#168 Diabetes Update with Jeff Colburn MD

August 26, 2019 | By Matthew Watto, MD

SGLT2 inhibitors, GLP1 agonists, insulin therapy, A1C pitfalls, glycemic targets, and more!

Step up your diabetes game! We answer your questions from #MedTwitter. Returning guest, Jeff Colburn MD, FACP, FACE (USU) gives us a much needed diabetes update. Topics include: the pitfalls of A1C testing, the A1C target controversy, lifestyle interventions, continuous glucose monitoring, pathophysiology of type 2 diabetes (T2DM), use of SGLT2 inhibitors, GLP1 agonists, and how to initiate and titrate insulin therapy. 

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Credits

Writer (including CME Questions) and Producer: Matthew Watto MD, FACP

Cover Art and Infographic: Bryan Brown MD

Hosts: Stuart Brigham MD; Matthew Watto MD, FACP; Paul Williams MD, FACP

Editor: Matthew Watto MD, FACP; Emi Okamoto MD

Guest: Jeff Colburn MD, FACP, FACE

Time Stamps

• 00:00 Pun, Intro, disclaimer, and guest bio
• 03:55 Guest one liner
• 05:45 Picks of the week*: Illusions (book) by Richard Bach, Industrial Accident: The Story of Wax Track Records (Documentary), Free Solo (Documentary), Peter Attia’s The Drive (Podcast) -episode with Jason Fung MD
• 12:28 A case of Type 2 Diabetes (T2DM); Four potential pitfalls when checking A1C 
• 19:58 Does tight glucose control improve outcomes?
• 24:05 Continuous glucose monitoring
• 29:08 Pathophysiology of diabetes and the metabolic syndrome
• 33:13 Beta cell regeneration
• 35:10 Can intensive lifestyle changes reverse T2DM?; DIRECT trial 
• 37:50 Next steps for patients uncontrolled on metformin; SGLT2 inhibitors – considerations for use, risk and benefits, how to counsel patients
• 42:40 SGLT2 inhibitors and degree of hyperglycemia; How real are concerns about amputations and Fournier’s gangrene?; How does eGFR affect their use and efficacy?; Euglycemic DKA
• 49:51 GLP1 agonists. Now available as oral agents.
• 53:40 2019 ADA guidelines for the management of hyperglycemia
• 54:51  How to manage the use of both insulin and oral hypoglycemic agents in combination
• 56:48 Insulin therapy. Choice of agent. How to start it. How to titrate.
• 60:40 Can patients with T2DM ever stop insulin?
• 62:00 Adding GLP1 and SGLT2 agents on top of insulin therapy
• 65:30 Using loop diuretics with SGLT2 inhibitors
• 66:30 Take home points
• 69:06 Outro

Diabetes Update Pearls from Kashlak

Dr. Colburn mentions the following rough calculation: A1C of 6% = average glucose of 126 mg/dL. Add 30 mg/dL for every 1% increase in A1C (e.g. 7% = average glucose 156 mg/dL and so forth).

When adding an SGLT2 inhibitor to insulin therapy, Dr. Colburn recommends lowering a patient’s total daily insulin dose by 20-30% to prevent hypoglycemia –expert opinion.

Check a basic metabolic panel one week after initiation of an SGLT2i –expert opinion.

Dr. Colburn points out that lower limb amputations, euglycemic DKA and Fournier’s gangrene are infrequent adverse outcomes with the use of SGLT2 inhibitors and should not prevent most patients from deriving a therapeutic benefit –expert opinion.

Once weekly GLP1 agonists take about 5 half lives (5 weeks) to reach steady state. Dr. Colburn recommends lowering a patient’s total daily insulin dose by 20-30% to make room for these agents –expert opinion.

Dr. Colburn recommends starting at basal insulin of 0.2-0.3 units per kg body weight per day. Target a fasting glucose of 80-130 mg/dL and go up by 2 units every 3 days until goal –expert opinion. Add short acting insulin once basal insulin reaches more than 50 units per day. At that point the patient is adequately “basaled” –expert opinion. 

Dr. Colburn recommends continuing metformin, GLP1 agonists and SGLT2 inhibitors in patients starting insulin therapy. They may serve as insulin sparing agents. Conversely, if adding a GLP1 agonist or SGLT2 inhibitor to insulin therapy, consider decreasing the current total daily dose of insulin by 20-30% to avoid hypoglycemia –expert opinion.

The A1C – “Ayyy One Sea!”

Four potential pitfalls when checking Hemoglobin A1C: 

1. High highs and low lows might average out to a favorable A1C. But, this is a far cry from someone with steady glucose control who has the same A1C value. 
2. A1C has a variability of 0.5% when run on the same patient on the same day. 
3. Long lived RBCs have time to accumulate excess sugars and thus A1C is falsely elevated (e.g. chronic iron deficiency anemia). Patients with fast RBC turnover can have a falsely low A1C (e.g. sickle cell, recent bleeding events, hemolysis) —Radin 2014. 
4. African American patients have an A1C that runs about 0.5% higher (Selvin 2011, Bergenstal 2017) than their actual average blood glucose (if compared to readings from a continuous glucose monitor). The mechanism is not clear. 

Estimating average blood glucose from A1C

Kashlak Pearl: Dr. Colburn mentions the following rough calculation: A1C of 6% = average glucose of 126 mg/dL. Add 30 mg/dL for every 1% increase in A1C (e.g. 7% = average glucose 156 mg/dL and so forth).

Diabetes Update: A1C targets and preventing complications

Dr. Colburn notes that glycemic control in type 2 diabetes (T2DM) is probably a minor factor in preventing macrovascular disease (strokes and heart attacks) compared to control of lipids, hypertension and improved lifestyle factors. The discordance between the observed benefits of strict glycemic control and guideline recommendations for strict A1C targets has been pointed out by some prominent endocrinologists —Rodriguez-Gutierrez R, Montori V 2016. See previous Curbsiders’ episode for more details –#96 Diabetes, a1c targets and acp guidelines controversy.  

Microvascular complications might be prevented by strict glycemic control (A1C <7%), but the data is based on surrogate markers (e.g. laser photocoagulation and albuminuria), NOT hard endpoints (e.g. renal failure, blindness, painful neuropathy) —Rodriguez-Gutierrez R, Montori V 2016.

The 2018 ACP Guidance Statement on A1C Targets for Glycemic Control in T2DM recommends an A1C of 7-8% for most patients with T2DM. The VA/DoD guidelines from 2017 (co authored by Dr. Colburn) share a similar target –see table below (Conlin PR, Colburn J et al 2017).

Table 1. Determination of average target HbA1c level over time (VA/DoD 2017) -The Curbsiders Diabetes Update

Continuous glucose monitoring (CGM)

Consider a CGM for patients with T1DM or patients with T2DM on intensive insulin therapy. For most patients who need more intense monitoring, Dr. Colburn recommends checking glucose four times daily in the week before an office visit to get a sense of glucose control. Check fasting glucose (used to dose long acting insulins), before lunch, before dinner and one postprandial glucose (2 hrs after any meal) –expert opinion.

Diabetes Update: Intensive lifestyle interventions

The DIRECT trial showed promise for reversal of T2DM during a primary care-led weight-management programme (Lean 2019). That said, Dr. Colburn worries that some patients may have already lost too much beta cell function to benefit from intense lifestyle modifications (i.e. they’ve lost the ability to produce sufficient insulin). Such patients will likely still need conventional therapy.

Mayo Clinic Shared Decision Making 

Dr Colburn recommends this resource to assist in shared decision making – Diabetes Medication Choice | Mayo Clinic Shared Decision Making …

2019 ADA Guidelines for the Management of T2DM

See Figure 4 https://clinical.diabetesjournals.org/content/37/1/11.figures-only 

SGLT2 inhibitors (SGLT2 i)

Kashlak Pearl: When adding an SGLT2 inhibitor to insulin therapy, Dr. Colburn recommends lowering a patient’s total daily insulin dose by 20-30% to prevent hypoglycemia –expert opinion.

For more tips on how to use SGLT2 inhibitors —#51 Diabetes treatment in 2017: New meds, insulin, and cardiac risk reduction

CV and Renal considerations

SGLT2 inhibitors provide cardiovascular (Zelniker 2019) and renal protection (Sedu 2018, CREDENCE Trial 2019). But, they are not effective for patients with an eGFR under 30. Thus, they’re not recommended for use in CKD 4-5, mainly because of decreased effectiveness at lower GFRs. These agents are particularly good for preventing hospitalization for heart failure. Dr. Colburn attributes this to their ability to improve blood pressure by exerting a diuretic effect. 

SGLT2i and Diuretics

Dr. Colburn recommends stopping thiazide diuretics in patients initiating an SGLT2 inhibitor due to risk of AKI and hypovolemia. On the contrary, he often continues loop diuretics alongside SGLT2 inhibitors, especially if these patients are euvolemic or hypervolemic. 

Kashlak Pearl: Check a basic metabolic panel one week after initiation of an SGLT2i –expert opinion.

Diabetes Update: SGLT2i Adverse events

Kashlak Pearl: Dr. Colburn points out that lower limb amputations, euglycemic DKA and Fournier’s gangrene are infrequent adverse outcomes and should not prevent most patients from deriving a therapeutic benefit –expert opinion.

Gential fungal infections

SGLT2 inhibitors have a clear association with fungal infections of the genitals (vaginal candidiasis in women and balanitis in men) —Johnnson 2013. 

Lower limb amputations

Lower limb amputations were increased by two fold in patients taking SGLT2 inhibitors in a study of registry data (Ueda 2018). BUT, a recent pooled meta-analysis of randomized controlled trials found only a small increased risk of amputations (Donnan 2019). Many clinicians recommend avoiding these agents in patients with peripheral vascular disease or history of previous amputations until we have more information…but this remains expert opinion.

Fournier’s Gangrene

The FDA recently issued a warning about the association of SGLT2i with Fournier’s gangrene (Bersoff-Matcha 2019). Dr. Colburn points out that this complication is a rare occurrence. 

Diabetes Update: GLP1 (Glucagon-like peptide 1) Agonists

An oral version of semaglutide seems promising and probably has similar outcomes to injectable GLP1 agonists (Husain 2019). 

Mechanism of actions

GLP1 is an endogenous hormone that improves glucose-dependent insulin release from the pancreas, decreases inappropriate glucagon secretion and slows gastric emptying (Lexicomp).

Benefits of GLP1 Agonists

The LEADER trial (Marso 2016) and others since showed a reduction in cardiovascular events among those with known (or at high risk) for CV disease. These drugs are associated with weight loss and drop A1C values by about 2%. They rarely cause hypoglycemia and the main side effect is nausea. 

Kashlak Pearl: Once weekly GLP1 agonists take about 5 half lives (5 weeks) to reach steady state. Dr. Colburn recommends lowering a patient’s total daily insulin dose by 20-30% to make room for these agents –expert opinion.

For more tips on how to use GLP1 agonists —#51 Diabetes treatment in 2017: New meds, insulin, and cardiac risk reduction

Diabetes Update: Insulin therapy

Dr. Colburn points out there is no clear benefit of any specific insulin formulation over others for patients with type 2 diabetes (e.g. glargine vs degludec OR aspart vs lispro).

Kashlak Pearl: Dr. Colburn recommends starting at basal insulin of 0.2-0.3 units per kg body weight per day. Target a fasting glucose of 80-130 mg/dL and go up by 2 units every 3 days until goal –expert opinion. Add short acting insulin once basal insulin reaches more than 50 units per day. At that point the patient is adequately “basaled” –expert opinion. 

Kashlak Pearl: Dr. Colburn recommends continuing metformin, GLP1 agonists and SGLT2 inhibitors in patients starting insulin therapy. They may serve as insulin sparing agents. Conversely, if adding a GLP1 agonist or SGLT2 inhibitor to insulin therapy, consider decreasing the current total daily dose of insulin by 20-30% to avoid hypoglycemia –expert opinion. 

Goals

Listeners will explain the pitfalls of hemoglobin A1C testing and targets; choose oral and injectable agents to manage type 2 diabetes (T2DM); and counsel patients about the risks and benefits of various treatment options.

Learning objectives

After listening to this episode listeners will…

1. Determine appropriate hemoglobin a1c goals for patients with T2DM and explain the pitfalls of A1C testing
2. Discuss the role of exercise and lifestyle modification in the treatment of diabetes and insulin resistance
3. Identify patients who might benefit from SGLT2 inhibitors and GLP1 agonist medications
4. Counsel patients about the renal and cardioprotective effects of SGLT2 inhibitors
5. Counsel patients about the various benefits of GLP1 agonists including cardioprotective effects
6. Choose an appropriate medication regimen for patients with T2DM
7. Determine need for insulin therapy and choose an appropriate regimen
8. Discuss the utility of continuous glucose monitors

Links*

1. Illusions (book) by Richard Bach
2. Industrial Accident: The Story of Wax Track Records (Documentary)
3. Free Solo (Documentary)
4. Peter Attia’s The Drive (Podcast) – episode with Jason Fung MD

*The Curbsiders participates in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising commissions by linking to Amazon. Simply put, if you click on my Amazon.com links and buy something we earn a (very) small commission, yet you don’t pay any extra.

Citation

Colburn J, Brigham SK, Williams PN, Watto MF. “#168 Diabetes Update with Jeff Colburn MD”. The Curbsiders Internal Medicine Podcast. http://thecurbsiders.com/episode-list. August 26, 2019.

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