Combinations exert synergy in glucose control and beyond in type 2 diabetes

Presenters: Ralph A. DeFronzo, MD, Chantal Mathieu, MD, PhD, Tina Visbøll, MD, DMSc, and David D’Alessio, MD

Glucose-lowering combinations for type 2 diabetes mellitus should take advantage of complementary mechanisms of action to improve glucose control while minimizing the risk of hypoglycemia and reducing the rate of adverse cardiovascular and renal outcomes, said speakers during a therapeutics symposium.

The rationale for various combinations that include incretins, SGLT2 inhibitors, GLP-1 receptor agonists, and pioglitazone was discussed.

The “ominous octet” in type 2 diabetes that contributes to hyperglycemia consists of decreased insulin secretion, decreased incretin effect, increased lipolysis, increased glucose reabsorption, decreased glucose uptake, neurotransmitter dysfunction, increased hepatic glucose production, and increased glucagon secretion,1 as described by Ralph A. DeFronzo, MD, chief, Diabetes Division, University of Texas Health, San Antonio.

Rational glucose-lowering combinations act synergistically to address these pathophysiologic defects. One such combination is an SGLT2 inhibitor and a GLP-1 receptor agonist.

SGLT2 inhibitors improve insulin sensitivity and increase insulin secretion and beta cell function.2 They function to correct a novel pathophysiologic defect—elevated glucose spillage into the urine—and reverse glucotoxicity as glucose level declines and beta cell function improves with treatment, thereby improving HbA1c.2 They promote weight loss and a decrease in visceral fat.2 Because SGLT2 inhibitors work on the kidney, they complement the action of other antidiabetic agents, said Dr. DeFronzo. They block sodium reabsorption at the level of the kidney and provide protection against major adverse cardiovascular events (MACE) and adverse renal outcomes.3 An added feature is no risk of hypoglycemia with the SGLT2 inhibitors.

Hemodynamic benefits are also realized with SGLT2 inhibitors; they decrease plasma volume because of their natriuretic effect in addition to lowering blood pressure. They reduce arterial stiffness, including aortic stiffness.2 These agents don’t inhibit sympathetic nervous system activity.2

Like the SGLT2 inhibitors, GLP-1 receptor agonists correct numerous pathophysiologic disturbances present in type 2 diabetes and also preserve beta cell function, promote weight loss, reduce the rate of MACE and adverse renal outcomes, including macroalbuminuria, and have an excellent safety profile with no risk of hypoglycemia.4-7 They exhibit antiatherogenic, anti-inflammatory, anti-oxidative stress, and antithrombotic properties, in addition to reducing blood pressure.

The SGLT2 inhibitors and GLP-1 receptor agonists have additive effects on glycemic control, insulin sensitivity, beta cell function, body weight, visceral fat, fatty liver disease, blood pressure, hemodynamics, and natriuresis.

Pioglitazone has a potent effect on the beta cell to improve insulin secretion and is a cost-effective agent for cardioprotection, correcting diabetic dyslipidemia, reversing lipotoxicity, inhibiting inflammation, and improving insulin resistance to prevent MACE,8 making it a potential third agent to be used in combination with the SGLT2 inhibitors and GLP-1 receptor agonists, said Dr. DeFronzo.

“It’s clear to me that we need to be going with combination therapy,” he said. “Triple therapy is the answer for glycemic control and prevention of cardiovascular complications and renal complications.”

Combining SGLT2 inhibitors and insulin makes sense on the basis of the pathophysiology of type 2 diabetes and the mechanisms of action of these agents, said Chantal Mathieu, MD, PhD, professor of endocrinology, University of Leuven, Belgium.

Adding an SGLT2 inhibitor has an insulin-sparing effect, she noted, and the deleterious effects of insulin, such as weight gain, an increase in blood pressure, and fluid retention, are countered by SGLT2 inhibitors. The combination of basal insulin and an SGLT2 inhibitor has a superior effect on HbA1c and allows the use of lower doses of each to improve tolerability.9,10 As with SGLT2 inhibitors, there is no hypoglycemia with the use of GLP-1 receptor agonists.

SGLT2 inhibitors induce glucosuria, related to an increase in plasma glucagon secretion.

Adding insulin to an SGLT2 inhibitor is a rational combination; therefore, because insulin suppresses glucagon and endogenous glucose production (EGP), which counteracts the rise in glucagon and EGP that occur with SGLT2 inhibitors.9-11

Insulin use alone is associated with a worsening in MACE in type 2 diabetes, but beneficial cardiorenal effects of SGLT2 inhibitors still occur in people with type 2 diabetes who need insulin for glucose control.

The complementary actions of insulin and GLP-1 receptor agonists was discussed by Tina Visbøll, MD, DMSc, professor of endocrinology, University of Copenhagen, Denmark.

Many patients do not achieve glycemic control with insulin despite a treat-to-target approach, and therapy intensification risks severe hypoglycemia and weight gain over time, she said.

Repeating elements of Dr. DeFronzo’s presentation on the beneficial cardiovascular effects of GLP1 receptor agonists, she said that the combination of basal insulin and a GLP-1 receptor agonist has the potential to delay underlying disease progression and disease-related vascular complications.12,13 “Insulin-treated patients with cardiovascular disease or high-risk individuals for cardiovascular disease should always be considered as potential candidates for addition of GLP-1 receptor agonist [and/or SGLT2 inhibitors],” said Dr. Visbøll.

Dual agonists and multi-receptor agonists are future prospects in glucose management, said David D’Alessio, chief, Division of Endocrinology, Duke University, Durham, N.C.

A range of evidence exists to support targeting of multiple GPCRs in drug development. Multiple points of regulation can be explored for drug effect, he said, with evidence for interaction, compensation, and coordination amongst the receptor signaling systems.

He presented data to show that a dual glucose-dependent insulinotropic peptide (GIP)/GLP-1 co-agonist reduced HbA1c in a dose-dependent manner versus placebo, exhibited synergism in reducing fat mass, and corrected adiposity-induced insulin resistance and pancreatic insulin deficiency compared with mono-agonists.14,15

Tirzepatide, a dual GIP/GLP-1 receptor agonist, reduced A1c and body weight more so than did dulaglutide in a double-blind randomized phase 2 trial.16

References

  1. DeFronzo RA. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 2009;58:773-795.
  2. DeFronzo RA, Norton L, Abdul-Ghani M. Renal, metabolic and cardiovascular considerations of SGLT2 inhibition. Nat Rev Nephrol 2017;13:11-26.
  3. McGuire DK, Shih WJ, Cosentino F, et al. Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes: a meta-analysis. JAMA Cardiol 2021;6:148-158.
  4. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311-322.
  5. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375:1834-1844.
  6. Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet 2019;394:121-130.
  7. Kristensen SL, Rørth R, Jhund PS, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol 2019;7:776-785.
  8. DeFronzo RA, Inzucchi S, Abdul-Ghani M, et al. Pioglitazone: the forgotten, cost-effective cardioprotective drug for type 2 diabetes. Diab Vasc Dis Res 2019;16:133-143.
  9. Van Baar MJB, van Ruiten CC, Muskiet MHA, van Bloemendaal L, Ijzerman RG, van Raalte DH. SGLT2 inhibitors in combination therapy: from mechanisms to clinical considerations in type 2 diabetes management. Diabetes Care 2018;42:1543-1556.
  10. Tang H, Cui W, Li D, et al. Sodium-glucose co-transporter 2 inhibitors in addition to insulin therapy for management of type 2 diabetes mellitus: A meta-analysis of randomized controlled trials. Diabetes Obes Metab 2017;19:142-147.
  11. Harris SB, Mequanint S, Miller K, Reichert SM, Spaic T. When insulin therapy fails: the impact of SGLT2 inhibitors in patients with type 2 diabetes. Diabetes Care 2017;40:e141-e142.
  12. Ida Maiorino M, Chiodini P, Bellastella G, et al. The good companions: insulin and glucagon-like peptide-1 receptor agonist in type 2 diabetes. A systematic review and meta-analysis of randomized controlled trials. Diabetes Res Clin Pract 2019;154:101-115.
  13. Giugliano D, Longo M, Caruso P, et al. Feasibility of simplification from a basal-bolus insulin regimen to a fixed-ratio formulation of basal insulin plus a GLP-1RA or to basal insulin plus an SGLT2 inhibitor: BEYOND, a randomized, pragmatic trial. Diabetes Care 2021 Apr 21:dc202623. doi: 10.2337/dc20-2623. Online ahead of print.
  14. Finan B, Ma T, Ottaway N, et al. Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans. Sci Transl Med 2013;5:209ra151.
  15. Frias JP, Bastyr 3rd EJ, Vignati L, et al. The sustained effects of a dual GIP/GLP-1 receptor agonist, NNC0090-2746, in patients with type 2 diabetes. Cell Metab 2017;26:343-352.e2.
  16. Frias JP, Nauck MA, Van J, et al. Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial. Lancet 2018;392:2180-2193.

Disclosures

Dr. DeFronzo discloses financial relationships with AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk, and Merck & Co., Inc.

Dr Mathieu discloses financial relationships with Novo Nordisk, Sanofi, Merck Sharp and Dohme Ltd., Eli Lilly and Company, Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Medtronic, ActoBio Therapeutics, Pfizer, Insulet, Zealand Pharma, Novo Nordisk, and Sanofi.

Dr. Visbøll discloses financial relationships with Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Gilead Sciences, Inc., Lilly Diabetes, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk, Sanofi, and Sun Pharmaceutical Industries Ltd.

Dr. D’Alessio discloses financial relationships with Eli Lilly and Co., Sun Pharmaceutical Industries Ltd., and Merck and Co.

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