#481 Prediabetes and Diabetes Prevention with Dr. Scott Isaacs

April 28, 2025 | By Malini Gandhi

Audio

Video

Transcript available via YouTube

Conquer prediabetes and diabetes prevention! We’re joined by Dr. Scott Isaacs, who provides essential pearls on navigating  screening tests for diabetes and prediabetes, identifying atypical cases of prediabetes, and individualizing management of prediabetes with lifestyle changes and medications.

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Show Segments

• Intro
• Case from Kashlak
• Why screen for prediabetes and diabetes?
• Who to screen for prediabetes and diabetes
• How to screen for prediabetes and diabetes
• Role of the physical exam
• Explaining a diagnosis of prediabetes to patients
• Atypical types of prediabetes
• Management of prediabetes: lifestyle changes
• Management of prediabetes: medications
• Outro

Disclosures

Dr. Isaacs reports no relevant financial disclosures. The Curbsiders report no relevant financial disclosures. 

Prediabetes and Diabetes Prevention Pearls

1. Over one-third of U.S. adults have prediabetes, the vast majority of whom don’t know they have it; thus, screening is essential.
2. The three methods of screening for prediabetes are: Hemoglobin A1c, fasting plasma glucose, and 2-hour plasma glucose during an oral glucose tolerance test (OGTT). The OGTT can be a helpful option in situations in which the validity of the A1c is in question (for instance, in conditions that impact RBC turnover) and the fasting plasma glucose is borderline.
3. Dr. Isaacs emphasizes a complications-centric rather than glucocentric approach when discussing prediabetes with patients, centering his conversations around big-picture  mitigation of overall cardiometabolic risk / multi-morbidities rather than just focusing on the blood sugar.
4. It is important to  keep an eye out for atypical cases of prediabetes, including pre-type 1 diabetes, pancreatic prediabetes, and prediabetes associated with endocrinopathies (Cushing’s and acromegaly).
5. Intensive lifestyle changes resulting in a 7% weight loss can decrease the risk of progression from prediabetes to diabetes by 58%, as shown in the landmark Diabetes Prevention Program study. Medications like metformin, pioglitazone, and GLP-1 agonists are also important options in the toolbox for prediabetes management.

Prediabetes and Diabetes Prevention – Notes

Why screen for prediabetes and diabetes?

Prediabetes and diabetes are incredibly common. About 38.1 million adults in the US have diabetes, which is about 14.7% of the US adult population, and 8.7 million U.S. adults (3.4% of the adult population) have undiagnosed diabetes (CDC National Diabetes Statistics Report). Prediabetes is even more common: about 97.6 million adults in the US have prediabetes, which is about 38% of the US adult population (CDC National Diabetes Statistics Report). Notably, the vast majority of people with prediabetes don’t know they have it (CDC National Diabetes Statistics Report). Thus, screening is essential.

Who should we screen for prediabetes and diabetes?

Given the widespread prevalence of prediabetes and diabetes, in practice most providers end up screening the majority of their patients for diabetes. 

Looking at the guidelines, there are two major screening recommendations in the United States: 1) the US Preventive Services Task Force (USPSTF) recommends that adults age 35-70 with overweight or obesity be screened (US Preventive Services Task Force, 2021), and 2) the American Diabetes Association (ADA) recommends that all adults 35 years or older be screened, and that adults under age 35 be screened if they have overweight or obesity plus at least one additional risk factor (American Diabetes Association Professional Practice Committee, 2024). These risk factors include: first-degree relative with diabetes, high-risk race/ethnicity, history of cardiovascular disease, hypertension, metabolic dyslipidemia with low HDL or high triglycerides, history of gestational diabetes, PCOS, or physical inactivity.

Though the USPSTF guidelines recommend an upper age limit of 70 at which point to stop screening for prediabetes or diabetes (US Preventive Services Task Force, 2021), Dr. Isaacs said he typically will keep screening past the age of 70.

How should we screen for prediabetes and diabetes?

Methods of screening for prediabetes and diabetes

According to the ADA, there are three methods of screening for prediabetes / diabetes: 1) fasting plasma glucose, 2) A1c, or 3) 2-hour plasma glucose during an oral glucose tolerance test (American Diabetes Association Professional Practice Committee, 2024). The fasting plasma glucose and A1c are most common in practice.

Dr. Isaacs recommends simultaneous testing with the A1c and fasting plasma glucose, since they are inexpensive, easy to perform, and can help facilitate a diagnosis since you don’t need a second patient visit to confirm an abnormal test result.

If you were to select one test, the A1c is the superior of the three, as it correlates best with rates of incident diabetes, diabetes complications, and all-cause mortality (Warren et al, 2017).

Cut-offs for defining  prediabetes and diabetes

The ADA cut-offs for prediabetes and diabetes (American Diabetes Association Professional Practice Committee, 2024) are:

• A1c ≥ 6.5% is diabetes, and A1c of 5.7-6.4% is prediabetes
• Fasting plasma glucose ≥ 126 is diabetes, and fasting plasma glucose 100-125 mg/dL is impaired fasting glucose (IFG), one of the forms of prediabetes
• Plasma glucose of  ≥ 200 mg/dL after a 2 hour oral glucose tolerance test (OGTT) is diabetes, and plasma glucose 140-199 mg/dL after a 2-hour OGTT is impaired glucose tolerance (IGT), one of the forms of prediabetes

Role of the oral glucose tolerance test

Dr. Isaacs notes that the OGTT, while more cumbersome and thus infrequently used outside of OB/GYN, can be a helpful test. The OGTT is performed by having patients drink a 75 g glucose load on an empty stomach, and testing the plasma glucose 2 hours later (American Diabetes Association Professional Practice Committee, 2024). Fasting glucose and the OGTT provide different sets of physiologic information. Impaired fasting glucose (IFG) is primarily associated with reduced first-phase insulin secretion with normal second-phase insulin secretion, and reflects hepatic insulin resistance in which insulin is not able to adequately suppress liver glucose production (gluconeogenesis) at night in the fasting state (Abdul-Ghani, 2006). In contrast, impaired glucose tolerance (IGT) captured by the OGTT is a result of defective first-phase and second-phase insulin release combined with muscle insulin resistance, in which peripheral glucose uptake is impaired leading to postprandial hyperglycemia (Abdul-Ghani, 2006). Patients can have impaired IFG, IGT, or both. Both IFG and IGT increase the risk of developing type 2 diabetes and cardiovascular complications, though IGT is a stronger predictor of type 2 diabetes and cardiovascular complications.

Dr. Isaacs finds the OGTT particularly useful in situations in which he is concerned about the accuracy of the A1c and the fasting glucose is borderline.

Pitfalls of hemoglobin A1c

Anything that impacts hemoglobin can affect the accuracy of the hemoglobin A1c. Conditions that increase the turnover of red blood cells will result in a falsely low A1c (for instance, chronic hemolytic conditions like thalassemia or G6PD deficiency, EPO treatment,  acute blood loss, HIV, and treatment for anemia) (American Diabetes Association Professional Practice Committee, 2024; Kim et al, 2009; Radin, 2014). On the other hand, conditions that decrease RBC turnover will result in a falsely elevated A1c (for instance, iron deficiency anemia, Vitamin B12 deficiency anemia, folate deficiency anemia) (Radin, 2014). In these situations in which the validity of the A1c is in question, Dr. Isaacs notes that an OGTT can be useful. 

Alternate metrics

Fructosamine (which measures the level of glycated proteins in the blood, primarily albumin, and reflects an average glucose level over 1-3 weeks) is not used to diagnose diabetes or prediabetes. There is no universally accepted reference range for fructosamine and it can vary between laboratories, and it is thus difficult to interpret and has limited clinical utility, according to Dr. Isaacs. 

CGMs are not currently approved for the diagnosis of prediabetes or diabetes (American Diabetes Association Professional Practice Committee, 2024), though a CGM can give an estimated average glucose (EAG) which is an estimate of the A1c based on the CGM data. 

Formulas such as the HOMA-IR, HOMA-B, and QUICKI use fasting glucose and insulin levels to estimate insulin resistance and beta-cell function. These are mainly used in research settings rather than in clinical practice. In the case of estimating insulin resistance, Dr. Isaacs finds the physical exam much more useful.

Role of the physical examination in assessing insulin resistance

As the patient walks in the door, you can evaluate their body habitus for central adiposity (e.g. weight concentrated around the midsection with leaner hips and thighs), which is associated with insulin resistance.

Waist circumference is another important part of the physical examination (Ross et al 2020). One tip that Dr. Isaacs shares to more easily measure waist circumference is to hand the patient the end of the tape measure and ask them to turn around and do a little spin. Waist circumference should be measured at the iliac crest rather than the belly button (Ross et al 2020), as the belly button location can be variable. Dr. Isaacs notes that waist circumference does not need to be measured in patients with a BMI > 35.

Finally, the skin provides critical clues to insulin resistance. Look for skin tags (small skin growths usually on the neck or groin) and acanthosis nigricans (Serap Karadag et al 2018) (dark, velvety patches of skin that are actually a carpet of miniature skin tags; these are typically most prominent on the neck, face, armpits, umbilicus, groin, elbows, knees, and hands – especially the knuckles). In women, look for acne and hirsutism that can hint at PCOS (which is associated with insulin resistance), though these signs are less specific. 

Explaining a diagnosis of prediabetes to patients

When talking to patients, Dr. Isaacs emphasizes that glucose is a continuous spectrum of risk, rather than distinct conditions with clear boundaries. He explains that progression from normal glucose levels to prediabetes to diabetes is a gradual process influenced by various factors, including lifestyle, genetics, and metabolic health, and there is a lot patients can do to prevent this progression.

In talking to patients, Dr. Isaacs emphasizes a complications-centric rather than glucocentric approach (Samson et al, 2023). He stresses that it is important to think about the big picture and discuss prevention of overall cardiometabolic risk and multi-morbidities (cardiovascular disease, steatotic liver disease, CKD, HFpEF), rather than just focusing on the blood sugar perspective. In this vein of a complications-centric rather than glucocentric approach, Dr. Isaacs will center his conversation with patients around the five AACE goals for the management of prediabetes (Samson et al, 2023): 1) Diabetes Prevention, 2) Improving CVD Risk Factors, 3) Preventing Progression of MASLD, 4) Weight Loss and Preventing Weight Gain, and 5) Improving Functionality and Quality of Life. 

Atypical types of prediabetes

While most patients with prediabetes will have pre-type 2 diabetes, it is important to not miss atypical types of prediabetes.

Pre-type 1 diabetes

According to Dr. Isaacs, clinicians should consider screening for pre-type 1 diabetes (also known as Stage 2, type 1 diabetes) in any patient with prediabetes who has evidence of autoimmune disease (including vitiligo, Hashimoto’s, celiac disease, rheumatoid arthritis, IBD, lupus, or others) given the link between type 1 diabetes and other autoimmune conditions (Nederstigt et al 2019). Dr. Isaacs notes that other populations with prediabetes who should be screened for pre-type 1 diabetes include those who are younger (<age 40), have a family history of type 1 diabetes (American Diabetes Association Professional Practice Committee, 2024), or have a lower BMI; screening should also be considered in patients with a family history of autoimmune diseases. Of note, patients can have both insulin resistance and autoimmune type 1 diabetes (so-called “double diabetes).

To test for pre-type 1 diabetes, Dr. Isaacs recommends obtaining diabetes autoantibodies (American Diabetes Association Professional Practice Committee, 2024). It is ideal to test for multiple diabetes autoantibodies, and many labs will offer a package for type 1 diabetes autoantibodies including Glutamic Acid Decarboxylase Antibodies (GAD-65), Insulin Autoantibody (IAA), Insulinoma-associated protein 2 autoantibody (IA-2A), Zinc transporter 8 autoantibody (ZnT8A), and Islet cell cytoplasmic autoantibodies (ICA). However, if you can only obtain one test, Dr. Isaacs recommends favoring the Glutamic Acid Decarboxylase Antibodies (GAD-65), which is found in 70-80% of patients with type 1 diabetes at clinical presentation (Notkins et al, 2001).

Dr. Isaacs will also obtain a fasting insulin and C-peptide when evaluating for pre-type 1 diabetes. Normal levels of insulin or C-peptide do not exclude pre-type 1 diabetes, but a lower fasting insulin or C-peptide in the setting of an elevated fasting glucose is suggestive of insulin deficiency and pre-type 1 diabetes.

Pancreatic “prediabetes”

Pancreatic “prediabetes” should be considered in patients with a history of pancreatitis, a history of pancreatic exocrine insufficiency (diarrhea, steatorrhea), or patients with a normal body weight who do not have other signs of insulin resistance. It is important to differentiate pancreatic prediabetes from other types of prediabetes as it can affect your management; for instance, you may start insulin sooner in a patient with pancreatic diabetes due to the association with insulin deficiency (Rickels et al, 2013).

Dr. Isaacs notes that 80% of patients with newly diagnosed pancreatic cancer have prediabetes or diabetes (Hart et al, 2016), but extremely rare for this to be a cause of prediabetes, and it is generally not recommended to screen individuals with prediabetes or diabetes for pancreatic cancer.

Cushing’s syndrome

Early Cushing’s can be difficult to spot and can mimic obesity / insulin resistance. On exam, clinicians should look out for cushingoid body habitus (central obesity, moon face, supraclavicular and dorsocervical fat pads), striae (especially wide >1 cm red / purple striae), thin skin in a young person, easy bruising, and proximal muscle weakness. Testing for Cushing’s can be done using the 1 mg overnight dexamethasone suppression test, late-night salivary cortisol, or the 24-hour urine free cortisol.

Dr. Isaacs notes that clinicians should be aware of Mild autonomous cortisol secretion (MACS), a common condition characterized by autonomous secretion of cortisol by the adrenal glands without overt clinical manifestations of Cushing’s syndrome, and which can increase the risk of dysglycemia and cardiometabolic comorbidities (Pelsma et al, 2023; Prete et al, 2022). MACs is typically picked up during hormonal screening for adrenal incidentalomas. Clinicians should also be suspicious of MACs in patients with resistant diabetes (e.g. patients with uncontrolled diabetes on three or more agents). While it isn’t possible to screen everyone with prediabetes for MACS, it is important to keep this condition in mind, especially in patients with prediabetes who have any adrenal abnormalities.

Acromegaly

Acromegaly was classically called the “handshake” diagnosis as it can cause swelling / growth of the hands or feet and old-time endocrinologists would pride themselves on making the diagnosis with a handshake. Asking about an increase in ring or shoe size can be a key question. Other signs of acromegaly include facial changes (thickening of facial features, protruding lower jaw, increases in spaces between the teeth often picked up on by dentists), deepening of the voice, thick oily skin, arthritis, and headaches. The screening test for acromegaly is an IGF-1 level; if the IGF-1 level is elevated, then a growth hormone suppression test should be obtained to confirm the diagnosis (Fleseriu et al, 2022).

Management of prediabetes

Dr. Isaacs will typically tell his patients that their risk of progression from prediabetes to diabetes is about 5-10% per year, but he emphasizes that this is their risk only if nothing is done, and that there is a lot of opportunity for modifying this risk.

Lifestyle changes

The landmark Diabetes Prevention Program (DPP) study found that intensive lifestyle modification (resulting in a 7% weight loss) was associated with a 58% reduction in the progression to diabetes compared to placebo (Knowler et al, 2002). Thus, healthy eating and exercise can have a large impact. Dr. Isaacs will start with the “easy wins”, including discussing cutting out sodas or sweet tea (in the South) and minimizing processed foods. He will then discuss the need for a caloric deficit for weight loss. Regarding particular types of diets (DASH, Mediterranean, ketogenic, etc), Dr. Isaacs doesn’t favor one diet over another, but rather emphasizes that patients should choose what works best for them and that they can sustain long-term.

Metformin

Metformin is the first line medication option for prediabetes. In the DPP study, metformin resulted in a 31% reduction in the progression to diabetes compared to placebo (Knowler et al, 2002). According to Dr. Isaacs, metformin results in a ~3-5% weight loss for most individuals, which likely contributes to its role in diabetes prevention. In the DPP study, metformin was most effective in individuals with a BMI of 35 or greater, women with a history of gestational diabetes, and individuals <60 years old (Diabetes Prevention Program Research Group, 2019). 

Dr. Isaacs will typically titrate patients up to a metformin dose of 2 grams per day over a few months. The immediate release (IR) formulation comes in 500, 850, and 1000 mg pills, and should be taken with meals (optimal time is in the middle of meals) to minimize GI side effects. The ER formulation comes in 500 and 750 mg pills (1000 mg pills are available but are expensive and very large), and can be taken with or without food. The IR formulation gives slightly more weight loss, though the ER formulation is better tolerated, and thus Dr. Isaacs tends to prefer the ER formulation. 

Dr. Isaacs also notes that clinicians should be aware of metformin “ghosts”, which are the remnants of ER metformin tablets in the stool and are often mistaken for undigested medications or intestinal parasites. These are benign and the medication has been absorbed, but sometimes patients can be startled by them.

Pioglitazone 

Pioglitazone has been shown to reduce the risk for type 2 diabetes in two landmark studies: 1) the ACT NOW trial, which demonstrated that pioglitazone resulted in a 72% reduction in progression to type 2 diabetes in patients with impaired glucose tolerance (DeFronzo et al, 2011), and 2) the IRIS trial, which demonstrated that pioglitazone reduced the risk of progression to diabetes by 52% in patients with insulin resistance and a history of stroke or TIA (Kernan et al, 2016). 

Dr. Isaacs notes that pioglitazone is the only medication that works by directly lowering insulin resistance (as opposed to secondarily reducing insulin resistance via weight loss). Pioglitazone is cost-effective and has a wide range of other benefits, including reducing cardiac events, strokes, inflammation, adverse lipid profiles, and hepatic steatosis / MASH.

Pioglitazone does carry risks, including weight gain, though Dr. Isaacs notes that weight gain is more significant with the 45 mg dose and is minimal (1-2%) with the 15 mg dose. He will tend to stick with the lower (15 mg) dose of pioglitazone, and combine it with weight loss-promoting agents like metformin, SGLT2 inhibitors, or GLP-1 agonists; this combination typically results in no weight gain. Other side effects of pioglitazone include edema (5-8%), which is most prominent in combination with insulin or amlodipine. Pioglitazone does not cause heart failure, though it can cause fluid retention, so should be avoided in patients with class III or IV CHF. Bone loss is also a concern, so a DEXA should be considered prior to pioglitazone use in post-menopausal women or other patients at risk of low bone density.

GLP-1 agonists

GLP-1 agonists have been found to reduce the risk of diabetes by about 75-95%. The studies that established the benefit of GLP-1 agonists in diabetes prevention were the SCALE Obesity and Prediabetes trial for liraglutide (le Roux et al, 2017), the SELECT and STEP trials for semaglutide (Perrealt et al, 2022; Kahn et al, 2024), and the SURMOUNT trial for tirzepatide (Jastreboff et al, 2025).

There is no good data on the efficacy of combined GLP-1 agonist and metformin compared to either medication alone in patients with prediabetes, though Dr. Isaacs uses this combination in practice.

GLP-1s are also important agents in pursuing a complications-centric rather than glucocentric approach to prediabetes / diabetes given their positive impact on various cardiometabolic complications / multi-morbidities, including cardiovascular health, sleep apnea, and renal function.

Other options 

Acarbose was found to reduce the risk of developing type 2 diabetes in the STOP-NIDDM trial (Chiasson et al, 2002), but Dr. Isaacs said it is rarely prescribed due to significant GI side effects.

Phentermine / topiramate can also help prevent diabetes due to its role in promoting weight loss.

Follow-up in patients with prediabetes

For patients with a normal A1c, guidelines recommend re-screening every three years ((American Diabetes Association Professional Practice Committee, 2024), though Dr. Isaacs usually screens more often (~once per year). For patients with prediabetes, guidelines recommend re-checking A1c once per year (American Diabetes Association Professional Practice Committee, 2024), though Dr. Isaacs will typically check more frequently, as he said it provides helpful feedback / motivation for patients. 

Links

1. 2025 AACE Annual Meeting

Goal

Listeners will develop an approach to screening for and managing prediabetes.

Learning objectives

After listening to this episode listeners will…

1. Identify a framework for who to screen for prediabetes / diabetes.
2. Develop an approach to explaining prediabetes to a patient
3. Recognize key principles in managing prediabetes, including lifestyle changes and the role of metformin and GLP-1 agonists

Citation

Gandhi MM, Isaacs S, Surani Z, Williams PN, Watto MF. “#481 Prediabetes and Diabetes Prevention with Dr. Scott Isaacs”. The Curbsiders Internal Medicine Podcast. thecurbsiders.com/category/curbsiders-podcast Final publishing date 28 April, 2025.