Espresso: Cord Prolapse

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What is cord prolapse? 

  • Definition 

    • When the cord moves out of the cervix in front of the fetal presenting part; can usually only happen when rupture of membranes has occurred 

      • Otherwise, it is called funic presentation (cord presenting with intact membranes)

    • Uncommon: 1.4-6.2/1000 

    • Majority of them happen in singleton gestation, but there is an increased risk in twin pregnancies of the second twin 

  • Risk Factors

    • PPROM - especially if the fetus is not in the cephalic position 

    • Multifetal gestation 

    • Polyhydramnios 

    • Fetal growth restriction 

    • Preterm labor 

    • AROM when fetal head is not well engaged 

      • Nearly half of cases are attributed to iatrogenic causes 

      • 57% occur within 5 minutes of membrane rupture, and 67% occur within 1 hour of rupture 

  • Why do we care? 

    • Compression of the cord → vasoconstriction and → fetal hypoxia 

    • Can lead to fetal death or brain damage if not rapidly diagnosed and managed 

How can I recognize cord prolapse? 

  • Exam 

    • Palpation of a pulsatile mass in the vaginal vault or at the cervix 

    • No need for radiographic or laboratory confirmation 

  • Fetal heart tracing 

    • Usually can see recurrent variable decelerations or fetal bradycardia 

  • Differential diagnosis 

    • Another mass in the vagina could be fetal malpresentation 

    • Other causes of fetal bradycardia/decelerations should also be considered 

How do I manage cord prolapse if it is found? 

  • Reduction of the cord – if possible 

    • This is usually not possible if there is large amount of cord in the vagina, and not recommended 

    • However, if there is small amount of cord at the internal cervical os, at times, it is possible to reduce it back beyond the present part 

    • However, if there is recurrent prolapse … 

  • Expedient delivery

    • Usually via cesarean delivery 

    • Prior to getting to the operating room, the goal should be decompression of the umbilical cord 

      • Elevate the fetal presenting part as interval to umbilical cord decompression can be associated with worse outcomes than interval to delivery 

        • Decompression can be done manually: place finger or hand in the vagina and gently elevate the head or presenting part off of the umbilical cord 

        • Do not put additional pressure on the cord → can lead to vasospasm 

      • Another way of decompression 

        • Place pregnant patient into steep Trendelenburg or knee-chest position 

        • Usually if there is not a provider who is able to do manual decompression or if there is prolonged interval to delivery (ie. transfer to hospital) 

      • If there is visible cord protruding from the introitus, try to place a warm, moist sponge or towel over the cord to prevent vasospasm

        • Or can replace into vagina 

What are the outcomes, and how do I prevent prolapse? 

  • Prognosis 

    • Fetal mortality is <10% now that we are able to complete cesarean sections in a timely manner 

    • In earlier studies, the range was 32-47% 

    • Gestational age and location of prolapse (in or out of hospital) can significantly determine outcomes 

      • Cord prolapse outside of hospital carries 18x increased risk of fetal mortality 

  • Prevention 

    • For patients who are at increased risk of cord prolapse (ie. PPROM, malpresentation), they should be encouraged to deliver at a hospital 

    • Early recognition training by both patient and providers

      • SIM! 

    • ACOG recommend against routine amniotomy in normally progressing labor unless needed for fetal monitoring 

      • AROM - if needed, make sure that there is engagement of the fetal head 

      • If AROM is needed, but there is polyhydramnios or high fetal station, can use a fetal scalp electrode to rupture the amniotic sac to slowly release fluid 

Espresso: Uterine Rupture

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What is uterine rupture? 

  • Definition

    • Spontaneous tearing of the uterine muscles which can lead to expulsion of the fetus into the peritoneal cavity

    • In the literature, uterine rupture can also incorporate less catastrophic phenomena, like uterine window or asymptomatic scar dehiscence without expulsion of the fetus

    • Focus today: intrapartum uterine rupture.

    • The true incidence of uterine rupture across all populations in pregnancy is likely very low.

      • With no history of surgery, the risk is 1/8000-17,000 deliveries 

    • With one prior low transverse cesarean, the incidence has been reported to be between 0.2-1.5%, though usually quoted as <1% 

    • With two prior low transverse cesareans, the incidence is reported to be between 0.8-3.9%, usually quoted as just over 1% 

    • However, there are things that can modify this risk: 

      • History of prior successful VBAC → reduce the risk of rupture from 1.1% to 0.2% 

    • In other types of incisions such as T-incisions and classical incisions, the rate of rupture can be as high as 4-9%

  • What are some other risk factors? 

    • By far, the biggest one is previous uterine surgery,

    • Other risk factors: 

      • Uterine scar presence

      • Uterine anomalies

      • Prior invasive molar pregnancy

      • History of placenta accreta spectrum

      • Malpresentation

      • Fetal anomaly

      • Obstructed labor

      • Induction of labor with use of prostaglandins

        • These other risk factors are much less significant than prior uterine surgery/presence of scar  

How do I recognize uterine rupture?

  • Again — only be discussing uterine rupture in labor 

    • There are a few studies looking at thinning of the myometrium on ultrasound, but this is controversial.

    • It is much more likely that you will encounter uterine rupture at time of labor and birth than during other times 

  • Diagnosis

    • High index of suspicion - know your patient’s risk factors and be on the lookout for uterine rupture given how catastrophic it can be for both maternal and fetal wellbeing 

    • Some of the classical signs: 

      • Sudden, tearing uterine pain

      • Vaginal hemorrhage

      • Cessation of contractions 

      • Destationing of the fetal head 

    • However, these classical signs are actually not necessarily reliable and not always present! 

    • The most reliable presenting clinical symptom is actually fetal distress 

      • One study of 99 patients with uterine rupture showed: 

        • Only 13 patients reported pain and 11 had vaginal bleeding 

        • However, bradycardia or signs of fetal distress (decelerations) were present in the majority.

    • Ultrasound examination 

      • Not necessarily reliable and if you are truly suspicious of uterine rupture, this should prompt immediate delivery 

  • Why do we need to diagnose uterine rupture promptly? 

    • Maternal complications

      • Maternal circulatory system delivers 500 cc of blood to the uterus every minute 

      • Uterine rupture increases the risk of hemorrhage, with studies showing that about 50% of cases result in EBL of 2000cc or greater 

      • This can lead to need for blood transfusion, and in more dire circumstances, hysterectomy  

    • Fetal complications 

      • Depends on how quickly the neonate is delivered after recognition of uterine rupture 

      • One study showed a neonatal mortality rate of 2.6%, and increases to 6% if uterine rupture occurs outside of the hospital

        • Older literature report rates as high as 13%  

      • Many neonates will require resuscitation and admission to the NICU 

Management

  • The best form of management is prevention or setting expectations - ie. counseling 

    • All patients who desires a trial of labor after cesarean section should be counseled about the risks and benefits of TOLAC 

    • Patients should deliver at a location where labor and delivery staff, anesthesia staff, and neonatal staff are available 24 hours in order to facilitate prompt delivery if needed. 

    • Patients who are at high risk of uterine rupture (ie. classical cesarean, T-incision, prior uterine rupture, >2 cesarean sections, history of prior fundal surgery) should be counseled against TOLAC 

    • We did a whole episode on TOLAC counseling back in 2019, so check it out here: https://creogsovercoffee.com/notes/2019/9/22/trial-of-labor

      • Note that the VBAC calculator we included in those notes is outdated! 

    • There is a new VBAC calculator available that does not include race as a predictor: https://mfmunetwork.bsc.gwu.edu/web/mfmunetwork/vaginal-birth-after-cesarean-calculator

  • What if it happens? The answer is prompt delivery via cesarean delivery 

    • Urgent delivery - as quickly as possible, but within 30 minutes generally 

    • Patient can be under general anesthesia or if they already have working regional anesthesia, this can also be used 

    • Cesarean delivery should be performed, and if there is a uterine rupture, the neonate can often be delivered via the area of rupture without creating a new hysterotomy 

      • However, if there is just a uterine window, a hysterotomy may be needed 

    • Once the neonate is delivered, pediatrics should be there immediately to facilitate resuscitation 

    • If uterine rupture is confirmed, a full exam of the uterus should be done to assess for other injury 

      • Ie. bladder injury, broad ligament hematoma 

    • If possible, the area of rupture should be repaired 

    • However, if it is not possible to repair the rupture due to significant damage, patient is not stable, or significant hemorrhage, then the next step should be hysterectomy 

  • Follow-up 

    • Debriefing - this should occur with the team who was present for uterine rupture 

    • But also, should discuss with your patient when they are at a place when they can discuss what happened 

    • Counsel patient that if they desire future pregnancy, TOLAC should not be attempted due to increased risk of repeat rupture 

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