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Newsletter Summer 2019 - Webcast Recap: Dr. Ralph DeFronzo on Type 2 Diabetes

Webcast Recap: Dr. Ralph DeFronzo on Type 2 Diabetes 

Jennifer Zhao 

Kinexum Associate 

Ralph DeFronzo, MD, Deputy Director of the Texas Diabetes Institute, spoke on “Prevention of Type 2 Diabetes (T2D): A Rational Approach Based on Its Pathophysiologyin Kinexum’s March public webcast. A preeminent authority in the field of diabetes and metabolism, Dr. DeFronzo reviewed the research behind the factors that lead to diabetes and the drugs available to treat T2D 

What leads to diabetes? 

As of 2017, about 30 million Americans have diabetes and 84 million Americans have prediabetes [1]. These numbers are expected to increase, along with the cost of treating diabetes. Of the $175 billion cost of treating diabetes in 2007, about one-third of costs were related to cardiovascular disease (CVD)/peripheral vascular disease (PVD), another one-third to microvascular complications (eye, kidney, nerve; all are related to high A1C), and another to other costs (e.g., office visits) [2]. 

Prediabetes can be diagnosed in three ways. A person has prediabetes if he or she hasimpaired fasting glucose (IFG) (fasting glucose = 100-125 mg/dL), impaired glucose tolerance (IGT) (2-hour glucose during an oral glucose tolerance test [OGTT] = 140-199 mg/dL), or HbA1c (measure of mean blood glucose over the preceding three months) = 5.7-6.4%.  

It is important to note that IFG and IGT are separate clinical entities with different prevalence and overlap, as can be shown by results of an OGTT (Figure 1). Even if a person has an A1C between 5.7-6.4% (diagnosis for prediabetes), a diagnosis based on A1C does not indicate whether the person has IFG or IGT. Whereas people with IFG have insulin resistance in the liverand impaired first-phase secretion of insulin, people with IGT have insulin resistance in the muscleand impaired second-phase insulin secretion. Another difference between IGT and IFG is that IGT, not IFG, is associated with increased CVD risk. As a result, people with IGT have the metabolic syndrome including insulin resistance, obesity, hypertension, and dyslipidemia. Because IFG and IGT have different pathophysiologic underpinnings, it is likely that people with either diagnosis will respond differently to different medications. 

 

Figure 1. Shape of oral glucose tolerance test (OGTT) of impaired fasting glucose (IFG) versus impaired glucose tolerance (IGT). 

However, both IFG and IGT have similarly high risk of progression to T2D. Figure 2 displays results from the Botnia study in Sweden of the 7-8 year incidence rate of conversion rate to diabetes based on glucose tolerance status. The conversion rate for combined glucose intolerance (CGI) is higher than IFG or IGT alone. 

 

Figure 2. Conversion rate to type 2 diabetes (T2D) based on glucose tolerance status. NGT=normal glucose tolerance, IFG=impaired fasting glucose, IGT=impaired glucose tolerance, CGI=combined glucose intolerance.  

Why should pharmacologic therapy be used to prevent the development of T2D in high-risk individuals? 

Although non-pharmacologic therapy (i.e., diet and exercise) is effective in the short term, it is not effective in the long term. In a meta-analysis of 46 randomized, controlled trials in which intensive dietary and lifestyle modification were instituted, the maximum decrease in body mass index(BMI) was 1.9 kg/m2, with weight regain of 0.36 kg/m2 per year during the maintenance phase [3, 4]. Consequently,all the lost weight was regained in 5 years. Although weight loss should still be encouraged for its immediate benefit, other approaches should be used in tandem for long-term benefit and to reduce A1C to a point that would reduce microvascular (eye, kidney, nerve) complications. 

Screening for T2D improves outcomes  

T2D meets the following criteria for whether a disease should be screened [5]: 

  1. Disease is serious 

  1. Natural history is known (normal glucose tolerance to prediabetes to diabetes) 

  1. Preclinical stage of disease is detectable (can be measuredby fasting glucose, A1C, or a glucose tolerance test) 

  1. Screening is quick, inexpensive, and valid  

  1. Effective therapies are available (diet and exercise, pharmacologictherapy) 

  1. Early treatment is more effective than late treatment (the greater loss of beta cells in the progression to diabetes increases the need for patients to go on insulin therapy) 

In 2012, the US Preventive Service Task Force (USPSTF) recommended screening for abnormal blood glucose (prediabetes) and T2D, especially for adults that were at least 45 years, overweight or obese, and with a first-degree relative with T2D. Additionally, ethnic minority groups, notably blacks and Latino Hispanics, are at increased risk for T2D [6]. 

What is the evidence that diabetes can be prevented in people with prediabetes? 

The US Diabetes Prevention Program (DPP) showed that weight loss is effective in preventing the progression from prediabetes to diabetes, but it cannot be maintained. In people with IGT, three groups were studied for three years:  

  1. heavy lifestyle change (reduced weight by 7%,ate a low-fat diet, and exercised for 150 min/week), 

  1. 850 mg metformin twice a day, and  

  1. light lifestyle change (received information on diet and exercise).  

There was a fourth group that took troglitazone, but it was not followed up because of side effects.  

The results showed that the metformin group decreased the conversion rate from IGT to T2D by 31%, compared to 58% for diet and exercise [7]. However, after 4 years, weight was regained in the lifestyle group (Figure 3) [8].Although weight loss was achieved with lifestyle intervention, 40-50% of individuals with IGT still progressed to T2D.  

 

Figure 3. Weight regain in the DPP study. The DPP was terminated after 3.2 years, and the DPP Outcomes Study (DPPOS) was initiated. 

Pharmacological therapy works 

The figure below shows thata number ofstudies have utilized pharmacological interventions for T2D prevention (Figure 4). Overall, several pharmacological interventions, including metformin, thiazolidinediones (TZDs), alpha-glucosidase inhibitors (AGIs), and others not shown, have been demonstrated to effectively reduce the risk for diabetes and the conversion from IGT to diabetes. TZDs have been the most effective in preventing the conversion; 18 IGT subjects would need to be treated for one year to prevent the development of one case of T2D [9]. This is likely to be very cost effective since pioglitazone is generic and costs only $5.00 per month. 

 

Figure 4.Examples of studies on pharmacological interventions for T2D prevention. 

Why not wait until the diagnosis of diabetes is made to start metformin therapy or start an agent that preserves betacell function? 

One reason is the delay made by physicians to intensifytherapy when a patient has an A1C greater than 8.0% andis already on a therapy; this is known as physician inertia [10].Physicians do not readily change treatment in people with diabetes. Another reason is that as time passes for people with IFG, IGT, and T2D, more beta cells (insulin-secreting cells) are lost. People with IFG and IGT have lost ~20% of their beta cell volume compared to people with NGT, and there is further loss in people with T2D [11].Thus, beta cell failure occurs early in the natural history of T2D and is more severe than previously thought. As a result, pharmacologic intervention should be initiated as early as possible to preserve beta cell function. 

Treatment of T2D should be based on pathophysiology 

The core characteristics of diabetes can be grouped into the ominous octet: 

  1. Insulin resistance in liver (increased hepatic glucose production, HGP) 

  1. Insulin resistance in muscle (decreased glucose uptake) 

  1. Beta cell failure (decreased insulin secretion) 

  1. Insulin resistance in fat cell (increased lipolysis) 

  1. Decreased incretin (GLP-1 and GIP) effectiveness (affecting insulin production)  

  1. Increased glucagon secretion from islet alpha cells 

  1. Neurotransmitter dysfunction in brain (resistance to appetite suppression) 

  1. Increased glucose reabsorption by the kidneys (glucosuria) 

There is no one drug that can correct all 8 pathophysiologic defects, so a combination of multiple drugs is needed to effectively treat T2D. Furthermore, treating T2D should be based on known pathogenic abnormalities (i.e., beta cell failure), not simply on the reduction in HbA1c. Because people with prediabetes also have insulin resistance in the liver, insulin resistance in muscle, and beta cell failure, treatment must be started early to prevent progressive beta cell failure, improve the insulin resistanceand halt the progression to T2D 

Below are overviews of several classes of drugs used to treat diabetes:  

Sulfonylureas (SUs) 

SUsbind to beta cells, and the increase in insulin secretion initially help patients overcome insulin resistance. However, they do not work long-term. Per the UKPDS study, HbA1c decreases initially, but later increases due to progressive beta cell failure [12]. 

Metformin 

Metformin acts on the liver andinhibits hepatic gluconeogenesis. With metformin treatment,HbA1c decreases initially, but later rises due to the lack of beta cell preservation. Nonetheless, in the UKPDS study, there was a 37% decrease in microvascular complications with metformin treatment [12]. 

The effect of metformin on cardioprotection remains unclear. In the UKPDS study, metformin monotherapy reduced myocardial infarction (MI), stroke, and diabetes-related death by about 40%. However, when metformin was added to SU treatment, diabetes-related death increased by 39% [12]. Nonetheless, metformin will remain as first-line therapy for T2D because of its efficacy and strong safety profile.  

Thiazolidinediones (TZDs) 

TZDs are insulin sensitizersand also have an effect on beta cell function. Unlike SUs and metformin, TZDs have been shown to decrease A1C and maintain that decrease in the long-term.  

Additionally, pioglitazone provides cardioprotection, reverseslipotoxicity, improves NASH/NAFLD, reduces blood pressure, reduces inflammation, correctsdiabetes dyslipidemia, and does not cause hypoglycemia[13, 14]. 

SGLT2 Inhibitors 

SGLT2 inhibitors correct a novel renal defect, have durable A1C reduction, reverse glucotoxicity (improve beta cell function and insulin sensitivity), provide cardioprotectionand renal protection, reduce blood pressure, cause weight loss, do not cause hypoglycemia, and have a good safety profile [15]. 

GLP-1 Receptor Agonists  

GLP-1 receptor agonistseffectively reduce HbA1c, preserve beta cell function, promote weight loss, correct 6 pathophysiologic defects of T2D, do not cause hypoglycemia, have an excellent safety profile, and provide cardioprotection [16]. Moreover, a single dose of liraglutide has been shown to restore beta cell insulin response to hyperglycemia in T2D patients [17]. 

Additional Resources 

The full recording of the webinar can be found here, and slides to Dr. DeFronzo’s presentation can be found here.  

About Ralph DeFronzo, MD 

Dr. Ralph DeFronzo is a leader in the diabetes field. He is responsible for many of the advances achieved in diabetes over the last 50 years, including developing the concept of insulin resistance, leading the US development of metformin, and discovering a new approach to diabetes treatment that targets glucose reabsorption in the kidneys. His most recent work, along with Dr. Bruno Doiron, has led to a possible cure for diabetes in mice and is being developed for studies in larger animals.  

Dr. DeFronzo's major interests focus on the pathogenesis and treatment of T2D and the central role of insulin resistance in the metabolic-cardiovascular cluster of disorders known collectively as the Insulin Resistance Syndrome. Using the euglycemic insulin clamp technique in combination with radioisotope turnover methodology, limb catheterization, indirect calorimetry, and muscle biopsy, he has helped to define the biochemical and molecular disturbances responsible for insulin resistance in T2D. 

Dr. DeFronzo graduated from Yale University with a degree in biology and biochemistry, followed by Harvard Medical School with further studies in endocrinology and nephrology. He holds the Joe R. & Teresa Lozano Long Distinguished Chair in Diabetes in the Long School of Medicine at UT Health San Antonio, where he has been on the faculty since 1988. He has received numerous awards, including the Harold Hamm International Prize for Biomedical Research in Diabetes (2017), the Novartis Award at the Annual Scientific Meeting of the American Diabetes Association (ADA) as the outstanding clinical investigator worldwide (2005), and the Albert Renold Award from the ADA for the training of more than 200 young diabetes investigators (2002). He is the author of 750 publications dating back to 1967. 

References 

[1] Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2017. https://www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf. Updated Mar 6, 2019. Accessed Jun 16, 2019.    

[2] American Diabetes Association. Diabetes Care. 2008;31(6):596-615. 

[3] Andersen JW, et al. Am J Clin Nutr. 2001;74(5):579-84. 

[4] Dansinger ML, et al. Ann Int Med. 2007;147(1):41-50. 

[5] Engelgau MM, et al. Diabetes Care. 2000;23(10):1563-80. 

[6] LeFevre ML; U.S. Preventive Services Task Force. Ann Intern Med.2014;161:587-93. 

[7] Diabetes Prevention Program Research Group. N Engl J Med.2002;346:393-403. 

[8] Venditti EM, et al. Int J Obes. 2008;32,1537-1544. 

[9] DeFronzo RA, et al. N Engl J Med. 2001;364:1104-15. 

[10] Brown JB, et al. Diabetes Care.2004;27:1535-40. 

[11] Butler AE, et al. Diabetes. 2003;52(1):102-10. 

[12] UKPDS Group. Lancet. 1998;352(9131):837-53 and 853-865.  

[13] Dormandy JA, et al. Lancet. 2005; 366(9493):1279-89. 

[14] Kernan WN, et al.N Engl J Med. 2016;374:1321-31. 

[15] Zinman B, et al. N Engl J Med. 2015;373:2117-28. 

[16] Triplitt C, DeFronzo RA. Expert Rev Endocrinol Metab. 2006;1(3):329-41. 

[17] Chang AM, et al. Diabetes.2003;52(7):1786-91.