PharmacologicalResearch160(2020)105052

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Blood pressure control in type 2 diabetes mellitus with arterial hypertension. The
important ancillary role of SGLT2-inhibitors and GLP1-receptor agonists
C. Berraa,*,1, R. Manfrinib,1, D. Regazzolic, M.G. Radaellia, O. Disoteod, C. Sommesee,
P. Fiorinaf,g,h, G. Ambrosioi, F. Follib,f,j
a
DEPARTMENT of Endocrine AND METABOLIC DISEASES, IRCCS MULTIMEDICA, Sesto SAN GIOVANNI, MILAN, ITALY
b
DEPARTMENTAL Unit of DIABETES AND METABOLIC DISEASE, ASST SANTI PAOLO e CARLO, MILAN, ITALY
c
DEPARTMENT of CARDIOVASCULAR DISEASE, HUMANITAS RESEARCH HOSPITAL, ROZZANO, MILAN, ITALY
d
Endocrinology AND DIABETOLOGY Service, ASST GRANDE OSPEDALE METROPOLITANO NIGUARDA, MILAN, ITALY
e
IRCCS MULTIMEDICA, Sesto SAN GIOVANNI, MILAN, ITALY
f
University of MILANO, MILAN, ITALY
g
TID INTERNATIONAL Center, Invernizzi RESEARCH Center, MILAN, ITALY
h
Endocrinology AND DIABETOLOGY Unit, ASST FATEBENEFRATELLI-SACCO, Luigi SACCO HOSPITAL, MILAN, ITALY
i
University of PERUGIA School of Medicine, PERUGIA, ITALY
j
Endocrinology AND METABOLISM, DEPARTMENT of HEALTH Science University of MILANO, ITALY

ARTICLEINFO
ABSTRACT
Keywords:
Diabetes and hypertension Type 2 diabetes mellitus and arterial hypertension are major cardiovascular risks factors which shares metabolic and
GLP1-Receptor agonists haemodynamic abnormalities as well as pathophysiological mechanisms. The simultaneous presence of diabetes and
SGLT2-Inhibitors Metabolic arterial hypertension increases the risk of left ventricular hypertrophy, congestive heart failure, and stroke, as compared
Syndrome Insulin resistence to either condition alone. A number of guidelines recommend lifestyle measures such as salt restriction, weight
reduction and ideal body weight mainteinance, regular physical activity and smoking ces- sation, together with
moderation of alcohol consumption and high intake of vegetables and fruits, as the basis for reduction of blood pressure
and prevention of CV diseases. Despite the availability of multiple drugs effective for hypertension, BP targets are
reached in only 50 % of patients, with even fewer individuals with T2DM-achieving goals. It is established that new
emerging classes of type 2 diabetes mellitus treatment, SGLT2 inhibitors and GLP1-receptor agonists, are efficacious
on glucose control, and safe in reducing HbA1c significantly, without increasing hypoglycemic episodes. Furthermore,
in recent years, many CVOT trials have demonstrated, using GLP1-RA or SGLT2-inihibitors compared to placebo (in
combination with the usual diabetes medications) im- portant benefits on reducing MACE (cardio-cerebral vascular
events) in the diabetic population. In this hy- pothesis-driven review, we have examined the anti-hypertensive effects of
these novel molecules of the two different classes, in the diabetic population, and suggest that they could have an
interesting ancillary role in controlling blood pressure in type 2 diabetic patients.

1. Introduction
abnormalities and pathophysiological mechanisms, including insulin
Type 2 diabetes mellitus (T2DM) is a major risk factor for cardio- resistance and hyperinsulinemia, with renin-angiotensin-aldosterone system
vascular diseases (CVD), and arterial hypertension–another major car- (RAS) hyperactivation [2–8]. In animal models it has been shown that
diovascular risk factor- is extremely common in T2DM patients [1]. hyperinsulinemia enhances sodium reabsorption in the distal nephron [9].
Hypertension and T2DM share both metabolic and haemodinamic Overactivation of RAS is a major player in the onset and maintenance of
hypertension, which may also be involved in the

ABBREVIATIONS: ACE-I, angiotensin-converting enzyme inhibitors; BP, blood pressure; CCB, calcium-channel blockers; CVD, cardiovascular disease; DBP, diastolic blood
pressure; DPPIV-i, dipeptidyl peptidase IV-inhibitors; EASD, European Association for the Study of Diabetes; ESC, European Society of Cardiology; GLP-1, glucagon-like
peptide-1; GLP1-RA, glucagon-like peptide-1 receptor agonist; ARBS, angiotensin receptor blockers; RAS, renin-angiotensin-aldosterone system; RCT, randomized controlled trial;
SBP, systolic blood pressure; SGLT2-i, sodium-glucose co-transport inhibitors; SNS, sympathetic system; T2DM, type-2 diabetes mellitus
⁎
Corresponding author at: Department of Endocrine and Metabolic Diseases, IRCCS MultiMedica, Via Milanese 300, Sesto San Giovanni, 20099 Milan, Italy.
E-MAIL ADDRESS: [email protected] (C. Berra).
1
Equal first authors.

https://doi.org/10.1016/j.phrs.2020.105052
Received 24 January 2020; Received in revised form 9 June 2020; Accepted 25 June 2020
Availableonline08July2020
1043-6618/©2020ElsevierLtd.Allrightsreserved.
 C. BERRA, et PHArmAcologicAlRese

Table
Best proven nonpharmacologic interventions for prevention and treatment of hypertension.

Lifestyle change Quantity effect on SBP

Aerobic exercise 90−150 min/week −5/8 mmHg

Dynamic resistance 90−150 min/week −4 mmHg
Isometric resistance 24 min/week −5 mmHg
Healthy diet high vegetables, fruits, whole grains, low fat −11 mmHg
Weight loss For every Kg reduction (target to ideal body weight) −5 mmHg
Reduced intake of sodium < 1.5 g per day or > 1 g reduction −6 mmHg
Enhanced intake of potassium 3−5 g per day −4 mmHg
Alcohol reduction < 2 (male) or < 1 (female) drink per day −4 mmHg

development of insulin resistance and T2DM [10–13]. Hyper- insulinemia

and aldosterone also enhance sodium retention by the kidney, leading to less evidence regarding the most effective first line antihypertensive approach
expansion of plasma volume and increased blood pressure (BP), abnormalities in hypertensive without overt nephropathy or micro- albuminuria [55,56].
in vascular remodelling and endothelial dysfunction [14–16]. Autonomic Interestingly new antidiabetic drugs are known to have antihypertensive
neuropathy might also be involved in dysregulation of BP in T2DM, since effect, and their use may represent a new op- portunity to optimize current
autonomic neuropathy is associated with a reduction/ loss of blood nocturnal hypertension management in patients with T2DM. In this review we
pressure dipping, higher heart rate, and greater BP variability compared to summarize the evidence on this specific topic. Regarding this a PubMed
non-diabetic subjects [17–21]. In T2DM patients, arterial hypertension is search was performed using the fol- lowing keywords: “Diabetes” and
twice more frequent than in the general population, its prevalence increasing “Hypertension”, “Hypertension” and “Sodium-Glucose Transporter 2
as a function of age and duration of diabetes, further increasing mortality and inhibitors”, "Hypertension" and "In- cretins/Glucagon Like Peptide 1
cardio- vascular morbidity [22–29]. The simultaneous presence of diabetes receptor", "Cardiovascular disease" and "Diabetes". We focused on relevant
and hypertension increase the risk of left ventricular hypertrophy, con- gestive RCTs, CVOTs and on good quality size pooled analysis and meta-analysis.
heart failure, and stroke, compared to either condition alone [30–32], BP
control is essential in the management of patients with diabetes at risk of, or
with overt heart failure [33]. Besides T2DM, hypertension usually coexists 2. Current antihypertensive medical therapy in diabetes mellitus
with other metabolic alterations, such as central obesity, dyslipidemia, and – when and how to start?
hyperuricemia, I.E. the metabolic syndrome [34]. The high incidence of
microvascular complications, A number of guidelines of recommend lifestyle changes such as salt
especially retinopathy and nephropathy, in patients with diabetes and restriction, weight reduction, regular physical activity and smoking
hypertension also contributes to worse prognosis and quality of life [35,36]. cessation, together with reduced alcohol consumption and high intake of
Several trials support the notion that managing hypertension in diabetes is vegetables and fruits, as the basis for reduction of BP [57] (Table 1). In
critical to reduce cardiovascular risk, as well as micro- vascular outcomes case that lifestyle modifications are insufficient to control BP, available
[37–39]. As an example, 5.6 mm Hg reduction of systolic blood pressure gudelines suggest initiation of antihypertensive treatment (in diabetic
(SBP) in T2DM could reduce cardiovascular deaths by 18 % [40]. Clinical patients) when office BP is ≥140/90 or ≥130/80 mmHg, according to the
and observational studies in diabetic patients clearly demonstrated that last ESC and AHA guidelines, respectively [51,52,58]. Early combination
achievement of BP values < 140/90 mmHg reduced cardiovascular events therapy, if compared to monotherapy, is more ef- fective in lowering BP,
and microvascular complications [41–48]. A meta-analysis of 73,913 patients even when low-dose combination therapy is compared to maximal dose
with T2DM demonstrated that achieving a SBP < 130 mmHg reduced stroke monotherapy [59]. It is important to em- phasize RAS inhibition as part of
by 39 % [49]. BP lowering had a favorable impact on retinopathy and the treatment strategy for many pa- tient groups, e.g. diabetes, left
albuminuria in a large systematic review and meta- analysis of 100.354 ventricular hypertrophy or proteinuria. Indeed, two-drug combination
T2DM patients should be preferred at first in diabetes, and inclusion of a RAS inhibitor
[50] also consistent with reduction of end-stage renal disease [43,45]. The has been shown to reduce albuminuria and progression to overt
ESC ESH Hypertension Guidelines clarify the benefits of BP re- duction nephropathy [46,60,61]. On the other hand, an excess of renal adverse
in diabetes to reduce macrovascular and microvascular com- plications. events occur when ACE-I, ARB or renin-in- hibitors are used
Initiation of antihypertensive therapy in diabetic patients is recommended simultaneously, thus discouraging the use of double blockage [62–65].
when the office BP is > 140/90, with two drug combi- nation (ACE Beta-blockers represent alternatives when there is a specific indication,
inhibitor or ARB with a CCB or thiazide/thiazide-like diuretic) [51]. The (angina, post-myocardial infarction, heart failure, heart rate control), or in
2019 ESC-EASD guidelines on diabetes, pre-diabetes and cardiovascular young women with, or planning, pregnancy, even though glycemic control
disease, suggest to individualize BP target: SBP to 130 mmHg and, if well could worsen, especially when in asso-
tolerated, lower than 130 mmHg but not than 120 mm Hg; in older people ciation with thiazides [66]. When the optimal dosage is achieved,
(> 65 years) target SBP should range between130−139 mmHg; diastolic switching to single-pill approach including multiple drugs improves
blood pressure (DBP) to < 80 mm Hg but not < 70 mm Hg. On compliance and BP control. In patients with T2DM and micro-
treatment SBP < 130 mmHg should be considered for patients at high albuminuria enrolled in the Steno-2 study [67], stepwise implementa- tion
risk of cerebrovascular events or diabetic kidney disease [52]. Caution of life style changes and pharmacological therapy targeting hy-
must be used in pursuing excessively low BP targets in older and in perglycemia, hypertension, dyslipidemia, and microalbuminuria, reduced
diabetic or non-diabetic subjects because there is evidence of an increase the risk of CVD and microvascular events by 50 %. Polypills comprising
in cardiovascular risk particularly for pressure values lower than 110/75 fixed-dose combination of one or more antihypertensive agents, statin and
mmHg [53,54]. Lifestyle changes are recommended (reduction of sodium low-dose aspirin have also emerged [68]. Secondary prevention studies
intake < 100 mmol/day; diets rich in vegetables and low-fat dairy have shown that the use of the polypill results in optimization of
products, exercise prescription) [52]. While there are strong adherence to treatment compared with separate medi- cations [69], so that
recommendations for the treatment of hypertension in non-diabetics and the ESC Guidelines for the management of myo- cardial infarction suggest
diabetics with nephropathy, there is that use of the polypill may be considered [70].

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Table 2
Blood pressure control and cardiorenal effects of SGLT2i vs placebo. Data from the main CVOTs.

Ɨ 3-point MACE: death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke. References ([98]; [99]; [100]; [101]; [121]).
*At the dose 10 mg/daily.
**At the dose 25 mg/ daily.

3. BP target in T2DM
of phlorizin led to the comprehension of relevant aspects of renal physiology
A number of randomized controlled trials evaluated different BP- and has allowed the identification of specific sodium-glu- cose co-transporters
lowering protocols in T2DM subjects [71]. In the ADVANCE trial, re- 1 and 2 (SGLT1 and SGLT2) [89]. SGLT1 is located primarily in the small
duction of SBP to less than 135 mmHg, compared with maintaing SPB intestine and, to a lesser degree, in the segment 3 of the proximal convolute
around 140 mmHg, was associated with a significant reduction in CVD tubule where it contributes to the re- absorption of 10 % of the glucose
and all-cause mortality in hypertensive T2DM patients [39], which was filtered. Physiologically the largest amount of the glucose reabsorption is at
later confirmed by large meta-analyses [40,72]. The overall benefit of the level of SGTL2 co-trans- porter located at proximal convolute tubule in
lowering BP in patients with T2DM disappears when SBP is lowered to < correspondence of the segment 1−2. Here 90 % of the filtered glucose is
130/80 mmHg [40,46] because there was an increment on stroke. Stroke transported against concentration gradient using sodium ATPase-dependent
incidence reduction were also reported in post hoc analysis on T2DM sodium/po- tassium pump [90,91]. The SGLT2-i inhibit the function of
patients in the ONTARGET study [73]. Reanalysis of the AC- CORD [47] SGLT2 at renal tubule level causing an increase of the renal glucose excretion
trial, focusing on BP-lowering effects, showed that intensive SBP and a reduction of circulating glucose levels [92,93]. The SGLT2-i de-
lowering to < 130 mmHg reduced overall incidence in CV events [74]. termine a dose-dependent glycosuria with a maximum excretion of glucose in
On the other hand, reducing SBP lower than 120 mmHg was as- sociated the urine that does not exceed 30–50 % of the filtered load corresponding to a
with increased risk of major CV events consistent with the J- glycosuria of about 70−80 g/day. Various hy- pothesis have been put forward
phenomenon. With regard to DBP, earlier evidence from HOT [75] and to explain this phenomenon: 1) a complete inhibition of SGLT2 increases the
UKPDS [76] trials suggested a benefit on major cardiovascular events amount of glucose re- absorbed by SGLT1 reducing glycosuria to about 50
when it was lowered to less than 85 mmHg; and the ADVANCE trial [39], % of filtered glu-
showed benefit on CVD outcomes at DBP of 75 mmHg, thus suggesting cose; 2) the increase levels of glucose in the proximal tubule, as a result of
that it is both safe and effective to lower it to < 80 mmHg in SGLT2 inhibition, could compete with the drug and thus prevent the full
T2DM patients. Thus, the first objective should be to lower BP to < inhibition of SGLT2; 3) it is possible that due to the high affinity of
140/80 mmHg, aiming at a SBP of 130 mmHg; if well tolerated, a target SGLT2-i for plasma proteins, the effective concentrations of the drug are
< 130 mmHg should be also considered in patients < 65 years old insufficient to achieve complete inhibition of SGLT2 co-transporters
because of the benefits on stroke prevention [51,52]. [94,95]. The effectiveness and safety of SGLT2-i have been evaluated in
large studies which showed a positive effect on glycometabolic control
4. Sodium-glucose co-transport inhibitors (SGLT2-i) and on other cardiovascular risk factors [96–100]. Canagliflozin, da-
pagliflozin and empagliflozin compared with placebo reduce glycated
In recent years novel classes of drugs have been developed to treat hemoglobin and fasting glucose (range reduction -0.6–0.9 % and 1.1–1.9
diabetes. These therapies reduce both hyperglycaemia and comorbid- ities of mmol/l respectively) [97]. Likewise it has been shown that SGLT2-i
diabetes, including hypertension [77–81]. A significant anti- hypertensive reduce body weight compared to placebo, increase, albeit modestly, the
effect is played by the SGLT2-i, a pharmacological class that cause glycosuria level of HDL cholesterol compared with placebo and decrease the excess
by blocking glucose reabsorption in the renal tubule [82–86]. Physiologically, of epicardial adipose tissue, considered a risk factor for coronary artery
the kidneys filter about 180 g of glu- cose over 24 h which are completely disease [102,103]. Those pleiotropic effects beyond glycemia control may
reabsorbed at the proximal con- voluted tubules by an active transport process drive to a meaningful reduction of cardiorenal complications in subjects
[87]. The possibility to induce pharmacologically glycosuria has been known with T2DM [99,105–110] (Table 2). Data from a number of clinical trials
since 1835, when French chemist isolated phlorizin, a glycoside able of also demonstrate that SGLT2 inhibition
inducing renal glucose loss and blocking intestinal glucose absorption [88]. resulted in reduced risk of hypoglycaemia except when used in com- bination
The study with insulin or insulin secretagogues [111,112,84]. In subjects

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which may experience hypotension (e.g. those with renal insufficiency,

reduced SBP, and in the elderly) therapy with SGLT2-i could increase changes, HbA1c and SBP values [118]. Concerning the effect on BP, it was
osmotic diuresis resulting in a possible drop in blood pressure due to demonstrated that the percentage of patients showing a lowering in SBP were
volume depletion [113]. However data on risk of volume depletion and higher in canagliflozin 100 and 300 mg daily (64 %, 67 % vs 50 % in the
related symptoms in subjects with or without diuretic therapy are placebo group). About 58 % of the placebo-subtracted lowering in SBP with
conflicting [98,104,116,121]. Recently the SGLT2-i dapaglifozin was canagliflozin were not dependent from weight loss, with 42 % being weight-
studied in a phase-3, placebo controlled trial on subjects with NYHA class loss-associated. The authors suggested that the mechanisms of weight-
II, III or IV heart failure and maximum ejection fraction of 40 % in independent-lowering BP are not com- pletely explainable, but they could
addition to recommended therapy with or without T2DM. A 30 % re- partially depend both on osmotic diuresis and on the sodium reabsorption
duction of worsening heart failure and a 18 % reduction of death from modifications induced by the therapy [118]. If osmotic diuresis was the main
cardiovascular causes independently of the coexistence of diabetes was mechanism, one would have expected a lesser reduction in BP in subjects
demonstrated [114]. Several studies have consistently shown the anti- with kidney im- pairment. However in subjects with stage 3 chronic kidney
hypertensive efficacy of all glycosuric drugs currently employed in disease, canagliflozin caused less weight loss and HbA1c reduction, but
clinical practice [76–80,92,95–103,105]. similar SBP decrease.
A large placebo-controlled study evaluated results from two trials
4.1. CANAGLIFLOZIN (CANVAS and CANVAS-R) with 10.142 partecipants affected by T2DM and
high cardiovascular risk (CANVAS Program). Subjects in CANVAS received
A placebo-controlled study assessed the efficacy of canagliflozin on BP randomly canagliflozin in a 1:1:1 ratio at a dose of 300 mg, at a dose of 100
control in 169 T2DM hypertensive subjects [115]. Patients received mg, or placebo. Subjects in CANVAS-R received ca- nagliflozin in a 1:1
canagliflozin at doses of 100 mg and 300 mg, or placebo for 6 weeks and ratio, at the starting dose of 100 mg daily with a possible increase to 300 mg
underwent 24 -h ambulatory BP evaluation before randomization, on day 1 of starting from week 13, or placebo. The follow up was 188.2 weeks. At the end
therapy, and after 6 weeks. As a primary outcome, the variation in mean 24 -h of the study there was a mean decrease both in SBP and DBP: - 3.93 mm Hg
SBP monitoring vs baseline to end of follow up time was considered. (95 % CI, –4.30 to –3.56) and –1.39 mm Hg (95 % CI, –1.61 to –1.17)
Canagliflozin 300 mg and 100 mg determined higher reductions in mean 24 - respectively (P < 0.001 for
h SBP vs placebo at week 6 (–4.9 mmHg, 95 % CI –8.4 to –1.5, and –3.3 all comparisons) [98].
mmHg, 95 % CI –6.7 to 0.2, P = 0.006
and P = 0.062, respectively) [115]. Volume depletion occurred in two 4.2. DAPAGLIFLOZIN
patients (3.6 %) taking the canagliflozin 300 mg. Osmotic diuresis also
occurred in 5 subjects (8.9 %) taking canagliflozin 300 mg, in 2 subjects An analysis of the data from the RCTs with dapagliflozin 10 mg/day
(3.5 %) taking canagliflozin 100 mg and in 3 subjects (5.4 %) taking included 4.655 hypertensive and non-hypertensive patients (non-hy-
placebo. Orthostatic hypotension defined as appearance of clinical pertensive subjects with SBP ≤ 140 mmHg and hypertensive subjects
manifestations on standing (e.g. dizziness, light headedness) or low- ering with SBP > 140 mmHg). At the end of the follow up a SBP reduction
in SBP and DBP respectively ≥20 mmHg and ≥15 mmHg after 2 min of was demonstrated in hypertensive and non-hypertensive patients of
standing, appeared in 7.1 %, 3.8 %, and 3.9 % subjects taking –3.6 mmHg (95 % CI –4.9 to –2,4) and –2.6 mmHg (95 % CI from –3.4 to –
canagliflozin 300 mg, 100 mg, and placebo respectively [115]. Four phase 1.8) respectively. Concerning DBP, a decrease has been observed in
3 placebo-controlled studies in 2.313 subjects with T2DM as- sessed the hypertensive and in non-hypertensive patients of –1.2 mmHg (95 % CI
efficacy of canagliflozin on BP levels. At doses of 100 mg and 300 mg –2 to –0.4) and of –1.2 mmHg (95 % CI –1.8 to –0.7) respectively [119]. In a
canagliflozin showed reductions in SBP vs placebo (–4.3 mm Hg, 95 % subgroup analysis of a larger systematic review the BP effects of
CI –5.0 to – 3.5, – 5.0 mm Hg 95 % CI –5.8 to –4.2, and –0.3 dapagliflozin compared to placebo was assessed and reductions in SBP and
mm Hg 95 % CI –1.2 to 0.5, respectively) and in DBP (– 2.5 mm Hg, 95 DBP from baseline of –3.2 mmHg (95 % CI –4.20 to –2.21) and
% CI –2.9 to – 2.0, – 2.4 mm Hg, 95 % CI –2.9 to - 1.9, and –0.6 mm Hg –1.74 mmHg (95 % CI –2.35 to –1.13), were observed [96]. A double- blind,
[95 % CI –1.1 to–0.02], respectively) [116]. Canagliflozin at both do- sages of placebo-controlled study evaluated the efficacy of dapagliflozin at the dose of
100 mg and 300 mg caused an increase of osmotic diuresis (e.g. augmented 10 mg vs placebo in 449 T2DM subjects and inadequately controlled
urine volume and augmented urine frequency) compared to placebo (6.7 %, hypertension (SBP > 140 mmHg and DBP > 85 mmHg at baseline) [120].
5.6 %, and 0.8 %). The incidence of adverse events related to intravascular The end-points were variations from baseline to week 12 in seated SBP and
volume reduction (e.g. orthostatic hypotension and postural dizziness) showed glycated hemoglobin. Patients assigned to da- pagliflozin 10 mg had
a similar lowering across all groups (1.2 significantly greater reductions in mean SBP to week 12 versus placebo: –
%, 1.3 %, and 1.1 %) [116]. Another study based on the pooled results 11.90 mmHg (95 % CI –13.97 to –9.82) vs
from four 26-week RCTs in 2.313 T2DM patients evaluated the effect of –7.62 mm Hg (–9.72 to –5.51), respectively [120]. A large randomized,
canagliflozin 300 and 100 mg on arterial elasticity parameters such as placebo-controlled study with dapagliflozin at the dose of 10 mg on
pulse pressure, mean arterial pressure, and double product (the last one 17.160 T2DM subjects and established atheromatous CVD or multiple risk
calculated by multiplying the SBP by the pulse rate and considered an factors for atherosclerotic cardiovascular complications showed a reduction vs
index of myocardial oxygen consumption) in T2DM subjects. As com- placebo of –2.7 mm Hg (95 % CI, 2.4–3.0) and –0.7 mmHg (95 % CI, 0.6 to
pared with placebo canagliflozin 100 mg and 300 mg showed a re- 0.9) in SBP and DBP respectively [121]. In the DAPA- HF clinical trial
duction in pulse pressure (−1.8 and −2.6 respectively vs 0.2 mmHg), mean including diabetic and non-diabetic patients dapagli- fozin lead to a reduction
arterial pressure (−3.1 and −3.3 respectively vs −0.5 mmHg), and double of SBP of -1.92 + 14.92 vs -0.38 + 15.27 mmHg in the placebo group (p =
product (−381 and −416 respectively vs −30 bpm × mmHg). The authors 0.002) regardless of the presence or absence of diabetes [114].
suggested that the ameliorations in these cardio- vascular parameters are
compatible with the assumption that SGLT2-i may contribute to positive 4.3. EMPAGLIFLOZIN
effects in more than one cardiovascular outcome in diabetic patient [117].
In another study the pooled results from 2.250 T2DM subjects included in A study evaluated for 12 weeks the effects versus placebo of em-
four phase 3 RCTs were eval- uated. Each study evaluated canagliflozin at pagliflozin 10 mg or 25 mg once daily specifically in 825 hypertensive T2DM
the two doses of 100 and 300 mg daily vs placebo as monotherapy, plus patients [122]. The study was randomized, placebo-controlled and double-
metformin, plus met- formin and sulfonylurea, or plus metformin and blind. At enrollement, mean seated office values were 130–159 mmHg
pioglitazone. The end- points between baseline and week 26 in each study and80–99 mmHg for the SBP and DBP respectively. At
were body weight

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 C. BERRA, et PHArmAcologicAlRese

the end of the follow up, the mean difference from baseline in 24-h SBP
ambulatory monitoring resulted −3.44 mmHg (95 % CI − 4.78 to analysis of controlled and randomized studies specifically analysed the
−2.09) and −4.16 mmHg (95 % CI − 5.50 to −2.83) with 10 mg and 25 efficacy of ertugliflozin in 1.544 patients with T2DM receiving daily
mg empagliflozin respectively (both P < 0.001). Similar results were ertugliflozin 5 mg or 15 mg or placebo. In subjects with baseline SBP >
obtained in DBP measurements: −1.36 mmHg (95 % CI − 2.15 to 130 to < 140 mmHg receiving ertugliflozin at the dose of 5 mg and 15
−0.56) and −1.72 mmHg (95 % CI − 2.51 to −0.93) with 10 mg and 25 mg mg a significant SBP reduction was observed (-3,9 mmHg and
empagliflozin respectively (both P < 0.001). The authors re- ported no -4,6 mmHg respectively). A more pronounced hypotensive effect was
significant changes in empagliflozin treated patients as compared to placebo observed in subjects with poorer pressure control at baseline, SBP > 140
for either serum sodium or hematocrit values. The empagliflozin group mm Hg, (-4,3 mmHg and -5,1 mmHg at the dose of 5 mg and 15 mg).
showed a greater proportion of patients with or- thostatic hypotension Also for the DBP it was observed a significant reduction at both
(defined as a decrease ≥20 mmHg or ≥10 mmHg in SBP and DBP between ertugliflozin dosages considered vs placebo (-1,9 mmHg and -1,7 mmHg
supine and standing measurements) than controls. Finally, the change in BP respectively) [128].
observed throughout the duration of the study did not determine changes in
pulse rate [122]. Another study investigated the long-term effects of 4.5. SOTAGLIFOZIN
empagliflozin at the dose of 10 mg, 25 mg, or placebo at week 76 for several
parameters including BP in 637 subjects with T2DM [120]. At the end of A multicenter randomized, placebo-controlled and double-blind study on
follow up, patients on empagliflozin showed a reduction of SBP of –4.4 1.402 subjects with type 1 diabetes in insulin therapy with pump or injections
mmHg (95 evaluated the effect of sotagliflozin 400 mg daily or placebo. In subjects
% CI –6.6 to –2.3) and –3.7 mmHg (95 % CI –5.9 to –1.5) with em- having a SBP of 130 mm Hg or higher at baseline, the pressure values
pagliflozin 10 mg and empagliflozin 25 mg respectively (both P < significantly decreased to week 16 in the sotagli- flozin group vs placebo
0.001) [123]. In 2.477 T2DM-hypertensive patients treated with group (−3.5 mm Hg; P = 0.002). Also the DBP values showed a significant
empagliflozin 10 mg/day and 25 mg/day, a subsequent analysis of pooled data reduction in the sotagliflozin group (-1,3 mm Hg; p < 0.001) [129]. A
of four phase III studies demonstrated that at the end of 24 weeks follow up, recent meta-analysis which included
there were reductions vs placebo of SBP and DBP of 3.238 type 1 diabetic patients older than 18 showed that sotagliflozin
–3.6 mmHg (95 % CI –4.5 to –2.7, P < 0.001) and –1.3 mmHg (95 % CI therapy reduced both SBP and DBP vs placebo (−3.85 mmHg and
–1.9 to –0.8, P < 0.001) respectively [124]. Another study analysed the −1.43 mmHg, both P < 0.001). These reduction in BP did not result in an
impact of empagliflozin 10 mg e 25 mg on BP control in 417 dippers and increased risk of orthostatic hypotension in SGLT2-i treated patients
350 non-dippers hypertensive subjects affected by T2DM [125]. In [130].
dippers, the mean variations in 24 -h SBP monitoring at week 12 were
−0.2 mmHg in the placebo group vs −3.8 mmHg and −3.9 mmHg in the 5. Systematic review and meta-analysis
empagliflozin 10 and 25 mg groups, respectively (both P < 0.001 vs
placebo). In non-dippers patients, the mean variations from baseline in 24 -h In the latest review and meta-analysis including 43 studies (N =
SBP monitoring at week 12 were 1.0 mmHg in the placebo group vs −1.6 22.528) the effect of SGLT2-i on BP among T2DM patients were eval-
mmHg in the empagliflozin 10 mg group (P = 0.013 vs pla- cebo) and −3.8 uated [131]. The SGLT2-i studied (dapagliflozin in 22 trials, canagli-
mmHg in the empagliflozin 25 mg group (P < 0.001 vs placebo). The authors flozin in 14 trials, empagliflozin in 4 trials, remogliflozin in 2 trials, and
speculated that empagliflozin could have ame- liorated mechanisms ipragliflozin in 1 trial) were compared with: placebo, metformin, si-
associated in the development and progression of autonomic dysregulation tagliptin, pioglitazone, glimepiride and glipizide. The pooled estimate of
[125]. In the CVOT EMPA-REG OUTCOME, including 7.020 T2DM the effect on SBP and DBP levels was –2.46 mmHg (95 % CI, –2.86 to
receiving empagliflozin 10 mg or 25 mg, a de- crease in SBP and DBP was –2.06) and–1.46 mmHg (95 % CI, –1.82 to –1.09 respectively. The
noted, but not statistically quantified [99]. In a more recent double-blind study authors conclude that SGLT2-i has a positive effect on BP as mono-
a specific population of non-obese T2DM older patients (mean age 70 years) therapy or add on teraphy with other drugs [131]. Other two large review
with uncontrolled nocturnal hypertension receiving antihypertensive therapy and meta-analysis including 33 and 27 studies respectively (N = 17.600
including angiotensin receptor blockers was treated with empagliflozin 10 mg and N = 12.690) showed results consistent with the largest- latest meta-
daily or pla- cebo to week 12 [126]. Patients underwent BP measurements at analysis [96,132].
base- line and weeks 4, 8, and 12 while 24 -h ambulatory BP monitoring was
performed at the start of the study and week 12. Overall 68 subjects received 6. BP reduction with SGLT2-i. Proposed mechanisms
empagliflozin and 63 placebo. Final data showed a meaning decrease to week
12 in nightime SBP values with empagliflozin (–6.3 mmHg; P = 0.004) but Several studies have shown that the reduction of BP is a class effect of
not with placebo (–2.0 mmHg; P = 0.367) [126]. SGLT2-i, since they induce an appreciable decrease in SBP and a lower decrease
in DBP as compared to other glucose-lowering drugs [126]. Several mechanisms
4.4. Ertuglifozin have been proposed to explain BP reduction with SGLT2-i. A significant role is
probably played by a haemodynamic me- chanism, since a reduction in plasma
In a multicentre, double blind study on T2DM patients inadequately volume of about 7% has been re- ported after 8 weeks of dapagliflozin therapy
controlled with metformin monotherapy, BP values has been evaluated at 23 [119]. Plasma volume re- duction is due to the diuretic and natriuretic effect
week after therapy with ertugliflozin at the dosage of 5 and 15 mg or placebo. induced by the inhibition of sodium reabsorption in the renal proximal convolute
At the end of follow up both the 5 mg and the 15 mg do- sages determined a tubule and also to osmotic diuresis [133,134]. Furthermore, unlike other causes
significant reduction vs placebo in SBP values (-4,4 mmHg, and -5,2 mmHg, of plasma volume loss, this remains constant over time [113]. Interest- ingly,
p = 0002 and p < 0001 respectively). Also for the DBP a similar result was despite the diuretic and natriuretic effect, therapy with SGLT2-i does not trigger
observed for ertugliflozin both with the dosage of 5 mg and with the 15 mg vs tachycardia. This suggests a possible interaction of these drugs with the
placebo (-1,6 mmHg, p = 0013 and -2,2 mmHg, p = 0001 respectively) sympathetic system (SNS). A sympathomodulatory effects of SGLT2-i has been
[127]. A recent post-hoc demonstrated in-vitro and in-vivo studies, thus providing evidence for a possible
cross-talk between the SNS and SGLT2 regulation that may not only account
for alterations of glucose

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metabolism in SNS (e.g. sympathetic system activity upregulated due to

hyperglicemia) but may potentially contribute to cardiovascular and renal 7. Glucagon-like peptide-1 receptor agonists (GLP1-RA)
protection by these molecules [135–137]. Intriguingly, the natriuretic effect
could be also one of the mechanisms to explain the reduction in In T2DM, incretin-based therapies are quite widely employed. This class
hospitalization for heart failure demonstrated by the controlled and of drugs improve postprandial glucose levels in a glucose-depen- dent manner
randomized studies in T2DM subjects treated with SGLT2-i [138]. by stimulating insulin secretion and suppressing glucagon secretion [145].
Moreover, the SGLT2-i cause a weight loss of approximately 2–3 K g over There are also improvements in insulin sensitivity and beneficial effects on
a 3-month period [96]. This weight loss is due both to calorie loss and lipid profile, BP and body weight [146]. Glucagon- like peptide-1 (GLP-1)
osmotic mediated diuresis. A meta-analysis of 25 RCTs (N = 4.874) showed and gastric inhibitory polypeptide (GIP) are two incretin hormones secreted
a relationship between weight loss and reduction in BP [139]. The average from the intestine (intestinal K and L cells, respectively) after glucose or other
weight reduction of −5.1 kg (with diet, increased physical activity, or the food ingestion. These hormones contribute to glucose homeostasis by
combined intervention) was associated with significant reduction both in improving insulin secretory re- sponses (known as incretin effect),
SBP and DBP: −4.44 mm Hg (95 % CI, −5.93 to suppressing glucagon secretion and delaying gastric emptying [145]. Effects
−2.95) and −3.57 mm Hg (95 % CI, −4.88 to −2.25) respectively. When of GLP1-RA on BP, mainly SBP have emerged from RCT and meta-analysis,
expressed per kilogram of weight loss, SBP and DBP lowered which were designed to study the impact of this class of molecules on
−1.05 mm Hg (95 % CI, −1.43 to −0.66) and −0.92 mm Hg (95 % CI, metabolic and glucose control. These studies demonstrated important benefits
−1.28 to −0.55), respectively [139]. Inhibition of SGLT2 can also reduce on SBP reduc- tion which appeared to be continuous in long term studies,
oxidative stress, improve endothelial dysfunction and arterial stiffness and with an additive antihypertensive effect in combination with antihypertensive
preserve the circadian pattern of arterial pressure [115,116,140–142]. All monotherapy and polytherapy [147]. In a large cohort of healthy and young
these factors can contribute to improve vascular capacitance thus improving adults, the levels of incretins seem to correlate positively with
SBP and DBP. Finally, a recent study dis- covered that the SGLT2-induced SBP and DBP, but this relationship appears to be reduced when insulin
mild ketogenesis, especially with pro- duction of betahydroxybutyrate, may resistance is considered. This may suggest that GLP-1-regulated path- ways
contribute to the control of BP [143]. In fact, in a murine model it has been mediate the relationship between insulin resistance and BP [148,149]. Several
demonstrated the effects of the ketone β-hydroxybutyrate on BP reduction clinical studies, both RCT and RWE, have in- vestigated the effect of GLP1-
[144]. The authors hy- pothesized both haemodynamic and metabolic RA on BP and other cardiovascular risk factors. In Table 3 are summarized
multifactorial mechanism to explain the hypotensive action of SGLT2-i BP and cardiorenal effects of GLP1- RA in the principal CVOT.
[143].

Table 3
Blood pressure control and cardiorenal effects of GLP1-RA vs placebo. Data from the main CVOTs.

ND = no data; Ɨ 3-point MACE: death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke; Ɨ Ɨ 4-point MACE: death from
cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina; Ɨ Ɨ Ɨ not significant on the basis of the
hierarchical testing plan; Ɨ Ɨ Ɨ Ɨ composite of death from cardiovascular causes or hospital admission for heart failure; * at the dose 1.5 mg once-
weekly subcutaneous; * * at the dose 1.0 mg once-weekly subcutaneous. References ([159]; [163]; [171]; [175]; [180]).

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7.1. EXENTATIDE AND EXENATIDE LAR

7.3. LIRAGLUTIDE
Exenatide is the synthetic version of Exendin-4, a peptide initially
discovered in the saliva of the Gila monster, with an omology with the native Liraglutide is derived from human GLP-1 [7–37] by substituting arginine
GLP1 of 53 % [150,151]. Exenatide LAR Exenatide ER is the long-acting for lysine at position 34, adding a palmitic acid chain with a glutamic acid
formulation of exanatide that contain the active ingredient of the original spacer on the lysine residue at position 26 to improve the pharmacokinetic
molecule formulation encapsulated in 0.06-mm-diameter microspheres of effects and to allow a once daily subcutaneous ad- ministration [164,165].
medical-grade poly-(D,L-lactide-co-glycolide) (PLG); allowing a weekly Wijkman et al. in a double-blind placebo-con- trolled trial on 124 insulin-
administration [152]. In T2DM patients, one of the first evidence of the effect treated patients evaluated the effect of lir- aglutide 1.8 mg daily vs placebo to
on BP by GLP-1-RA was found when adding exenatide treatment to insulin understand baseline variables predicting SBP reduction. They found in the
therapy, with reduction of 9.2 mmHg from baseline, independently of weight liraglutide patiens a re- duction in SBP of -5.69 mmHg (CI -9.11 to -2.26)
loss [153]. A short double-blind placebo-controlled trial aimed at evaluating with a correlation with BMI reduction, higher baseline of DBP and by lower
the effect of exenatide bid on ambulatory BP monitoring after 12 weeks baseline mean CGM [166]. The most studied GLP1-RA with regard to BP
showed only a statistically non-significant trend in decreasing mean 24 -hs, effects is Liraglutide, and a recent large meta-analysis from Zhao et al. of 18
daytime and also nightime SBP, without significant changes in DBP [154]. randomized trials (RCTs) on 7.616 individual in liraglutide group, a mean
Reduction both in SBP and DBP (-3.5 and -3.3 mmHg respectively) were SBP reduction of 3.18 mmHg (95 % CI -4.32 to -2.05) was ob- served; no
observed in T2DM patients exenatide-treated in a follow up > 3 years [155]. significant effect on DBP, except treatment with high dosage liraglutide (3.0
T. Okerson evaluated the effects of exenatide (fixed dose 10 ug sub- mg/day) [167]. This meta-analysis included the LEAD 1–5 registration study.
cutaneously) on BP on pooled data comprising 2.171 subjects from six In the LEAD-6 trial, a 26-week open-label, par- allel-group, multinational
rendomized, placebo or insulin-controlled trials lasting 24–52 weeks. study, inadequately controlled T2DM pa-
After 6 months of treatment with exenatide significant reduction of SBP tients were randomly assigned to receive additional treatment with liraglutide
vs placebo (-2.8 (0.75) mm Hg) and vs insulin treated patients (-3.7 (0.85) 1.8 mg once a day (n = 233) or exenatide 10 microg twice a day; a SBP
mmHg) were observed, with a weak correlation with weight loss [156]. reduction of 2.51 mmHg was observed in the liraglutide arm and 2 mmHg in
Wang et al. analysed 16 RCTs which enrolled 3.443 diabetic patients in the exenatide group, while DBP decreased 1.05 in the liraglutide arm and 1.98
therapy with GLP1-RA and 2.417 subjects in therapy with other drugs in the exenatide one, respectively [168]. In real-life setting, liraglutide caused
used to treat T2DM (control group); the authors compared the effect of a relevant reduction in SBP and DBP after 18 months of treatment (-3.9
liraglutide ed exenatide on BP changes vs other common therapies used to mmHg and -1.9 mmHg, respectively) [169], and after 36 months of treatment
treat T2DM and found that the most important effect on SBP reduction is (-10.41 mmHg and -3.69 mmHg, respectively) [170]. In the LEADER trial, (a
observed in patients who are in highest BP cate- gories [157]. Treatment double-blind, pla- cebo-controlled) on 9.340 T2DM subjects with high
with GLP1-RA exenatide reduced SBP and DBP by 1–5 mmHg compared cardiovascular risk factors, 4.668 treated with liraglutide obtained a mean
with some other anti-diabetic drugs including insulin, glimepiride and SBP reduction of
placebo; in particular exenatide reduced SBP when compared with both 1.2 mmHg (CI 1.9 to 0.5) and DPB of 0.6 mmHg (CI 0.2–1.0) after 3.5 years
placebo and insulin, with mean difference of [171].
-5.24 and -3.46 mmHg respectively (95 % CI of -6.88 to -3.59 and -3.63 to -
3.29 p < 0.00001, respectively); also DPB was reduced in the ex- enatide- 7.4. DULAGLUTIDE
treated group compared to placebo and sitagliptin [157]. In the DURATION
registration study (DURATION 1–6) the use of exenatide once-weekly was Dulaglutide consists of two modified human GLP-1 analogue se- quence
associated with an improvement of cardiovascular risk markers. An analysis linked to an Fc fragment of human IgG4. These engineering features result in
of data pooled from eight studies including registration study on exenatide a prolonged half-life which makes it suitable for once- weekly dosing [172].
once weekly on 1.830 subjects found a lowering of SBP of -3.3 mmHg (CI - The effects of dulaglutide on BP was also ex- tensively studied. Ferdinand et
3.9; -2.6) and of DBP -0.8 mmHg (CI al. in a randomized double-blind, pla- cebo-controlled 26 week trial analysed
-1.2; -0.4) [158]. Other data on efficacy of once-weekly exenatide on BP were the effects of dulaglutide on BP and heart rate in diabetic patients using
presented in the Exenatide Study of Cardiovascular Event Low- ering ambulatory blood pressure monitoring (ABPM). The authors demonstrated
(EXSCEL) [159]. This was a pragmatic, randomized, double-blind, placebo- that 1.5 mg weekly dulaglutide reduced significantly the SBP (−2.8 mmHg;
controlled, event-driven study with primary outcomes as the first occurrence 95 % CI:−4.6,
of death from cardiovascular causes, nonfatal myo- cardical infarction, or −1.0; p ≤ 0.001) as compared to placebo, in T2DM patients with also three or
nonfatal stroke (MACE). On 7.356 subjects treated with exenatide once- fewer medications for hypertension. The lowering in SBP was evident already
weekly for a median of 2.4 years SBP was statistically lower than in control after four weeks, when dulaglutide concentration reach the steady state [173].
group of -1.57 mmHg (CI -1.91; -1.21 p < 0.001). In the DURATION 8 Recently, also Ludvik B et al. in a randomized, phase 3b, double-blind,
study, the add-on treatment with ex- enatide LAR and dapaglifozin reduced parallel-arm, placebo-controlled superiority study demonstrated that 1.5 mg
mean SBP after 52 weeks -4.5 mmHg, while exenatide LAR alone -0.7 weekly dulaglutide as an add-on treatment to SGLT2-i resulted not only in
mmHg, and dapaglifozin alone superior glycaemic control and weight loss but also in a SBP reduction vs
-2.7 mmHg [160]. placebo group (change
–4,5 mmHg (SE 0.97) vs -1.4 mmHg (SE 0.97) p = 0.021), but no
7.2. LIXESENATIDE differences in DBP [174]. The reduction in SBP was consistent with that
reported in previous dulaglutide studies. Dulaglutide led to an addi- tional
Lixisenatide is derived from the sequence of the peptide exendin-4 decrease of SBP, beyond that observed in the placebo group, suggesting an
omitting a proline at position 38 and adding six lysine residues at the C- additive effect of the combination regimen. The same results were reported in
terminus; athough its half-life is only 3 h, its increased binding affinity the DURATION 8 study, the add-on treatment with exenatide LAR and
allows it to be administrated once daily [161]. Lixisenatide attenuated the dapaglifozin reduced mean SBP after 52 weeks
decrease in postprandial SBP both in healthy subjects and in T2DM -4.5 mmHg, while exenatide LAR alone -0.7 mmHg, and dapaglifozin alone -
patients [162]. In the “ELIXA” study, designed for evaluate the effect of 2.7 mmHg [160]. In the REWIND multicenter, double-blind, placebo-
the GLP1 after a recent acute coronary syndrome (randomized double- controlled trial on 4.949 type 2 diabetes patients treated with
blind, placebo-controlled trial on 3034 subject treated), a lowering in SBP 1.5 mg weekly dulaglutide versus placebo during a median follow-up of
of -0.8 mm Hg (CI -1.3 to -0.3 p = 0.001) was reported [163]. 5.4 years the reduction of SBP 1.7 mmHg (CI 2.07−1.33 p < 0.001)
[175].

7
 C. BERRA, et PHArmAcologicAlRese

7.5. SEMAGLUTIDE
heterogeneity in mechanisms of action among the various anti- hypertensive
Semaglutide is chemically similar (94 % structural homology) to classes (diuretics, calcium channel antagonists, RAS-in- terfering agent, beta-
human glucagon-like peptide-1 (GLP-1), differences being two amino blockers, vasodilators), it could be interesting to implement better strategies
acid substitutions at positions 8 and 34 that result in a reduced de- of add-on treatment depending on the en- hancement of the efficacy or the
gradation by dipeptidyl peptidase-4 (DPP-4); in addition lysine at po- reduction of eventual side effects (i.e beta-blockers associated with GLP1-
sition 26 is acylated with a spacer and C-18 fatty di-acid chain, this RA, due to their positive chrono- tropic effects, or reducing diuretic treatment
increases the drug binding to blood protein (albumin) and reduces renal by employing SGLT2-i; both categories may enhance the efficacy or RAAS).
clearance. These chemical modifications allow once-weekly adminis- The reduction in SBP, a major cardiovascular risk factor, is of much relevance
tration [176,177]. Efficacy of semaglutide one-weekly was evaluated in since drugs such as GLP-1 receptor agonist or SGLT2-i have been shown to
meta-analysis based on phase III RCTs in T2DM patients compared with reduce cardiovascular risk in cardiovascular outcome studies in asso- ciation
other therapies (anti-diabetic) or placebo. Nine studies were evaluated with several nonglycemic effects on the endothelium and kidney [199,200].
(manly from the SUSTAIN registration studies) on 5.774 patients in Although in most studies BP reductions induced by SGLT2-i and GLP1-RA
semaglutide. On these subjects SBP showed a significant reduction (-2.55 were modest, these effects are part of a series of extra- glycemic and
mmHg, 95 % CI:-3.22 to -1.88 p < 0.001) but not the same on DBP extrapancreatic effects positively impacting on cardio- vascular protection
[178]. The SUSTAIN 9 double-blind, parallel-group trial evaluated the observed in cardiovascular outomes trial (e.g. na- triuretic and osmotic effect,
adding of once-weekly semaglutide on type 2 diabetic patients treated weigth loss, reduction RAS activity, amelioration endothelial function,
with SGLT2-i (as monotheraphy, or with metfromin or sulpho- nylurea). reduction inflammation, reduction
On 151 subjects treated on week 30 as well as positive effi- cacy on kidney failure, visceral and pericardial fat lowering, reduction ur- icaemia)
HbA1c and body weight a reduction in mean SBP of 6.32 [92–100,142]. In this synergy of pleiotropic effects it is pos- sible that
mmHg (CI: -9.12 to -3.52) vs placebo group was observed (p < 0.0001) even a modest reduction in BP may play an ancillary im- portant role in
[179]. In the randomized, double-blind, placebo-controlled, parallel- cardiovascular risk protection. The 2019 ESC guidelines on diabetes, pre-
group SUSTAIN-6 trial, among patients receiving semaglutide, as diabetes and cardiovascular disease developed in col- laboration with the
compared with the placebo group, the mean SBP was 1.3 mm Hg lower in EASD recommend to consider the effect of GLP1-RA and SGLT2-i on BP
the group receiving 0.5 mg (P = 0.10) and 2.6 mm Hg lower in the group [52]. Further randomized clinical trials need to be conducted to unravel
receiving 1.0 mg (P < 0.001) [180]. the full spectrum of these effects, particularly on BP and overall
cardiovascular risk and mortality in patients with hy- pertension and
8. Blood pressure reduction with GLP1-RA. Proposed diabetes and/or prediabetes.
mechanisms
Declaration of Competing Interest
Almost all studies with different GLP1 showed beneficial effects on SBP
regardless of the duration of action (short-vs long-acting prepara- tion) also if
Dr. C. C. Berra participated to scientifc boards sponsored by: Eli Lilly,
most data are derived from studies designed to evaluate effect of glycemic
Astra Zenica, Novo Nordisk, Boehringer, Mundipharma, Sanofi, conducted
effects or event driven on MACE. Hypertension is a known independent risk
clinical studies sponsored by: Eli Lilly, Novo Nordisk, Sofar and gave
factor for premature death in T2DM, so it is an important features of the
lectures at national conferences sponsored by: Boehringer, Eli Lilly, Sanofi,
extra-glycemic effect of the class. The effect on SBP reduction seems to be
Novo Nordisk. We thank Federica Berra for kindly creating the graphical
continuous and durable in long term studies. The physiological mechanisms
abstract.
by which GLP1 and GLP1-RA may affect BP remain uncertain. Several
mechanisms mediating BP- lowering effects have been proposed: vascular
Acknowledgements
pathways, myocardial remodelling pathways, renal and central nervous
system pathways have been suggested from animal studies. In particular, in
This work has been supported by The Italian Ministry of Health- Ricerca
rodents seem to be involved central and peripheral nervous system pathways
Corrente. To IRCCS Multimedica - Franco Folli is supported by the Italian
and vaso- pressin release could be involved [181–186]. GLP-1 may affect BP
Ministry of Health - Ricerca Finalizzata.
with a diuretic, and natriuretic effect, acting also on the kidney [187,188].
Weight loss is known to lead to BP lowering [189,190], but the impact of
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