Persistent Vulvar Pain

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Reading: Committee Opinion No. 673 - Persistent Vulvar Pain 

What is persistent vulvar pain? 

    • Persistent vulvar pain is a complex disorder and often very frustrating to both the patient and the provider 

    • Because it is difficult to treat and even with appropriate treatment, pain may not resolve completely 

  • Terminology and Classification - from 2015 Consensus Terminology and Classification of Persistent Vulvar Pain 

    • From the International Society for Study of Vulvovaginal Disease: 

      • Can be caused by a specific disorder or it can be idiopathic 

      • Idiopathic vulvar pain = vulvodynia

    • Vulvar pain caused by specific disorder: 

      • Infectious (ie. recurrent candidiasis, herpes) 

      • Inflammatory (lichen sclerosus, lichen planus, etc.) 

      • Neoplastic (ie. Paget disease, SCC) 

      • Neurologic (postherpetic neuralgia, nerve compress or injury) 

      • Trauma

      • Iatrogenic (postoperative, chemotherapy, radiation) 

      • Hormonal deficiencies (ie. genitourinary syndrome of menopause, lactational amenorrhea) 

    • Vulvodynia = vulvar discomfort, most often reported as burning pain, which occurs in the absence of relevant visible findings or a specific, clinically identifiable neurological disorder for at least 3 months 

      • Descriptors 

        • Localized (ie. vestibulodynia, clitorodynia), general, or mixed (can be localized or generalized) 

        • Provoked (ie. insertional, contact), spontaneous, or mixed (provoked and spontaneous) 

        • Onset (primary or secondary) 

        • Temporal pattern (intermittent, persistent, constant, immediate, delay) 

How do we evaluate what the cause of vulvar pain is? 

  • Exclude other causes before assigning vulvodynia 

    • Vulvodynia = diagnosis of exclusion 

  • History

    • Do your normal OPQRS – how long has the patient been having pain? Where is it? 

    • Also obtain medical and surgical history

    • Sexual history - make sure to ask permission 

    • Allergies 

    • Previous treatment 

  • Physical exam 

    • Know your anatomy!  

UPTODATE

  • Cotton swab test

    • Using a cotton swab and moving across the labia → start on thighs → labia majora → interlabial sulci. Then test vestibule in the 2, 4, 6, 8, 10 o’clock position 

  • R/o infection  

    • Wet mount, vaginal pH, fungal culture, and gram stain 

  • Vulvoscopy - usually not needed 

  • If there is concern, you can also biopsy an area - can find dermatoses 

  • Musculoskeletal evaluation 

    • Palpation of the different muscles within the pelvis to see if there is referred pain

    • Palpation of the pubovaginalis portion of the levator ani, obturator internus, and urethrovaginal sphincter 

Treatment 

  • Unfortunately, the evidence for treating vulvodynia is based on clinical experience and observational studies - few randomized studies exist 

    • If there is obvious cutaneous or mucosal disease present 

    • If there is not, do the cotton swab test 

      • If no areas of tenderness then consider alternative diagnosis 

      • If there is tenderness or burning with cotton swab test, do a yeast culture 

        • Positive yeast culture: antifungal 

        • If negative, or if antifungal does not provide adequate relief, move to:

          • Vulvar care measures

            • Cotton underwear and no underwear at night 

            • Avoid vulvar irritants and douching 

            • Mild soaps for bathing, or anti-allergenic soaps, do not apply directly to vulva 

            • Apply preservative free emollient (ie. coconut oil) 

            • Switch to 100% cotton menstrual pads 

            • Use water based lube for intercourse 

            • Cool gel to vulvar area for relief 

          • Topical medications - ie. estrogen cream, tricyclic antidepressants can be compounded 

          • Oral medications - TCAs and anticonvulsants; use one drug at a time 

            • TCAs should be used for up to 3 weeks to assess adequate pain control 

          • Injections (ie. botox for trigger point injections, can also use steroids for trigger point injections ) 

          • Biofeedback/physical therapy - assess for pelvic floor dysfunction 

          • Dietary modification 

          • CBT 

          • Sexual counseling 

        • If still no adequate relief and localized pain → can consider surgery with vestibulectomy 

          • Should only be done if other treatments have failed 

          • Success rate is 60-90% compared to 40-80% for nonsurgical interventions 

        • If generalized pain - consider increasing the dose of medication, combining meds, etc. 

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

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