diabetes research and clinical practice 159 (2020) 107772

Contents available at ScienceDirect

Diabetes Research
and Clinical Practice
journal homepage: www.elsevier.com/locat e/dia bre s

From pump to sink: The hydraulic connection of

Never like today, the pharmacological armamentarium cardiorenal efficacy of these newer diabetes drugs. The fur-
against type 2 diabetes mellitus (T2DM) is so extensive. There ther refinement [9] of an initially suggestion [10] has led to
are at least eleven different classes of drugs clinicians may the concept of the hydraulic connection in T2DM. To be hon-
use to fight the metabolic abnormalities of T2DM, namely est, there would have been no hydraulic connection without
metformin, sulfonylureas, glinides, alpha-glucosidase inhibi- CVOTs. The connection put together the four elements that
tors, thiazolidinediones, dipeptidyl-peptidase 4 inhibitors full represents an hydraulic system: the pump, the pipes,
(DPP-4i), glucagon-like peptide-1 receptor agonists (GLP- the filter, and the sink. For analogy, these elements translate
1RA), colesevelam, sodium–glucose cotransporter-2 inhibitors in the corresponding elements of the diabetic patient, namely
(SGLT-2i), the big insulin family, bromocriptine, as well as all the heart (pump), the blood vessels (pipes), the kidney (filter)
their oral or injectable combinations. Despite this, overall gly- and the whole body (sink).
cemic control has not improved in recent years [1], which MACE don’t fit all cardiovascular risk
may cast some doubt about the utility of so many newer anti- MACE (major cardiovascular events, including nonfatal
hyperglycemic drugs. Although hyperglycemia is a hallmark myocardial infarction, nonfatal stroke and cardiovascular
of the diabetic state, the results of large interventional trials death) was the primary endpoint of all CVOTs. Although
in T2DM demonstrated that the risk of both macrovascular the classic MACE endpoint captures most of the cardiovascu-
and microvascular complications remains still high or very lar morbidity/mortality burden of T2DM, it does not include
high after intensive and successful glycemic control; this hospitalization for heart failure (HF), or diabetic kidney dis-
remaining risk has been called residual vascular risk [2]. ease (DKD). And yet, HF is a prominent early manifestation
Accordingly, the paradigm of diabetes treatment has been of cardiovascular disease (CVD) in T2DM, often occurs before
shifting from the mere control of hyperglycemia (the mythical a myocardial infarction event [11], and has a 5-year survival
hemoglobin A1c value less than 7%) to a more useful compro- rate of only 12%. On the other hand, DKD still represents
mise between the need of maintaining glucose levels within the main factor accounting for the substantial global increase
acceptable targets (to avoid metabolic decompensation) [3] in end stage kidney disease (ESKD) [12]. Cardioprotection in
and reducing the unacceptable burden of cardiovascular and HF and nephroprotection in DKD therefore remain major
renal (cardiorenal) complications of T2DM. unmet needs in T2DM. However, both hospitalization for HF
Beyond glycemic control and the occurrence of renal events were at best secondary
The origin of this compromise can be found in the many outcomes in most CVOTs. Despite these shortcomings, which
pleiotropic effects some newer antihyperglycemic drugs, are being addressed by specific trials in both diabetic and
namely DPP-4i, GLP-1RA, and SGLT-2i, have demonstrated in nondiabetic people with reduced or preserved ejection frac-
the last decade; this has opened the way to the slogan ‘‘be- tion (EMPEROR-Reduced, NCT03057977; EMPEROR-Preserved,
yond glycemic control” to celebrate the possibility to delay NCT03057951), or have already been addressed for DKD pro-
the apparently ineluctable progression of cardiorenal compli- gression in diabetic patients [13], CVOTs shed some light on
cations of T2DM. The starting point of this new era was the the clinical relevance of CVD versus HF and DKD in patients
guidance issued in 2008 by the U.S. Food and Drug Adminis- with T2DM.
tration to pharmaceutical sponsors requiring proof of cardio- The new therapeutic paradigm
vascular safety as a prerequisite for the approval of new Table 1 summarizes the evidence so far accumulated
glucose-lowering drugs [4]. Cardiovascular outcome trials about the effects of DPP-4i, GLP-1RA and SGLT-2i on the car-
(CVOTs) started soon after and the first two trials were pub- diorenal and metabolic risk in T2DM. The pump and the filter
lished about 5 years later [5,6]. Luckily, these newer antihyper- seem to represent the best targets for the protective effects of
glycemic drugs have not only demonstrated their the SGLT-2i family, at least for those so far investigated
cardiovascular safety in T2DM, but some have also showed (empagliflozin, canagliflozin and dapagliflozin); in fact, they
evidence for superiority against placebo on some cardiovas- may offer cardiorenal protection by reducing hospitalization
cular endpoints [1]. Nowadays, with 14 large-scale CVOTs for HF, progression of DKD, and incidence of MACE. The esti-
already published and more than 130 000 patients evaluated mates for HF hospitalization begin to separate within weeks
[2,7,8], it is possible to drawn some conclusion about the and are maintained thereafter until the end of the trial; so,
2 diabetes research and clinical practice 159 (2020) 107772

Table 1 – Effects of newer diabetic drugs on the hydraulic connection in type 2 diabetes.
The Pump (heart failure)
 SGLT-2i reduce the risk of hospitalization for HF
 There is a class effect for SGLT-2i, as it is significant for each drug of the class
 The SGLT-2i effect is evident regardless of a history of HF or established CVD
 The SGLT-2i effect is independent of the reduction of HbA1c levels
The Pipe (major cardiovascular events)
 Both GLP-1RA and SGLT-2i reduce the risk of MACE
 There is no class effect, because it is not significant for each drug of both classes
 The effect is mainly evident in T2DM patients with established CVD
 The effect is partly dependent on the reduction of HbA1c levels
The Filter (diabetic kidney disease)
 DPP-4i, GLP-1RA and SGLT-2i reduce UACR
 SGLT-2i only reduce the progression of DKD
 There is a class effect for SGLT-2i
 The effect of SGLT-2i is independent of the reduction of HbA1c levels
The Sink (hemodynamic and metabolic effects on the body)
 Heart: reduce pre-load and after-load and increase EF (SGLT-2i); increase cardiac output (GLP-1RA); increase substrates
(ketones, FFA) to the heart (SGLT-2i)
 Vessels: reduce blood pressure and vascular inflammation (SGLT-2i and GLP-1RA); reduce volume load (SGLT-2i); increase
hematocrit (SGLT-2i)
 Renal: increase glycosuria (SGTL-2i), natriuresis and diuresis (SGLT-2i and GLP-1RA), and uricosuria (SGLT-2i)
 Metabolic: reduce body weight (SGLT-2i and GLP-1RAs), food intake and gastric emptying (GLP-1RA); increase negative
caloric balance (SGLT-2i)
HF, heart failure; MACE, major cardiovascular events; UACR, urine albumin-to-creatinine ratio; DKD, diabetic kidney disease; EF, ejection
fraction; FFA, free fatty acids.

it is highly likely that the mechanisms responsible for the Declaration of Competing Interest
reduction in HF events are beyond glucose lowering; in fact,
the outstanding 31% reduction of HF hospitalization is com- No compensation was received for writing the manuscript.
pletely independent of amelioration of HbA1c levels [2]. Dr. Giugliano has been an advisory board member and/or
GLP-1RA may work as well, primarily by lessening the risk has received Speaker’s fee with Eli Lilly, Boehringer Ingel-
of MACE, depending on the particular drug of the class: at heim, Novo Nordisk, Novartis, Mundipharma, Sanofi.
the present, a significant reduction of MACE has been Dr. Esposito has been an advisory board member and/or
reported for liraglutide, semaglutide, albiglutide [2] and has received Speaker’s fee with Eli Lilly, Boehringer Ingel-
dulaglutide [7]. Finally, the great number of pleiotropic effects heim, Novo Nordisk, Novartis, Mundipharma, Sanofi.
may have contributed to the cardiorenal benefits of SGLT-2i Dr. Ceriello: Advisory Board membership: Abbott, Astra
and GLP-1RA. Interestingly enough, observational studies Zeneca, Boehringer Ingelheim, DOC Generici, Eli Lilly, Jans-
from large retrospective data that have assessed a broad pop- sen, Mundipharma, Novo Nordisk, OM Pharma. Lectures:
ulation of T2DM patients yielded results consistent with Astra Zeneca, Berlin Chemie, Boehringer Ingelheim, Eli Lilly,
those obtained in CVOTs [14], providing support for their car- Mundipharma, Novo Nordisk, Roche Diagnostics. Research
diorenal benefits. Grants: Astra Zeneca, Eli Lilly, Mitsubishi, Novartis.
A time for precision medicine
The evidence produced by CVOTs seems to go in the direc-
R E F E R E N C E S
tion of precision medicine, in order to address ‘‘non-glucose
centric” unmet needs in T2DM patients who require ameliora-
tion of both their glycemic control and their poor cardiorenal
outlook. Clinicians may dream for the ideal drug that simulta- [1] Lipska KJ, Yao X, Herrin J, et al. Trends in drug utilization,
glycemic control, and rates of severe hypoglycemia, 2006–
neously obtains glycemic targets and prevents the onset or
2013. Diab Care 2017;40(4):468–75.
slows the progression of HF, MACE and DKD. Within this con- [2] Giugliano D, Meier JJ, Esposito K. Heart failure and type 2
text, the cardiorenal benefits exerted by SGLT-2i and some diabetes: from cardiovascular outcome trials, with hope. Diab
GLP-1RA are outcomes that patients ultimately value, includ- Obes Metab 2019;21(15):1081–7.
ing clinical microvascular disease (ESKD and need for dialysis), [3] Home P. Controversies for glucose control targets in type 2
and macrovascular disease (myocardial infarction, heart fail- diabetes: Exposing the common ground. Diab Care 2019.
https://doi.org/10.2337/dci19-0002. pii: dci190002.
ure, and ultimately death) [15]. Depending on many factors,
[4] Food and Drug Administration, Guidance for Industry:
including but not limited to availability, price, contraindica-
Diabetes Mellitus—Evaluating Cardiovascular Risk in New
tions, tolerability and side effects, many T2DM patients may Antidiabetic Therapies to Treat Type 2 Diabetes (Food and
miss the therapeutic opportunity associated with the use of Drug Administration, Silver Spring, Maryland, 2008). Available
SGLT-2i and/or GLP-1RA. However, those who don’t miss this at: www.fda.gov/downloads/Drugs/Guidances/ucm071627.pdf
opportunity may enjoy their cardiorenal benefits [16,17]. [accessed Jine 21, 2019].
 diabetes research and clinical practice 159 (2020) 107772 3

[5] Scirica BM, Bhatt DL, Braunwald E, SAVOR-TIMI 53 Steering and atherosclerotic cardiovascular disease: a report of the
Committee and Investigators, et al. Saxagliptin and American College of Cardiology Task Force on Expert
cardiovascular outcomes in patients with type 2 diabetes Consensus Decision Pathways. J Am Coll Cardiol 2018;72
mellitus. N Engl J Med 2013;369(14):1317–26. (24):3200–23.
[6] White WB, Cannon CP, Heller SR, EXAMINE Investigators, et al. [15] Rodriguez-Gutierrez R, McCoy RG. Measuring what matters in
Alogliptin after acute coronary syndrome in patients with type diabetes. JAMA 2019;321(19):1865–6.
2 diabetes. N Engl J Med 2013;369(14):1327–35. [16] American Diabetes Association. 9. Pharmacologic
[7] Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan approaches to glycemic treatment: Standards of Medical Care
M, Pais P, REWIND Investigators, et al. Dulaglutide and in Diabetes–2019. Diab Care 2019;42(Suppl 1):S90–S102.
cardiovascular outcomes in type 2 diabetes (REWIND): a [17] Giugliano D, Maiorino MI, Longo M, Esposito K. Are gliflozins
double-blind, randomised placebo-controlled trial. Lancet the new statins for diabetes?. Diab Res Clin Pract
2019. https://doi.org/10.1016/S0140-6736(19)31149-3. 2019;153:191–3.
[8] Husain M, Birkenfeld AL, Donsmark M, Dungan K,
Eliaschewitz FG, Franco DR, et al. Bain SC; for the PIONEER 6 Dario Giugliano a,*
Investigators. Oral semaglutide and cardiovascular outcomes
Katherine Esposito b
in patients with type 2 diabetes. N Engl J Med 2019. https://doi.
org/10.1056/NEJMoa1901118.
Antonio Ceriello c
a
[9] Giugliano D, De Nicola L, Maiorino MI, Bellastella G, Esposito K. Division of Endocrinology and Metabolic Disease,
Type 2 diabetes and the kidney: insights from cardiovascular Department of Advanced Medical and Surgical Sciences,
outcome trials. Diabetes Obes Metab 2019. https://doi.org/ Università della Campania L. Vanvitelli, Naples, Italy
10.1111/dom.13743. b
Diabetes Unit, Department of Advanced Medical and Surgical
[10] Verma S, Juni P, Mazer CD. Pump, pipes, and filter: do SGLT2 Sciences, Università della Campania L. Vanvitelli, Naples,
inhibitors cover it all? Lancet 2019;393(10166):3–5.
Italy
[11] Shah AD, Langenberg C, Rapsomaniki E, et al. Type 2 diabetes c
and incidence of cardiovascular disease: a cohort study of 1.9 Department of Cardiovascular and Metabolic Diseases, IRCCS
million people. Lancet Diab Endocrinol 2015;3(2):105–13. MultiMedica, Milan, Italy
[12] 8 USRDS annual data report. End-stage Renal Disease (ESRD) * Corresponding author at: Division of Endocrinology and
in the United States. Available at https://www.usrds.org/adr. Metabolic Diseases, University Hospital L. Vanvitelli,
aspx [accessed June 21, 9]. Piazza L. Miraglia, 2, 80138 Naples, Italy.
[13] Perkovic V, Jardine MJ, Neal B, for the CREDENCE Trial
E-mail address: [email protected] (D. Giugliano)
Investigators, et al. Canagliflozin and renal outcomes in type
2 diabetes and nephropathy. N Engl J Med 2019. https://doi.
org/10.1056/NEJMoa1811744. Available online 28 June 2019
[14] Das SR, Everett BM, Birtcher KK, et al. 2018 ACC Expert
consensus decision pathway on novel therapies for
cardiovascular risk reduction in patients with type 2 diabetes