

participants’d

ailyactivities

Noincrease

inrisk

ofsevere

hypoglycaemia

reported

Significant

increase

inrate

ofsevere

hypoglycaemiain

pram

lintide

group.

No

difference

intherate

ofnonseverehypoglycaemia

noted

Significantlyincreasedrates

ofnausea,vom

itingand

sinu

sitisin

thepram

lintide

group

One

participantin

thepram

lintide

groupcomplainedof

nausea,

which

resolved

onalteration

ofdose,and

thepram

lintide

was

subsequentlytitrated

upagain

1846 Diabetes Ther (2018) 9:1831–1851

showed a nonsignificant reduction of - 0.07%(95% CI: -0.37% to 0.23%).

One study looked at the effects of sitagliptinon postprandial glucose levels in those withtype 1 diabetes treated with a closed-loop sys-tem. In this small study, the authors found astatistically significant decrease in postprandialglucose when sitagliptin was added, and theycommented that insulin delivery was lower inthe sitagliptin group [64]. No adverse eventswere reported by the authors, and there was nosignificant difference in the rate of hypogly-caemia between groups.

Despite the lack of convincing effects ofthese agents on HbA1c in type 1 diabetes, therehas been an interest in preserving b-cell func-tion using these agents [65, 66]. Although earlyresults are promising, no firm conclusions canbe drawn, and this remains an area for futureresearch.

CONCLUSION AND FUTUREPERSPECTIVES

A number of studies have explored the use ofadjuvant therapy in patients with T1DM, butthese have been generally small, of short dura-tion and have been primarily focussed on gly-caemia, measured as the change in HbA1c.There is more to glycaemia than HbA1c, and theroles of adjuvant therapy in hypoglycaemia,glucose excursion following meals and gly-caemic variability are yet to be fully investi-gated. Also, more attention should be given tonon-glycaemia risk factors such as weight, waistcircumference, blood pressure and insulinresistance markers. In contrast to T2DM studies,there is a lack of hard clinical outcome trialswith different therapies in T1DM due to diffi-culties encountered with the funding of suchwork, given the relatively small number ofpatients with T1DM and the commercial via-bility of using adjuvant therapies in thosepatients.

Studies so far suggest that adding metforminto insulin therapy in T1DM temporarily lowersHbA1c and decreases weight and insulinrequirements, but these effects are not sus-tained. The side-effect profile is favourable and

the risks associated with this therapy are small.Therefore, metformin can be added to insulintherapy in these patients, but only short-termuse is justified given current data. It remains tobe seen whether intermittent treatment withmetformin is superior to long-term use, whichwould require carefully designed studies con-ducted over 3–5 years.

There has been a flurry of research studiesinvestigating SGLT2 inhibitors in T1DM, andthese agents appear to show the most promisein correcting hyperglycaemia. Just as for met-formin, studies investigating the effects ofSGLT2 inhibitors on glycaemic measures otherthan HbA1c are generally lacking. Weight andBP reductions with SGLT2 inhibitors are addi-tional favourable effects that may prove toreduce vascular complications and appropriateoutcome studies are needed. In contrast tometformin, however, there are some safetyconcerns primarily related to the precipitationof DKA, although the incidence of this compli-cation appears to vary with the agent applied.GLP-1 agonists may seem like credible partnersto insulin, but studies in T1DM failed to showsizeable effects of them on glycaemia, althoughtheir role in reducing weight is unquestionable.There are concerns, based on two large multi-centre RCTs, that there may be increased ratesof symptomatic hypoglycaemia and hypergly-caemia with ketosis in those taking liraglutidewith type 1 diabetes, and further investigationinto this is required. Conclusions on the use ofDPP-4 inhibitors in type 1 diabetes are difficultto draw as there have been few high-qualityclinical trials examining this topic. Pramlintidehas certainly shown positive effects on gly-caemic control and weight, and does not appearto have a significant risk profile. The addition ofmultiple further injections per day may be abarrier to its use by many patients with type 1diabetes, however.

One criticism of adjuvant treatment studiesin T1DM is the assumption that T1DM patientsare a homogeneous group of individuals whopresent similar responses to such therapies. It islikely that adjuvant therapies will work best in aparticular subset of patients, so future studiesshould perhaps have a more focussed approachand concentrate on higher-risk groups. For

Diabetes Ther (2018) 9:1831–1851 1847

example, overweight T1DM patients are knownto have a higher risk of complications, so futureadjuvant studies are needed to investigate thisgroup of individuals. Also, studies investigatingvascular surrogate markers in the higher-riskgroup would be of interest and would help todecide whether longer-term outcome studiesusing adjuvant therapies in T1DM arewarranted.

It is clear that the treatment of T1DM isevolving, and restricting therapy to insulinreplacement alone is an approach that is toosimplistic. Future longer-term adjuvant studieson appropriate subgroups of T1DM patients andinvestigations of various glycaemic parameters,surrogate vascular markers and even harderclinical outcomes will help to refine ourunderstanding of the role of such therapies ininsulin-deficient states.

ACKNOWLEDGEMENTS

Funding. No funding or sponsorship wasreceived for the publication of this article. Thearticle processing charge was funded by theauthors.

Authorship. All authors meet the Interna-tional Committee of Medical Journal Editors(ICMJE) criteria for authorship of this article,take responsibility for the integrity of the workas a whole, and have given their permission forthis version to be published.

Disclosures. Harriet Warnes and RebeccaHelliwell have no disclosure to declare. SamMatthew Pearson has received fees for speakingat events organised by Novo Nordisk. Ramzi A.Ajjan has received research grants, honorariaand provided educational support and consul-tancy for Abbott Diabetes Care, AstraZeneca,Bayer, Boehringer Ingelheim, Bristol-MyersSquibb, Eli Lilly, GlaxoSmithKline, Merck Sharp& Dohme, Novo Nordisk, Roche and Tadeka.

Compliance with Ethics Guidelines. Thearticle is based on previously conducted studiesand does not contain any studies with human

participants or animals performed by any of theauthors.

Data Availability. Data sharing is notapplicable to this article, as no datasets weregenerated or analysed during the current study.

Open Access. This article is distributedunder the terms of the Creative CommonsAttribution-NonCommercial 4.0 InternationalLicense (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommer-cial use, distribution, and reproduction in anymedium, provided you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons license, andindicate if changes were made.

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