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 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

Diabetes I: Beyond Gestational DM

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What is diabetes?

  • Diabetes is a Greek word meaning siphon - to pass through.

    • Mellitus, which is the common form we think of, is a Latin word meaning “sweet.” 

    • Insipidus, which is another form of diabetes we won’t talk about today, is a Latin word meaning “tasteless.” 

      • These terms refer to the effect of the disease on the urine, where mellitus is the passage of glucose through urine, making it sweet; while insipidus is unregulated water passing through urine, making it dilute.

  • Diabetes mellitus:

    • Around 8.8% of the world’s population has diabetes mellitus.

    • There are two main types.

      • Type 1 DM: this refers to a deficiency of insulin (10-15% of those with DM)

      • Type 2 DM: this refers to a resistance to insulin (85-90% of those with DM)

Type 1 Diabetes 

  • Insulin deficiency 

    • Thought to be primarily related to an autoimmune process leading to loss of pancreatic beta-cells.

  • Previously referred to as “juvenile diabetes” owing to predilection for onset in childhood:

    • 90,000 children diagnosed each year worldwide

    • Most common form of diabetes in those under age 15

      • Peak incidence at 12-14 years of age.

  • Has geographic predilection for Scandinavia, Europe, North America, and Australia. Incidence:

    • Over 10/100k in Europe, Russia, USA, Canada, Australia

    • Relatively rare in Asia - China, India, Middle East all <5/100k

  • Clinical onset of diabetes is marked by hallmark symptoms, and these are ultimate reason for diagnosis in >95% of cases:

    • Polydipsia (increased thirst)

    • Polyuria (increased urination)

    • Weight loss

    • Abdominal pain

    • Ketoacidosis (previous podcast!)

  • Given the insulin deficiency, treatment revolves around replacement of insulin with synthetic forms.

    • No successful studies thus far with immunologic interventions or preventive therapies.

Type 2 Diabetes

  • Acquired insulin resistance

    • This operates in three ways of pathophysiology:

      • Peripheral tissue insulin resistance: 

        • Overactivation of peripheral insulin receptors leads to downregulation - tissues are overextended.

      • Pancreatic beta cell dysfunction: 

        • Beta cells churning out loads of insulin - they get tired and “wear out.” 

      • Pancreatic alpha cell function increasing:

        • Hypothesized that the bar for hypoglycemia is raised physiologically - so inappropriate, early secretion of glucagon keeping blood sugars high.

    • T2DM’s insulin resistance is similar to gestational diabetes mellitus, where secretion of human placental lactogen creates an adaptogenic resistance to insulin (increasing glucose availability from the fetal perspective).

  • T2DM has a high prevalence worldwide, and is increasing.

    • A global pandemic of metabolic disease?!

      • Some estimate over 590 million worldwide will be affected by 2035.

      • Increasing prevalence worldwide, but most notable in US, Asia-Pacific, North Africa.

    • Highly associated with obesity - 90% of patients are obese or overweight at diagnosis.

      • Excess energy consumption combined with insufficient energy expenditure.

      • Generally adult-onset, but increasing prevalence in younger populations particularly with comorbid obesity.

  • Clinical onset is not typically acute:

    • Prediabetes often is manifest in these patients before diagnosis

      • 5-10% progress from prediabetes to T2DM annually.

      • Can be manifest for years-decade before progression.

    • Can manifest with similar acute symptoms to T1DM, but is most commonly insidious.

      • May be diagnosed incidentally with other healthcare-seeking, particularly major metabolic disease events (MI, stroke) or in seeking unrelated care (i.e., surgeries).

      • Common less acute presentations can include:

        • Fatigue, malaise

        • Infections (i.e., recurring genitourinary candidiasis)

        • Blurred vision

Some other, rarer forms of diabetes mellitus:

  • Latent autoimmune diabetes in adults (LADA) - a special type of DM that shares features with T1 and T2DM

    • Some may refer to this as “type 1.5” because of the mixed features:

      • Does not require insulin therapy for the first six months after diagnosis.

      • Typically acquired after age 35

      • Autoimmunity of T1DM - identifiable autoantibodies against pancreatic beta cells.

    • Depending on the stage in which they are identified or treated in their disease course, they may be responsive to oral insulin-sensitizing medications, or may require insulin.

  • Maturity Onset Diabetes of the Young (MODY) - hereditary form of DM with disruption of insulin production.

    • Typically an autosomal dominant inheritance:

      • Affected individuals have a 50% chance of passing to offspring.

    • Depending on the affected gene, hyperglycemia may be mild or severe, and treatment depends on which form of MODY a patient has.

    • Must be diagnosed before age 25.

  • Cystic fibrosis associated diabetes - given the failure of the exocrine pancreas in CF, most patients will develop a T1DM-like diabetes over time.

    • As therapies have gotten better for CF, some patients also develop T2DM features.

  • Steroid-associated diabetes - given hyperglycemia-inducing effects, those on chronic steroid therapy can develop diabetes akin to type 2 diabetes.

Diagnosing Diabetes Mellitus

  • Type 1 and type 2 diabetes 

    • Diagnosed according to the same ADA criteria for diabetes - one or more of:

      • Fasting glucose of > 126 mg/dL (with fasting defined as no caloric intake for at least 8 hours).

      • Glucose of > 200 mg/dL on a 2 hour, 75g oral glucose tolerance test (OGTT).

      • Hemoglobin A1c of > 6.5%.

      • Random glucose of > 200 mg/dL in a patient with classic hyperglycemia symptoms.

  • Prediabetes 

    • Diagnosed with any of the following:

      • Hemoglobin A1c of 5.7 - 6.4%.

      • Glucose of 140-199 mg/dL on a 2 hour, 75g OGTT.

      • Fasting glucose of 100-125 mg/dL

Complications of Diabetes

  • Acute

  • Chronic

    • Most of the major complications of diabetes that we think about result from chronic disease.

    • Many of the complications are due to microangiopathy, or damage to smallest blood vessels.

      • Excess blood glucose likely leads to incorporation of the excess sugar within capillary basement membranes.

      • This incorporation of excess sugar weakens the basement membranes, making them prone to micro-aneurysms.

      • When the microaneurysms rupture, new vessels and connective tissue must form, which causes sclerosis and narrowing of the arterioles surrounding the capillary.

      • This overall leads to worsened tissue perfusion and tissue function, and ultimately systemic hypertension.

    • Microangiopathy shows up everywhere:

      • Nephropathy

        • Damage to the renal glomeruli (capillaries of the kidney involved in filtration) worsen their filtering ability → glucosuria → microalbuminuria → CKD, renal failure, dialysis.

      • Neuropathy

        • Damage to the small vessels leading to nerve endings ultimately starves them of oxygen, impairing sensation.

          • This tends to develop in a “stocking and glove” form, affecting most distal extremities (smallest capillaries).

      • Retinopathy

        • Damage to small vessels in the retina, with growth of poor quality small new blood vessels (proliferative retinopathy) → macular edema → blindness 

          • Diabetic retinopathy is the most common cause of blindness among non-elderly adults in the world.

      • Sexual and reproductive dysfunction

        • Damage to small vessels leads to decreased sensation in women (and erectile dysfunction in men).

        • Infertility is more prevalent in patients with type 1 diabetes.

        • PCOS / oligo-ovulatory states are linked with insulin resistance and diabetes.

      • Encephalopathy

        • Linkage of diabetes and microvascular changes in the brain to cognitive decline, dementia.

    • Ultimately, this microangiopathy will contribute to the development of macroangiopathy, affecting larger blood vessels and complications such as:

      • Coronary artery disease → angina, myocardial infarction

      • Peripheral vascular disease → claudication, diabetic foot → amputation

      • Ischemic strokes

      • Hypertension