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Is the Popularity of Dipeptidyl-Peptidase-4 Inhibitors Justified? Insights From Mechanistic Studies and Clinical Trials

  • Milton Packer
    Correspondence
    Requests for reprints should be addressed to Milton Packer, MD, Baylor Heart and Vascular Institute, Baylor University Medical Center, 621 N. Hall Street, Dallas TX 75226.
    Affiliations
    Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, Texas
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Published:January 04, 2018DOI:https://doi.org/10.1016/j.amjmed.2017.11.055
      Because of their ease of use and patient acceptability, dipeptidyl peptidase-4 (DPP-4) inhibitors are commonly prescribed to lower blood glucose in type 2 diabetes, typically, together with metformin.
      • Nauck M.A.
      • Meier J.J.
      • Cavender M.A.
      • Abd El Aziz M.
      • Drucker D.J.
      Cardiovascular actions and clinical outcomes with glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors.
      DPP-4 inhibitors do not require parenteral administration, and unlike other incretin-based agents, they have few gastrointestinal adverse effects. When compared with older antidiabetic drugs, DPP-4 inhibitors do not cause weight gain and are unlikely to trigger episodes of hypoglycemia.
      • Nauck M.A.
      • Meier J.J.
      • Cavender M.A.
      • Abd El Aziz M.
      • Drucker D.J.
      Cardiovascular actions and clinical outcomes with glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors.
      In contrast to sodium-glucose transporter 2 (SGLT2) inhibitors, they do not lead to genitourinary infections. Collectively, these features contribute to the popularity of DPP-4 inhibitors in the management of diabetes.
      Yet, aside from the symptomatic benefits of controlling blood glucose, antidiabetic drugs should prevent macrovascular and microvascular events. So we should ask: is the prominent place of DPP-4 inhibitors supported by a favorable effect of these drugs on the course of type 2 diabetes?

      Experimental Effects of DPP-4 Inhibitors on the Heart and Kidneys

      DPP-4 inhibitors are incretin-based drugs, but their actions are related not only to potentiation of glucagon-like peptide (GLP-1), but also to the enhancement of stromal cell-derived factor-1 (SDF-1). The insulinotropic action of GLP-1 is responsible for the hypoglycemic actions of DPP-4 inhibitors. By comparison, SDF-1 is a chemokine that promotes inflammation, regeneration, and repair.
      • Anderluh M.
      • Kocic G.
      • Tomovic K.
      • Kocic R.
      • Deljanin-Ilic M.
      • Smelcerovic A.
      Cross-talk between the dipeptidyl peptidase-4 and stromal cell-derived factor-1 in stem cell homing and myocardial repair: potential impact of dipeptidyl peptidase-4 inhibitors.
      Long-acting GLP-1 analogs do not potentiate the actions of SDF-1.
      • Nauck M.A.
      • Meier J.J.
      • Cavender M.A.
      • Abd El Aziz M.
      • Drucker D.J.
      Cardiovascular actions and clinical outcomes with glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors.
      What are the consequences of simultaneous potentiation of endogenous GLP-1 and SDF-1? Experimentally, DPP-4 inhibitors exert positive inotropic effects that have been ascribed to their ability to enhance the actions of GLP-1 to stimulate cyclic adenosine monophosphate.
      • Packer M.
      Is the way to someone's heart through their stomach? The cardiorenal paradox of incretin-based hypoglycemic drugs in heart failure.
      Meaningful increases in cyclic adenosine monophosphate in certain cardiomyocyte microdomains can lead to calcium overload and deleterious clinical effects. Moreover, SDF-1 can promote cardiac inflammation, and in experimental diabetes, potentiation of SDF-1 by DPP-4 inhibitors causes cardiac fibrosis.
      • Chu P.Y.
      • Walder K.
      • Horlock D.
      • et al.
      CXCR4 antagonism attenuates the development of diabetic cardiac fibrosis.

      Effect of DPP-4 Inhibitors on the Clinical Course of Diabetes

      Four large-scale trials have evaluated the early effect of DPP-4 inhibitors on the clinical course of patients with type 2 diabetes (Table).
      • Green J.B.
      • Bethel M.A.
      • Armstrong P.W.
      • et al.
      Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes.
      • Scirica B.M.
      • Bhatt D.L.
      • Braunwald E.
      • et al.
      Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus.
      • White W.B.
      • Cannon C.P.
      • Heller S.R.
      • et al.
      Alogliptin after acute coronary syndrome in patients with type 2 diabetes.
      • Gantz I.
      • Chen M.
      • Suryawanshi S.
      • et al.
      A randomized, placebo-controlled study of the cardiovascular safety of the once-weekly DPP-4 inhibitor omarigliptin in patients with type 2 diabetes mellitus.
      The duration of these trials was too brief to yield useful information about their effects on diabetic retinopathy or neuropathy. However, these trials elucidated the response to these drugs on the heart and the kidneys during the first few years of treatment.
      TableEffects of DPP-4 Inhibitors on Clinical Events During Up to 4 Years of Treatment in Large-Scale Cardiovascular Outcomes Trials in Patients With Type 2 Diabetes
      DrugStudy FeaturesEffect on Risk of Macrovascular EventsEffect on Renal FunctionEffect on Retinopathy and Neuropathy
      Sitagliptin
      • Green J.B.
      • Bethel M.A.
      • Armstrong P.W.
      • et al.
      Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes.
      14,735 patients followed for median of 3.0 yearsNo effect on cardiovascular death, nonfatal myocardial infarction, and nonfatal strokeEarly decline in glomerular filtration rate that persisted for up to 4 yearsNot reported during period of follow-up
      Saxagliptin
      • Scirica B.M.
      • Bhatt D.L.
      • Braunwald E.
      • et al.
      Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus.
      16,492 patients followed for median of 2.1 yearsNo effect on cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke; concern about increased risk of heart failureNo effect on rate of decline of glomerular filtration rate; no reduction in risk of serious adverse renal eventsNot reported during period of follow-up
      Alogliptin
      • White W.B.
      • Cannon C.P.
      • Heller S.R.
      • et al.
      Alogliptin after acute coronary syndrome in patients with type 2 diabetes.
      5380 patients followed for median of 1.5 yearsNo effect on cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke; concern about increased risk of heart failureNo effect on rate of decline of glomerular filtration rate; no reduction in risk of serious adverse renal eventsNot reported during period of follow-up
      Omariglptin
      • Gantz I.
      • Chen M.
      • Suryawanshi S.
      • et al.
      A randomized, placebo-controlled study of the cardiovascular safety of the once-weekly DPP-4 inhibitor omarigliptin in patients with type 2 diabetes mellitus.
      4202 patients followed for median of 1.8 yearsNo effect on cardiovascular death, nonfatal myocardial infarction, and nonfatal strokeNo effect on rate of decline in glomerular filtration rateNot reported during period of follow-up
      In each trial, the use of dipeptidyl peptidase-4 (DPP-4) inhibitors decreased glycated hemoglobin by 0.2-0.3% at 2 years of follow-up.

      Effect of DPP-4 Inhibitors on the Heart in Clinical Trials

      In the 4 large-scale trials of DPP-4 inhibitors, treatment for up to 4 years did not alter the risk of cardiovascular death, myocardial infarction, and stroke (Table).
      • Green J.B.
      • Bethel M.A.
      • Armstrong P.W.
      • et al.
      Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes.
      • Scirica B.M.
      • Bhatt D.L.
      • Braunwald E.
      • et al.
      Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus.
      • White W.B.
      • Cannon C.P.
      • Heller S.R.
      • et al.
      Alogliptin after acute coronary syndrome in patients with type 2 diabetes.
      • Gantz I.
      • Chen M.
      • Suryawanshi S.
      • et al.
      A randomized, placebo-controlled study of the cardiovascular safety of the once-weekly DPP-4 inhibitor omarigliptin in patients with type 2 diabetes mellitus.
      The lack of benefit is intriguing, because signaling through the GLP-1 receptor would be expected to retard the growth and minimizes the instability of atherosclerotic plaques.
      • Sudo M.
      • Li Y.
      • Hiro T.
      • et al.
      Inhibition of plaque progression and promotion of plaque stability by glucagon-like peptide-1 receptor agonist: serial in vivo findings from iMap-IVUS in Watanabe heritable hyperlipidemic rabbits.
      However, the action of DPP-4 inhibitors to potentiate SDF-1 enhances inflammation in atherosclerotic blood vessels, thereby potentially promoting plaque instability.
      • Ma W.
      • Liu Y.
      • Ellison N.
      • Shen J.
      Induction of C-X-C chemokine receptor type 7 (CXCR7) switches stromal cell-derived factor-1 (SDF-1) signaling and phagocytic activity in macrophages linked to atherosclerosis.
      Mutual neutralization of the actions of GLP-1 and SDF-1 on plaque biology may account for the lack of any net effect of DPP-4 inhibitors on the risk of major thromboembolic events.
      Long-term treatment with DPP-4 inhibitors has been accompanied by an increase in the risk of new-onset heart failure. The US Food and Drug Administration has mandated warnings about this risk in the labeling for 2 members of the drug class (saxagliptin and alogliptin).
      • US Food and Drug Administration
      Diabetes medications containing saxagliptin and alogliptin: drug safety communication—risk of heart failure.
      Although no increase in the risk of heart failure was reported in a trial with sitagliptin,
      • Chu P.Y.
      • Walder K.
      • Horlock D.
      • et al.
      CXCR4 antagonism attenuates the development of diabetic cardiac fibrosis.
      postmarketing analyses by the Food and Drug Administration indicated a disproportionate reporting of adverse heart failure events among users of all members of the drug class.
      • Raschi E.
      • Poluzzi E.
      • Koci A.
      • Antonazzo I.C.
      • Marchesini G.
      • De Ponti F.
      Dipeptidyl peptidase-4 inhibitors and heart failure: analysis of spontaneous reports submitted to the FDA Adverse Event Reporting System.
      Nonrandomized observational studies have been difficult to interpret because they relied on comparator groups that can increase the risk of heart failure in their own right. The possibility of harm has been highlighted by the results of a trial with vildagliptin in patients with established left ventricular dysfunction,
      • McMurray J.J.
      • Ponikowksi P.
      • Bolli G.B.
      • et al.
      VIVIDD Trial Committees and Investigators
      Vildagliptin in Ventricular Dysfunction Diabetes Trial (VIVIDD).
      which reported an adverse effect of the drug on cardiac remodeling; numerically more vildagliptin-treated patients experienced a cardiovascular hospitalization or died.

      Effect of DPP-4 Inhibitors on the Kidney in Clinical Trials

      In the 4 large-scale trials, DPP-4 inhibitors did not slow the rate of decline in renal function over the course of follow-up (Table).
      • Green J.B.
      • Bethel M.A.
      • Armstrong P.W.
      • et al.
      Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes.
      • Scirica B.M.
      • Bhatt D.L.
      • Braunwald E.
      • et al.
      Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus.
      • White W.B.
      • Cannon C.P.
      • Heller S.R.
      • et al.
      Alogliptin after acute coronary syndrome in patients with type 2 diabetes.
      • Gantz I.
      • Chen M.
      • Suryawanshi S.
      • et al.
      A randomized, placebo-controlled study of the cardiovascular safety of the once-weekly DPP-4 inhibitor omarigliptin in patients with type 2 diabetes mellitus.
      Early after initiation of treatment, many antidiabetic drugs lead to a mild decline in glomerular filtration rate.
      • Packer M.
      Early worsening of renal function after treatment with antihyperglycemic drugs: a consistent but neglected finding in large-scale trials.
      In the case of SGLT2 inhibitors and GLP-1 receptor agonists, the initial fall in the glomerular filtration rate is superseded by an improvement in renal function during long-term follow-up.
      • Wanner C.
      • Inzucchi S.E.
      • Lachin J.M.
      • et al.
      Empagliflozin and progression of kidney disease in type 2 diabetes.
      • Mann J.F.E.
      • Ørsted D.D.
      • Brown-Frandsen K.
      • et al.
      Liraglutide and renal outcomes in type 2 diabetes.
      In contrast, the initial decrease in glomerular function with DPP-4 inhibitors persists up to 4 years.
      • Cornel J.H.
      • Bakris G.L.
      • Stevens S.R.
      • et al.
      Effect of sitagliptin on kidney function and respective cardiovascular outcomes in type 2 diabetes: outcomes from TECOS.
      What can account for these differences? Recent studies have proposed that the hyperfiltration in diabetes results from the hyperreabsorption of sodium in the proximal tubule.
      • Lovshin J.A.
      • Rajasekeran H.
      • Lytvyn Y.
      • et al.
      Dipeptidyl peptidase 4 inhibition stimulates distal tubular natriuresis and increases in circulating SDF-1α1-67 in patients with type 2 diabetes.
      This augmented response reduces the delivery of sodium to the macula densa, which (through tubuloglomerular feedback) causes afferent arteriolar vasodilation and glomerular hyperfiltration. Agents that attenuate this proximal tubular hyperreabsorption of sodium can slow the progression of kidney disease beyond an effect produced through glycemic control.
      • Lovshin J.A.
      • Rajasekeran H.
      • Lytvyn Y.
      • et al.
      Dipeptidyl peptidase 4 inhibition stimulates distal tubular natriuresis and increases in circulating SDF-1α1-67 in patients with type 2 diabetes.
      Both SGLT2 inhibitors and GLP-1 receptor agonists exert their primary natriuretic action in the proximal tubule. In contrast, the primary natriuretic effect of DPP-4 inhibitors occurs in the distal tubule (beyond the macula densa), and thus, they do not influence tubuloglomerular feedback to modulate glomerular hyperfiltration.
      • Lovshin J.A.
      • Rajasekeran H.
      • Lytvyn Y.
      • et al.
      Dipeptidyl peptidase 4 inhibition stimulates distal tubular natriuresis and increases in circulating SDF-1α1-67 in patients with type 2 diabetes.
      The modest effect of DPP-4 inhibitors to reduce albuminuria may reflect an action to minimize hyperglycemia-induced increases in podocyte protein permeability, rather than a benefit on nephropathy.
      • Swärd P.
      • Rippe B.
      Acute and sustained actions of hyperglycaemia on endothelial and glomerular barrier permeability.
      Although they have been reported to modulate renal injury in experimental models, the action of DPP-4 inhibitors to potentiate the proinflammatory effects of SDF-1 can also exacerbate the progression of kidney disease.
      • Sayyed S.G.
      • Hägele H.
      • Kulkarni O.P.
      • et al.
      Podocytes produce homeostatic chemokine stromal cell-derived factor-1/CXCL12, which contributes to glomerulosclerosis, podocyte loss and albuminuria in a mouse model of type 2 diabetes.

      Conclusions

      DPP-4 inhibitors produce sustained and well-tolerated decreases in blood glucose. However, in large-scale clinical trials, the use of these drugs for periods of up to 4 years does not reduce the risk of atherosclerotic vaso-occlusive events or slow the rate of decline in glomerular function. Furthermore, DPP-4 inhibitors may increase the risk of new-onset heart failure or have adverse effects on cardiac remodeling in patients with established heart failure. In light of their limited benefits, their potential risks during the first few years of use, and the established cardiovascular risk reduction during the same time period with other drug classes, is the current popularity of DPP-4 inhibitors justified?

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