Dr. Ralph Defronzo Interview

Dr. Ralph Defronzo Interview

Steve Freed, RPh, CDE from Diabetes in Control conducted a terrific interview with Ralph DeFronzo, MD, who is an endocrinologist and Deputy Director of the Texas Diabetes Institute.  Dr. DeFronzo has been a pioneer in conducting studies to elucidate the pathophysiology of type 2 diabetes mellitus, and in the evaluation of treatment strategies that address the underlying defects.  Dr. DeFronzo recently surpassed 750 publications and it is difficult to overstate his influence on the field of diabetology.  The full interview on video and a transcript may be obtained at www.diabetesincontrol.com and http://www.diabetesincontrol.com/dr-ralph-defronzo-full-transcript/.

Below is a summary of Dr. DeFronzo’s key points.

  1. Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are two subtypes of prediabetes with different pathophysiologies:
    • IFG is characterized by hepatic insulin resistance and impaired first-phase insulin secretion;
    • IGT is characterized by skeletal muscle insulin resistance and impairment of second-phase insulin secretion.
  2. Progressive loss of pancreatic beta-cell function is the hallmark of progression from prediabetes to type 2 diabetes mellitus (T2D), and then to more severe T2D. Impairment of beta-cell response is due to a combination of dysfunction (hibernation) and loss of beta-cell mass.  This process can be arrested or slowed by drug therapies that have direct or indirect effects.
    • Direct effects – thiazolidinediones and GLP-1 agonists appear to have direct effects on the pancreas that help to preserve beta-cell mass, in part through reducing apoptosis.
    • Indirect effects – other drugs that lower glucose will reduce glucose toxicity, which, in turn, will improve beta-cell function and insulin sensitivity. DeFronzo believes that sulfonylureas should rarely be used and favors metformin and SGLT-2 inhibitors over other classes of glucose-lowering drugs.
  3. Recently published data support effects of three classes of hypoglycemic agents to reduce cardiovascular risk.
    • Pioglitazone (a thiazolidinedione) – the IRIS trial
    • SGLT-2 inhibitors – EMPA-REG Outcome and CANVAS
    • GLP-1 agonists – SUSTAIN-6 and LEADER
  4. DeFronzo advocates triple-therapy from early in the disease process (which can be costly) to address the underlying insulin resistance and arrest the progression of beta-cell impairment. This involves use of:
    • Pioglitazone (a thiazolidinedione),
    • A GLP-1 agonist,
    • Metformin or an SGLT-2 inhibitor.

Abbreviations:  CANVAS, Canagliflozin Cardiovascular Assessment Study; EMPA-REG, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; GLP-1, glucagon-like peptide-1; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; IRIS, Insulin Resistance Intervention after Stroke; LEADER, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; SGLT-2, sodium-glucose cotransporter-2; SUSTAIN-6, Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes; T2D, type 2 diabetes mellitus.

Relevant references

Abdul-Ghani M, Migahid O, Megahed A, Adams J, Triplitt C, DeFronzo RA, Zirie M, Jayyousi A. Combination therapy with exenatide plus pioglitazone versus basal/bolus insulin in patients with poorly controlled type 2 diabetes on sulfonylurea plus metformin: The QATAR Study. Diabetes Care. 2017;40:325-331. Erratum: 2017 June 14 [Epub ahead of print].

DeFronzo RA. Banting Lecture. From the triumvirate to the ominous octet: A new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58:773-795.

Kaul S. Mitigating cardiovascular risk in type 2 diabetes with antidiabetes drugs: A review of principal cardiovascular outcome results of EMPA-REG OUTCOME, LEADER, and SUSTAIN-6 trials. Diabetes Care. 2017;40:821-831.

Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR, for the CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017 June 12 [Epub ahead of print].


Dr. Ralph Defronzo Interview

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