Diabetes V: Intrapartum and Postpartum Glucose Management

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Great! Your patient is here in labor or for induction… now what?

  • Glycemic goals - why do we have them and what are they? 

    • Why do we have them? 

      • It is a good idea to avoid hyperglycemia in labor due to risk of fetal hypoxemia and neonatal hypoglycemia 

      • Fetal hypoxemia 

        • Some evidence that fetal hypoxia can result from diabetes with uncontrolled blood sugars 

        • Also increased blood sugars that lead to ketoacidosis can increase fetal acidosis and hypoxia 

      • Neonatal hypoglycemia 

        • Increased maternal blood sugars increases fetal production of insulin 

        • High levels of insulin after delivery with no exposure to maternal blood sugar → hypoglycemia and NICU admission 

    • What are they? 

      • Initially, there was recommendation by ACOG that blood sugar be between 60 -100 mg/dL

      • However, there was a study that showed that tight control maternal control did not results in better initial neonatal glucose concentrations compared to a more liberalized management strategy 

      • Hamel H et al 2019, Obstet Gynecol: https://pubmed.ncbi.nlm.nih.gov/31135731/

      • The goals can be different depending on your institution, but based on the above study, the goal is to be between 60 - 120 mg/dL 

      • Based on ACOG’s Practice Bulletin, goal should be <110 mg/dL 

  • How often should we monitor blood sugar? 

    • ACOG recommends checking blood sugar levels q1 hour in active labor 

    • If not on an insulin drip and during labor, please follow the protocol at your hospital, as certain hospitals have adopted a more liberalized form of glucose management 

    • One example of protocol: 

      • If not in active labor, can check blood sugar every 4 hours 

      • In active labor, can check every 2 hours, but if needs treatment → recheck in 1 hour after treatment 

    • If we follow Hamel et al’s protocol, the plan is to check every 4 hours, but to check more frequently if treatment is needed 

Example protocol - acog practice bulletin, pregestational diabetes mellitus

Treating Hyperglycemia

  • Use insulin! 

      • Coming in for scheduled induction/cesarean: we usually ask patients to take half the dose of long acting insulin.

        • Example: patient is on 20 NPH during the day and 40 NPH at night. They are coming in for a 7 am induction and will not be eating much during labor 

        • Patient should be instructed to take 40 NPH the night prior (to help with fasting), and can be given or should take 10 u NPH that morning, as patient likely will not be eating much during the day they are being induced 

        • Do not take short acting insulin the day of if patient is not eating 

    • In patients who come in laboring:

      • Ask patients what insulin they have taken that day 

      • If still in labor and time for long acting insulin, if patient is not eating, can plan for half of the long acting insulin 

    Ok, so that takes care of long acting insulin, but what if the patient is having elevated blood sugars during labor? 

    • Short acting insulin 

      • If a patient is having elevated blood sugars above protocol, they can be given short acting insulin to bring down their blood sugars 

      • How much to give: 

        • This will come down to the patient, but this is a good time to remember the rules we taught you before! 

        • Type 1s: use the rule of 1800: 1800 / TDD insulin (units) = expected ICF

        • Type 2/GDM: use the rule of 1500: 1500 / TDD insulin (units) = expected ICF

          1. So if I’m taking 50 units total of insulin per day, as a T2DM/GDM I would have a correction factor of 30 - meaning 1u of insulin would bring my blood sugar down about 30 mg/dL

          2. This is helpful for the floor - if you need to cover someone, knowing their total daily insulin dose (or approximating using their weight) can help you provide more reliable amounts of insulin. 

        • You may also have protocols within your hospital with certain types of sliding scales 

    • Insulin drip 

      • Who needs an insulin drip? 

        • Patients whose blood sugars are difficult to control 

          1. Very high blood sugars (>200 mg/dL) 

          2. Those who require multiple treatments with short acting insulin (> 2 times, usually)

          3. Those who have an insulin pump that cannot be used in the hospital 

      • How do I manage an insulin drip? 

        • Most of the time, insulin drips should be co-managed either with endocrinology or with MFM - so ask for help! 

        • We cover this in our episode for diabetic ketoacidosis!

        • As a brief overview: the insulin in a drip is usually regular or rapid-acting insulin 

          1. Most of the time, if the blood sugar is <200mg/dL, there is a protocol in the hospital to follow for labor 

          2. Can usually start at 1-1.5u/hr, but if patient is in DKA or has very high blood sugars, can also start at 0.1u/kg/hr or even first start with a bolus of 0.1u/kg 

        • Blood sugar should be checked every hour and insulin drip can be adjusted up and down by 1u/hr depending on blood sugar control 

  • Hypoglycemia - Low blood sugars 

    • If patient is not eating or patients with T1DM, they will need to placed on some form of dextrose so that they do not go into DKA; pregnant patients are also more likely to be in euglycemic DKA 

    • Again, there is usually a protocol in the hospital, but these patients should be placed on D5NS if not eating and in active labor or if blood sugar drops <70 mg/dL 

    • These can follow the usual maintenance fluid calculations, using the 4-2-1 formula for how much fluid is needed per hour 

      • 4 mL/kg/hr for the first 10 kg 

      • 2 ml/kg/hr for the second 10 kg 

      • 1 ml/kg/hr for the remainder 

      • Example 

        • For a patient who weighs 70kg: 

          1. 40 ml/hr (4*10) + 20 ml/hr (2*10) + 50 ml/hr (1*50) = 110 ml/hr 

    • Another method to calculate is 2.5mg of dextrose/kg/min 

    • For everyone who is getting insulin, you should order an as needed D50 injection or D25 injection depending on what your hospital has 

      • This is in the event of acute hypoglycemia or who may be unresponsive and not able to take PO 

    • If someone is able to take PO, you should follow the 15/15 rule: basically, consume 15g of glucose and check blood sugar in 15 minutes 

      • Usually 3 glucose tablets 

      • Approximately 4 oz of regular juice or soda

Let’s say we get our patient through labor and birth … what about the postpartum period? 


  • Insulin requirements postpartum 

    • Insulin requirements go down significantly postpartum, especially if the patient is breastfeeding 

    • If the patient was on insulin prior to pregnancy, they should return to their prepregnancy insulin regimen 

    • If patients were not on insulin, but were diagnosed with T2DM during their pregnancy, then during recovery in the hospital, our general recommendation depends on pre-pregnancy or early pregnancy A1C 

      • For T2DM, patients with A1C > 9.0%, they should generally stay on insulin 

      • If <9.0%, then can have discussion with endocrinology and MFM to try oral medications, and would need to be safe during breastfeeding if patient desires to breastfeed 

        • Hopefully this plan was made as an outpatient! 

      • General consensus for continuing insulin is to half their long acting insulin and then put them on a sliding scale 

      • After approximately 24 hours, calculate how much sliding scale they needed, and this can be turned into short acting insulin if needed 

      • Consult endocrinology and MFM for guidance, and also make sure patient has endocrinology or PCP follow up 

Diabetes IV: Continuous Glucose Monitors (CGMs)

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Background 

  • What is a continuous glucose monitor? 

    • CGM - a wearable device typically put on the back of the arm, stomach, or buttocks that is composed of a sensor and a transmitter 

      • The sensor is a small needle/probe that sits in the skin and measures interstitial blood sugar 

      • It typically will clip into a transmitter that can then send this information to a device (ie. via bluetooth to your phone or to a website that your physician can check) 

      • Sometimes, it requires scanning the transmitter with a phone or another device to show the blood sugar 

    • Some logistics 

      • Typically can be worn for 7-14 days 

      • Should be active >70% of the time 

    • Other cool things it can do 

      • Also, certain CGMs can sync with insulin pumps to help better regulate blood sugar (ie. closed-loop insulin technology) 

  • Who will you see that has a CGM? 

    • Most likely patients with T1DM - insurance is more likely to cover 

    • Some patients with T2DM, though much less common 

    • Now, it seems that more patients with GDM who are not able to do fingersticks may obtain or desire a CGM.

    • Glycemic targets in pregnancy

      • Remember that the ADA and ACOG recommends targets for fasting of <95 mg/dL, 1 hr postprandial <140 mg/dL, and 2-hour postprandial of <120 mg/dL  

What are the numbers I should be looking at in a CGM? 

  • The targets can be confusing because instead of just 4 time points, we now have many, many more! 

    • Many CGMs will sample blood sugar every 5 minutes 

  • Things to look at should be glucose targets 

    • Targets can be individualized, but in pregnancy, the target should be between 63-140 mg/dL per the ADA 

    • Can ask patient to generate a report for you or when you log into their reports, you can generate a report for the last XX amount of days 

    • Some people will spend some time both above and below target (note that some patients’ targets may be individualized and different) 


Is a CGM actually useful in treating diabetes? (ie. does it improve outcomes?) 

    • Multiple studies done in patients with T1DM and pregnancy 

  • Largest: Continuous Glucose Monitoring in Women with Type 1 Diabetes in Pregnancy (CONCEPTT) - multicenter RCT that compared self-monitored blood glucose + CGM to SMBG alone in 325 women who were either planning pregnancy or who were pregnancy 

    • Those with CGM had a small but statistically significant difference in A1C (-0.19%) 

    • Those with CGM in pregnancy had statistically significant less time above range than control, without an increase in time below range or in number of severe hypoglycemic episodes 

    • Also there were differences in neonatal outcomes! 

      • In CGM group, there was lower incidence of:

        • LGA

        • Neonatal hypoglycemia,

        • NICU admissions

  • What about T2DM? 

    • Outcomes here are less robust, and there are fewer studies - no RCTs have specifically studied T2DM in pregnancy with CGM to date 

  • GDM?

    • Largest study was prospective cohort in 2014 - 340 women with GDM who had 4 weeks of blinded CGM + standard care or standard care alone

      • Those blinded to CGM had lower rate of preeclampsia, improvement in CGM metrics, and lower rate of neonatal composite outcome (ie. premature delivery, macrosomia, LGA status, SGA, obstetric trauma, neonatal hypoglycemia, hyperbilirubinemia, and respiratory distress)  

    • Studies also show that those with CGM are more likely to receive insulin therapy 

  • So some conclusions: 

    • Clearly, CGM can improve outcomes in T1DM and those that are pregnant

    • Less clear in those who have T2DM and GDM 

How do I manage those with CGMs? 

  • This should be done with endocrinology or MFM 

    • The goal is to get the patient at least 70% into the target range as described above

    • We won’t go into pumps  

  • For those with injectable insulin

    • It is still helpful to look at when the patient is having spikes in blood sugar and adjust based off of that 

  • If there are spikes after breakfast or dinner → add fast acting or regular insulin at those times 

  • If there are spikes with lunch → can either add fast acting with lunch or increase long acting in the morning 

  • If there are spikes with fasting, look at overnight glucose 

    • If there is a drop in glucose in the middle of the night (ie. 4 am) and then an increase, this is known as the Somogyi effect 

    • The way to address this is either (1) to decrease night time long acting insulin or (2) to add a protein snack after dinner 

  • If overall blood sugar is elevated in the AM between meals, can increase AM long acting insulin 

Diabetes III: Insulins

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What is insulin?

  • Peptide hormone produced by pancreatic beta cells

    • Regulates metabolism by promoting absorption of glucose from blood into liver, fat, and muscle, for these cells to convert to glycogen or fat.

    • Simultaneously, is a strong inhibitor of gluconeogenesis in the liver.

  • How did we get synthetic insulin?

    • 1869 - Paul Langerhans identifies small tissue clumps throughout the bulk of pancreas not previously described in Western literature - islets of Langerhans (where Beta cells are clustered)

    • 1889 - Joseph Von Mering removes pancreas from a healthy dog and identifies sugar in the urine, which was later isolated to the function of the islets of Langerhans.

    • 1916 - Nicolae Paulescu develops a pancreatic extract that normalizes blood sugar in diabetic dogs.

    • 1921 - Frederic Banting and Charles Best isolate extract from islets in dogs, and later move towards experiments in cows.

    • 1922 - Leonard Thompson, a 14-year old Canadian boy, receives first injection of insulin from cows

      • So impure he suffered a severe allergic reaction.

      • Received another injection 12 days later which was noted to eliminate his glucosuria.

    • 1922 - the team of researchers, recognizing the need for quality control and safe distribution, make a pact to patent insulin and transfer it to a public university.

      • They settled on the University of Toronto, which bought the patents to insulin and the purification processes of bovine insulin in 1923 for $1.

      • Banting and JRR Macleod would share the 1923 Nobel Prize for this work.

    • 1978 - first synthetic “human” insulin was engineered in E. coli with recombinant DNA technology by the Beckman Research Institute and Genentech.

      • Genentech would go on to sell the first commercially available form of this - Humilin.

  • Today, there are multiple types of insulin used for optimal control of diabetes mellitus, all of which are synthetic forms.

    • However, shared amongst them has been the absurdly high cost in the USA. 

  • New legislation has spurred reduction in cost which will start benefiting patients this year!

    • Inflation Reduction Act 2023: Capped cost of insulin at $35/mo for all Medicare beneficiaries

      • Eli Lilly subsequently announced (March 1, 2023) that they are capping out-of-pocket insulin costs at $35/mo.

        • www.insulinaffordability.com will allow all patients regardless of insurance status to procure Lilly-branded insulin at $35/mo.

        • Some of these price changes will not take effect until later in 2023.

      • Sanofi (maker of Lantus) has also capped the cost of Lantus at $35/mo as of March 16.

      • Novo Nordisk (maker of NovoLog) will follow with plans to implement cost-lowering on its insulin products on Jan 1, 2024.

Types of Insulin

  • Broadly, five main types: ultra-long acting, long-acting (basal), intermediate-acting, short-acting, and rapid acting

    • We’re going to stick with three categories for ease - basal (long-acting), intermediate, and short/rapid.

    • You may also see forms of insulin we mention in “U200” or “U500”

      • These are “ultra concentrated.” 

      • Typically, insulin in rapid-acting forms is concentrated at 100 units per mL - “U100.”

        • If you see U500, for example - that means that the concentration is now 500 units in one mL - or five times more concentrated.

        • These formulations are helpful for patients who have high insulin requirements, and are available across the spectrum of long-to-rapid acting insulins.

  • Long-Acting, Basal Insulins

    • These provide a low-peak, sustained coverage of insulin over multiple hours-days. 

      • “Background coverage” of insulin so there is always some on board - in effect, these control your fasting blood sugar values.

      • Long-acting coverage is obtained by modifying the base insulin molecule with an amino-acid substitution or linking to other molecules to slow absorption 

    • Varieties:

      • Degludec

        • Brand name: Tresiba

        • Duration of action: 42 hours

          • Minimizes plasma concentration variability with once-daily dosing.

        • No noticeable “peak of action” - so minimal nocturnal hypoglycemia.

      • Glargine

        • Brand name: Lantus, Basaglar, Semglee, Toujeo (U300)

        • Duration of action: 24 hours

          • Half life is 12 hours, though, so some individuals benefit from BID dosing.

        • No noticeable “peak of action.”

      • Detemir

        • Brand name: Levemir

        • Duration of action: Less than 24 hours

          • Often requires BID dosing, particularly in T1DM or pregnancy.

        • Does have a small peak effect at 6-8 hours post-injection.

  • Intermediate-Acting Insulins

    • These are not quite enough to provide full coverage through the day, but in practice are often employed in multiple injection therapies for basal coverage of fasting and nighttime sugar levels.

    • Varieties:

      • Neutral protein Hagedorn (NPH) 

        • Suspension of insulin, protamine, and zinc in a buffered solution that helps to delay release of insulin in the bloodstream.

        • Duration of action: 14-16 hours

          • Requires BID dosing to achieve basal coverage

        • Peak effect: 4-6 hours

          • If given at night, a bedtime snack is frequently required to avoid nocturnal hypoglycemia

          • There can also be a “dawn effect” that is pronounced with NPH - fasting concentrations remain above target, as the insulin effect peaks early relative to waking time.

        • Can be mixed with regular insulin or rapid-acting insulins to minimize the number of daily injections. 

          • Regular insulin should be drawn up before the NPH to avoid injecting buffer solution into the rapid-acting insulin vial.

      • U-500 regular insulin

        • We’ll talk more about regular insulin momentarily, but U500 is the 5x concentrated form of it. 

        • Duration of action: approximately 20 hours

        • Peak effect: 4 hours

          • In effect, similar to NPH, but has a quicker peak onset.

        • Rarely used in T2DM, but given that the GLP-1 agonists are not used in pregnancy, occasionally you may encounter this for patients needing lots of insulin.

          • Important to recognize that given the high concentration, the pharmacokinetics actually are closer to an intermediate than a short-acting in this form.

  • Short/Rapid-Acting Insulins

    • These insulins are intended to provide rapid coverage, typically in response to mealtime insulin demands.

      • These are also the insulins that you will see in insulin drips and insulin pumps, as they rapidly change blood glucose concentrations and if given IV or constantly SQ, need to be frequently titrated to maintain control.

    • Varieties:

      • Regular insulin

        • Human insulin is complexed with zinc, slightly delaying absorption.

        • Duration of action: ~8 hours

        • Peak effect: 2-3 hours

          • This can be challenging timing, as postprandial rise in blood sugar usually occurs at ~1-2 hours after eating

          • Because of this, some folks using regular insulin may have post-meal hypoglycemia if they eat meals not containing much carbs/fat.

      • Rapid acting insulins - aspart, lispro, glulisine

        • All are human insulin analogs with amino acid modifications to facilitate rapid absorption.

        • Duration of action: ~4 hours

        • Peak effect: ~1 hour

          • Preferred insulin in pumps - most of the algorithms driving pump management are built on rapid-acting insulin pharmacokinetics.

          • Recognize that when correcting with rapid acting insulin, you are only getting to peak effect at 1 hour - so careful with redosing frequently, as you may “stack” insulin effect and cause hypoglycemia with frequent boluses.

            • We’ll save intrapartum glucose management for another episode!

UPTODATE

Approach to Insulin Therapy

  • In pregnancy, insulin requirements:

    • May decrease slightly in the first trimester, particularly pronounced at about 10 weeks.

    • After 10-12 weeks, insulin needs start to increase rapidly thanks to the action of the placenta.

    • By the end of pregnancy:

      • T1DM: expect 2-3x increase in insulin requirement 

      • T2DM: expect 3-6x increase in insulin requirement

    • These insulin requirements then rapidly fall off postpartum with the loss of the placenta and the mediating hormones in insulin resistance, hPL and progesterone.

    • Historically, with pregnancy and DM control, we’ve employed a split-mix regimen.

      • We covered this in our previous episodes with Dr. Coustan on GDM, but we’ll re-link that algorithm to our website.

      • This is built off of using NPH for basal coverage, and regular or rapid-acting insulins for meal coverage, with cheap insulin and convenient 2x daily injections.

      • Potential disadvantages:

        • NPH - we discussed the challenges with peak-effect issues of NPH

        • Fasting control - may need to split into three injections, with NPH taken just before bed, to improve control if the nighttime peak is too early

        • Risk of nocturnal hypoglycemia - for the same reason

      • How to start a split-mix regimen:

        • Specifically in the context of GDM, and T2DM – for T1DM, please do not do this (though they’ll come to you on their insulin of choice already).

          • Weight in kg, x 0.7 - 1.0  (based on trimester/underlying insulin resistance) = total daily insulin dose

          • Split into ⅔ of that into AM dose, and ⅓ into PM dose.

          • AM dose: ⅔ should be NPH, and ⅓ should be rapid-acting.

          • PM dose: ½ should be NPH, and ½ should be rapid acting (though you may find some folks need less rapid acting and more basal).

    • More and more, we’re seeing folks utilize a basal-bolus regimen.

      • This combines a newer, longer-acting basal insulin with rapid-acting insulin to cover mealtimes.

      • Advantages:

        • For GDM and T2DM, basal insulin may be all that is needed for some individuals with appropriate lifestyle counseling.

        • Basal provides more stable overnight coverage.

        • Rapid-acting insulin allows for individual meal titration (whereas with split-mix, your AM NPH covered lunch – what if the nausea comes and you can’t eat lunch?)

      • Disadvantages:

        • For GDM and T2DM in particular, we may be slower to getting folks to control as we may be prone to be less aggressive with upfront insulin - completely anecdotal, don’t have to say it.

        • Requires 4-5x daily injections - most basal insulins cannot be mixed with rapid-acting insulins.

      • How to start a basal-bolus regimen:

        • Again, specifically in the context of GDM or T2DM in pregnancy:

          • Weight in kg x 0.7 - 1.0 (based on trimester/underlying insulin resistance) = total daily insulin dose – this step is the same.

          • Split into 50% basal coverage, and 50% mealtime coverage.

            • Based on your insulin of choice, your basal may be injected once or twice daily.

            • Rapid mealtime coverage split into TID, but dose may vary by time of day and number of carbs patient eats.

              • For even tighter control, rather than a set number of units with mealtime coverage, patients can calculate the dose to give with a carb ratio.

                • You can approximate carb ratios for mealtime coverage using the rule of 500

                  • 500 / TDD = number of grams of carbs covered by 1u of insulin.

                  • So if my expected TDD is 50u (based on our previous weight calculation), my carb ratio would be 1:10

        • Some folks may need only basal coverage to get controlled, and that’s OK!

          • You can start at some reasonable dose of basal insulin, then have the patient increase by 2u every other day until fastings are under 95 mg/DL.

          • Reassess mealtime control at that point and need for mealtime insulin.

    • How to titrate insulin to achieve better control:

      • Small steps are OK – adjust by small amounts (10% steps) most frequently.

      • If you’re finding globally high or low sugars, consider where your basal insulin is at - this likely needs adjustment.

      • If you’re finding situationally high sugars, recall some pregnancy physiology that can make insulin timing challenging:

        • Delayed gastric emptying: may need to “pre-bolus” rapid insulin 30-45 mins before a meal to allow for mealtime peak and insulin peak to coincide better.

        • Nausea: similarly, may need to split rapid insulin up into microboluses, as folks may not eat what they originally intended to eat!

      • Know your insulin correction factor (ICF) 

        • This is the expected blood sugar drop in mg/dL for every 1 unit of correctional insulin given.

          • I.e., an ICF of 50 means that my blood sugar will drop 50 mg/dL for every unit of correctional insulin given.

        • ICF is a function of expected total daily dose of insulin:

          • Type 1s: use the rule of 1800: 1800 / TDD insulin (units) = expected ICF

          • Type 2/GDM: use the rule of 1500: 1500 / TDD insulin (units) = expected ICF

            • So if I’m taking 50 units total of insulin per day, I would have a correction factor of 30 - meaning 1u of insulin would bring my blood sugar down about 30 mg/dL

            • This is helpful for the floor - if you need to cover someone, knowing their total daily insulin dose (or approximating using their weight) can help you provide more reliable amounts of insulin. 

    • Disclaimer regarding all of this:

      • While we love to provide this as a guide that has been pretty consistent across places we’ve trained, please do not substitute this for true medical advice!

        • Some folks may be more insulin sensitive, particularly with longstanding T1DM with comorbidities, or insulin-naive folks with GDM.

        • These are some good starting rules that are generally helpful, but your mentors can help guide you with more complex or concerning scenarios.

Diabetes II: Goals and Treatment with Non-Insulins

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Treatment Goals for Diabetes

  • Once diagnosed with DM, the goal is to improve glycemic management. 

  • A general target to start is an A1c of < 7.0%.

    • An A1c of 7% corresponds to an average estimated glucose of 154 mg/dL - so obviously there is room for improvement!

      • Why 7%, then?

        • An A1c drop of 1% corresponds to important improvements in microvascular outcomes, with diminishing returns once you get below 7%.

    • Just to provide some reference ranges for what it looks like below 7%:

      • A1c 6.5%: 140 mg/dL (the point at which prediabetes becomes diabetes)

      • A1c 6.0%: 126 mg/dL

      • A1c 5.7%: 117 mg/dL (the point at which we diagnose prediabetes)

      • A1c 5.5%: 111 mg/dL

      • A1c 5.0%: 96.8 mg/dL

        • Check out MDCalc to play with the A1c conversion calculator. 

    • With older age, targets can become more permissive as absolute benefit is lessened.

  • Treatment goals should also align with other comorbid conditions that predispose to cardiovascular disease:

    • Smoking cessation

    • Reducing lipids with statin therapy

    • Diet

    • Exercise

    • Weight loss

  • Patients can have A1c checked approximately every 3-6 months, and/or engage with some form of glucose checking.

    • With insulin therapy, CGM or fingersticks are a must due to risk of hypoglycemia.

    • Self-monitoring of blood glucose is not necessary in most patients with T2DM (outside of pregnancy), but may be beneficial to provide data to patients in their lifestyle interventions.

    • Remember our targets for therapy in pregnancy:

      • Fasting: 95 mg/dL

      • 1 hour postprandial: 140mg/dL, OR

      • 2 hour postprandial: 120 mg/dL

Lifestyle Changes and their Importance with Diabetes Control

  • All patients with new diabetes should receive intensive education regarding nutrition and diet, weight management, exercise, and the potential role of surgical therapy.

  • Diagnosis of diabetes can be a “wake up call” for many patients who may have otherwise been in denial - and we should take advantage to help them achieve new, healthier goals.

    • Nutrition, Diet, and Weight Loss

      • Focusing on consistency in carb intake, avoiding weight gain, and balanced nutrition.

      • Despite importance of weight loss, few patients achieve and sustain substantial weight loss.

        • Benefits even at 5-10% weight loss, but most significant at > 15%.

      • Caloric restriction can be helpful in resolving diabetes:

        • DiRECT Trial - T2DM of less than 6 years and not on insulin, randomized to intensive supervised caloric restriction vs usual care.

          • 24% of therapy group had lost 15kg or more of body weight at 1yr (vs 0% of usual care).

            • This was only maintained by 11% in the intervention group at 2 years.

          • 46% of therapy group had resolved DM at one year (vs 4% in control)

            • This was maintained by 36% (vs 3%) at two year follow up.

    • Exercise

      • Regular exercise is beneficial, independent of weight loss!

        • Can also delay or reverse progression of prediabetes to T2DM

      • Recommendations:

        • 30-60 mins of moderate intensity aerobic activity (40-60% VO2 max) on most days of the week (i.e., 150 mins per week, not skipping more than 2 days in a row).

        • Resistance training at least twice per week.

    • Surgical Weight Loss

      • Results in largest degree of sustained weight loss in those with T2DM and obesity

      • Appropriate for patients with:

        • BMI > 40, or

        • BMI >35 - 39.9 when hyperglycemia is inadequately managed by lifestyle measures and optimal medical therapy

    • Emotional Support and Psychotherapy

      • Many patients with these diagnoses may suffer from depression concurrently which can interfere with self care.

      • Psychotherapy may improve some measures of diabetes management and glycemic control based on metaanalysis of 12 trials.

Pharmacologic Therapy

  • When to start it?

    • Advised to start concurrently with diagnosis if A1c is > 7.5 - 8%, alongside lifestyle interventions.

    • If a highly motivated patient is near 7.5%, it is reasonable to trial 3-6 months of lifestyle modification before starting.

  • What med do I start?

    • For most patients, metformin is a reasonable first option.

    • However, it is getting added alongside or replaced by some newer therapies more these days!

      • Based on initial A1c, patient conditions, and tolerance of side effects, this is an individualized decision that likely is best decided with PCP or endocrinologists - though OB/GYNs may be writing for these meds, especially with transition out of pregnancy care.

  • Review of Medications:

    • Metformin

      • Biguanide medication that is standby of T2DM therapy, as it is:

        • Inexpensive

        • Efficacious at reducing hyperglycemia

        • Promotes modest weight loss

        • Well-tolerated.

      • A good first-line choice for most patients. Specific contraindications:

        • GI intolerance - can improve with slower titration or XR formulations

        • CKD/ESRD (GFR < 30) - concern for development of lactic acidosis 

        • Hepatic impairment - risk of hepatotoxicity, lactic acidosis

      • Pregnancy and reproductive considerations

        • Often an excellent choice given metformin may:

          • Promote weight loss

          • Lower A1c and risk of fetal anomalies

          • Appears safe to continue in pregnancy (though does cross the placenta)

    • GLP-1 (glucagon-like peptide 1) agonists - liraglutide, semaglutide, dulaglutide

      • Binds GLP-1 receptors which are present in pancreatic cells, gastric mucosa, and elsewhere.

      • Overall effects include:

        • Stimulating glucose-dependent insulin release from pancreas

        • Slow gastric emptying

        • Inhibit post-meal glucagon release

        • Reduce food intake/appetite

      • Excellent therapy choice alone or as combination with metformin in patients where weight loss is desired

        • Semaglutide in the news lately - Ozempic (brand name) - for weight loss 

        • Can be used in patients with significant renal impairment, unlike metformin

        • Low rates of hypoglycemia

      • Contraindications: 

        • History of pancreatitis - postmarketing reports of hemorrhagic and nonhemorrhagic pancreatitis.

        • Predominantly are injectable medications - so must learn to inject SQ

      • Pregnancy and reproductive considerations:

        • Limited data on exposures and thus not recommended for use prior to, or during pregnancy 

          • Recommended to discontinue > 2 mos prior to pregnancy

        • No breastfeeding data, either.

    • SGLT2 inhibitors - empagliflozin, canagliflozin, dapagliflozin

      • Inhibit SGLT2 receptors in the proximal tubule of the nephron - promoting renal excretion of glucose

      • Generally considered as adjunctive rather than initial therapy, but can be combined with metformin.

        • Good adjunctive therapy choice in T2DM with normal or mild impairment in kidney function not meeting goals with other first line agents, or with other significant comorbidities (cardiovascular disease).

      • Higher rates of hypoglycemia than other meds - should monitor fasting and pre-meal glucoses for a few weeks after starting meds.

      • Contraindications:

        • T1DM

        • CKD with eGFR < 30-45

        • History of prior DKA - can increase risk due to dehydration

          • Obtain ketones in patients with nausea, vomiting, or malaise on these meds and patient should discontinue therapy until symptoms resolve and has been evaluated. 

        • Cause some dehydration due to free water loss with the glucosuria, so should be used with caution in patients on diuretics or other meds that may predispose to AKI

      • Pregnancy and reproductive considerations:

        • Given glucosuria, some patients may be more prone to genitourinary Candida infections - need to be monitored for this and consider discontinuing SGLT2 inhibitors in patients with recurrent bacterial UTIs or GU fungal infections

        • Not recommended in pregnancy due to adverse renal effects observed in animal studies.

        • No breastfeeding data.

    • Sulfonylureas - Glipizide, Glyburide, Glimepiride

      • Bind to a ATP-potassium channel in pancreatic beta cells, blocking them and lowering action potential of the cell → in turn allowing for increased responsiveness of cells to calcium → increasing insulin

      • Can be considered if contraindications to metformin exist, and may be useful in some forms of MODY

        • Often used in combination therapy with metformin

      • Should not be combined with insulin due to higher incidence of hypoglycemia

      • Contraindications:

        • Glyburide avoided in CKD - glipizide is shorter acting and has liver metabolism

        • No demonstrated cardiovascular benefit - so if CVD present, other agents are preferred

        • Patients prone to hypoglycemia - can exacerbate.

      • Pregnancy and reproductive considerations:

        • Once used in pregnancy, but now largely discontinued:

          • Some sulfonylureas (glyburide, glipizide) may persist and be metabolically active in newborns for 4-10 days, predisposing to hypoglycemia if exposed near delivery - advised to discontinue at least 2 weeks prior to delivery.

        • Can be used in breastfeeding - appears safe overall with limited passage into milk.

    • DPP-4 (dipeptidyl peptidase 4) inhibitors - linagliptin, saxagliptin, alogliptin, vildagliptin

      • Endogenous DPP-4 deactivates GLP-1 - so in principle, works like the GLP-1 agonists but increase endogenous supply (rather than providing exogenous stimulation)

        • Effects on GLP-1 activity though are much more modest than with GLP-1 agonists.

      • Generally used as add-on therapy in patients needing additional glucose lowering, as do not have protective cardiac or renal effects (compared to other agents)

        • Can be combined with metformin, TZDs, sulfonylureas, basal insulins, and/or SGLT2 inhibitors.

      • Contraindications:

        • History of pancreatitis

        • Liver disease for some agents - may worsen

        • Heart failure for some patients - may worsen

      • Pregnancy and reproductive considerations:

        • Limited data in pregnancy and reproduction, so are not recommended.

    • Thiazolidinediones - i.e., pioglitazone

      • Work by acting on adipose and muscular tissues to increase glucose utilization, but mechanisms are not entirely understood.

      • Generally an add-on therapy - may rarely be used initially in patients with contraindications to metformin and sulfonylureas, and decline injectable SGLT2 inhibitors

      • Contraindications:

        • Heart failure / any fluid overload

        • History of fracture, or high risk of fracture (i.e., osteoporosis or low BMD)

        • Active liver disease

        • Active or prior history of bladder cancer

        • Pregnancy

        • Macular edema

      • Pregnancy and reproductive considerations:

        • If used in reproductive-aged patients, weight loss and improvement in glycemic control has been shown to cause ovulation in anovulatory patients → unintended pregnancy

        • Limited pregnancy and breastfeeding data, but do cross the placenta; therefore not recommended for use.

Overview literature: NEJM 2021

(c) NEJM 2021

(c) NEJM 2021

Updates on Gestational Diabetes Screening

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We last talked on the podcast about gestational diabetes with Dr. Coustan very shortly after we began in December 2018. Those podcasts are so good, and feature the man himself who is co-credited with the “Carpenter-Coustan” criteria we all know…

But if you’ve been watching journals recently, you probably have seen a lot of interesting papers with respect to GDM screening. So today’s episode will be a bit of an update on part one of those past GDM podcasts! Treatment fortunately hasn’t changed much so we won’t update that part today.

By the way – ACOG PB 190 on Gestational Diabetes Mellitus is still an excellent read!

Physiology of Insulin Resistance in Pregnancy 

  • Progesterone effects on insulin resistance

    • Normally, insulin binds to insulin receptor → phosphorylation of beta-subunit of receptor and leads to phosphorylation of the insulin receptor substrate I (IRS-I) 

    • Progesterone reduces expression of IRS-1  

  • Human placental lactogen effects on insulin resistance

    • Both insulin-like and anti-insulin effects 

    • Generally decreases maternal insulin sensitivity

    • Decreases maternal glucose utilization

    • Increases lipolysis and free fatty acids

      • This allows for free fatty acids to become available for mother’s metabolism (do not cross placenta) so fetus gets glucose preferentially

  • On the fetal side, exposure to hyperglycemia:

    • Leads to increase in its own endogenous insulin production and production of insulin-like growth factor 1

      • These lead to increased growth, fat deposition, and risk for macrosomia.

Prevalence and classifications of diabetes 

  • Prevalence - hard to know b/c not everyone is tested

    • 2009: 7% of pregnancies were in people with diabetes.

      • 86% of these cases were GDM  

  • Classification: The White Classifications

    • Depending on where you are, you may still see these in use; they are also helpful in classifying pre-gestational diabetes.

    • Named for Dr. Priscilla White, who developed the schema in the 1950s and 1960s

      • Class A1: diet-controlled GDM

      • Class A2: medication-controlled GDM

      • Class B: onset at age 20 or older or with duration of less than 10 years

      • Class C: onset at age 10-19 or duration of 10–19 years

      • Class D: onset before age 10 or duration greater than 20 years

      • Class E: overt diabetes mellitus with calcified pelvic vessels

      • Class F: diabetic nephropathy 

      • Class H: ischemic heart disease

      • Class R: proliferative retinopathy

      • Class RF: retinopathy and nephropathy

      • Class T: prior kidney transplant

Complications of GDM - ie. Why do we care? 

  • Maternal complications

    • High risk of developing preeclampsia, undergoing C/S

    • Increased risk of developing type 2 diabetes later in life (up to 70% of patients with GDM develop T2DM within 22-28 years after pregnancy) 

  • Fetal complications

    • Increased risk of macrosomia, neonatal hypoglycemia, hyperbilirubinemia, shoulder dystocia and birth trauma 

    • Increased risk of stillbirth 

    • Fetal exposure to maternal diabetes may contribute to adult-onset obesity and diabetes in offspring 

Screening for GDM - The Basics 

  • Used to be medical history and past obstetric outcomes and family history → fails to get 50% of patients with GDM 

  • All pregnancies should be screened between 24-28 weeks of gestation, with one of two strategies:

    • Two Step:

      • 1973: O’Sullivan et al - described a 1 hr GTT with 50g of glucose  

        • Carpenter-Coustan criteria: positive if >/= 130 mg/dL, though some institutions use 140 mg/dL

      • If screened positive, should get a follow up test with 3hr GTT (100g)

        • Diagnose if 2 abnormal values 

          • However, even 1 elevated → increased risk of adverse perinatal outcomes compared to those without GDM or elevated values

      • Carpenter-Coustan: Fasting: 95, 1 hr: 180, 2 hr: 155, 3 hr: 140  

      • Alternative criteria (not in wide use): National Diabetes Data Group: 105, 190, 165, 145 

    • One-Step alternative screening: International Association for the Study of Diabetes in Pregnancy Group (IASDPG) method:

      • 75g 2hr test - just one test!

      • Fasting: 92 mg/dL, 1hr: 180 mg/dL , 2hr: 153 mg/dL 

      • If > 1 elevated = GDM

  • “Early GDM screening” to look for early gestational diabetes  should be considered in some patients with risk factors.

    • The best test to use for early screening is up for debate, however:

      • Some might consider A1c, but because of new red cell generation / faster turnover in pregnancy, may artificially lower the A1c

      • Some consider using an OGTT, but then it might be hard to convince patients to do it again if they screen negative.

      • Some might consider a trial of “glucose profiling” with a glucometer but not any rigorous testing done about this.

ACOG PB 190


Updates in the World of GDM Screening:

  • What’s better: two-step Carpenter-Coustan style, or one-step IASDPG style?

    • In the last year, two randomized trials (NEJM, AJOG) and a systematic review/meta analysis (Green) have been published to help answer this question. 

    • Because findings are similar, summarized from the meta-analysis:

      • Patients with one-step screening are more likely to be diagnosed with GDM (16.3% vs 8.3% in the meta-analysis)

      • Patient with one-step screening are more likely to be started on medications (7.1% vs 3.8%)

      • Patients undergoing one-step screening were more likely to have NICU admission (5.1% vs 4.5%)

      • Patients undergoing one-step screening were more likely to have babies experience hypoglycemia (9.3% vs 7.6%)

      • Rates of LGA  babies are similar between strategies (8.8% one step, 9.2% two step)

      • Rate of primary cesarean delivery was similar between groups (24.0% one step vs 24.7% two-step).

    • What can we conclude from this?

      • One-step testing seems to lead to increased resource utilization (more diagnoses, more folks on treatment, more NICU admissions)

      • One-step testing does not appear to differ from two-step testing for some maternal short-term outcomes (LGA, cesarean delivery rate) or fetal outcomes (did not cover above but shoulder dystocia, RDS, stillbirth, neonatal death were all similar between groups)

      • We don’t have any significant evidence about long-term outcomes for mother or fetus (i.e., later-in-life diabetes diagnoses, obesity rates in offspring, etc.)

        • An editorial about the meta-analysis makes the case that one-step testing might still be cost-effective if the increased resource utilization means fewer downstream consequences… remains to be seen and tough to study!

  • Early GDM screening: do we have anything new?

    • Since our last podcast, there have been two US-based RCTs about this (Roeder, Harper)

      • In the Roeder paper, patients with an A1c of > 5.7% or fasting glucose of > 92 were randomized to hyperglycemia therapy and nutritional counseling at the time of enrollment (early pregnancy) vs usual timing (3rd trimester)

        • The study was ended early due to poor enrollment, but:

          • Treatment in early pregnancy didn’t improve maternal or neonatal outcomes, including fat mass, weight percentile, macrosomia, or maternal weight gain.

          • Treatment also didn’t significantly reduce the diagnosis rate of GDM at a usual-timing screening test (14.2% early treatment vs 25.8% usual treatment, p=0.17)

      • In the Harper paper, obese patients (BMI > 30) were randomized to a traditional two-step test in early pregnancy (14-20 weeks) versus traditional timing.

        • Those who screened negative early were also re-tested at traditional timing.

        • Early screening did not reduce a composite perinatal outcome, nor did it seem to affect other important secondary outcomes.

      • What can we take away from these papers?

        • We still have a ways to go on proving the value of the “early GDM screen,” particularly of doing multiple glucose challenge tests.

  • Guidance before the 1st step of the two-step approach:

    • One common patient question is whether fasting or eating anything in particular might make one more likely to “screen in” on the 50g, 1h OGTT.

      • In the January 2023 Green Journal, a group at Stanford randomized patients to a 6-hour fast prior to the 1hr test, versus eating within 2hr of the OGTT.

      • The “fed” group actually had a lower rate of screening positive (13%) versus the “fasting” group (31%).

        • Ultimately, the incidence of GDM was also higher in this “fasting” group (12.4% vs 5.1%). 

      • The group theorizes this is due to a phenomenon previously called “starvation diabetes,” in which fasting leads to an increase in glucagon and decrease in insulin, thus making one transiently glucose intolerant; and then later, insulin kicks back in and returns you to a normal metabolic state. 

      • This study only had about 100 individuals per arm of the trial, so hard to draw conclusions about neonatal/obstetrical outcomes, but none different in what they were able to assess.

    • What can we take away?

      • Hard to know totally, but probably don’t encourage fasting prior to the 1hr OGTT!