Diagnosis and Management of Osteoporosis (Hamann 7/23/2026)

 A recording of this presentation is available HERE. 

***

Thanks so much to Dr. Kendal Hamann, SMGR Endocrinologist, for an outstanding Grand Rounds presentation on Osteoporosis. Dr. Hamann covered the basics and the nuances of osteoporosis diagnosis, reminded us that the DEXA scan results are only part of the clinical picture, and clarified when bisphosphonates should be first vs. second line.

Please watch the recorded version above if you want all the details.

4 clinical pearls:

• Use the FRAX score (10 year fracture score) to guide who should be treated for osteoporosis
• Even patients whose T score doesn't improve on bisphosphonates, there is a 30-50% decrease in fractures
• Rebound fractures are real. Never start denosumab (Prolia) without a plan for bisphosphonates after completion
• Check DEXA 2-5 years into treatment, at start of drug holiday (which is generally 5 years into bisphosphonates), then 2-5 years later

Osteoporosis= decreased BONE STRENGTH, which is a combination of Bone DENSITY (BMD) + Bone TURNOVER + Bone ARCHITECTURE

Normal BMD T>1.0, osteopenia BMD 1>T>-2.5, osteoporosis T<-2.5

Diagnosis of osteoporosis= 

• Fragility fracture (most commonly, fracture of wrist spine, hip from standing height) 

OR 

• T-score of <-2.5 by DEXA scan. 
• Of note, 50% of people with fragility fractures will NOT meet criteria by DEXA

Normal aging vs. Disease

Bone density peaks around 30 years in women and decreases p after that, with a particular drop after menopause. It is part of the normal aging process BUT also leads to significant morbidity and mortality. 

• Vertebral fractures cause pain, loss of mobility, loss of height, even restrictive lung disease and abdominal issues. Plus, once you have a vertebral fracture, you have 20% risk of a second one in the next year. 
• Hip fractures: 30% 1 year mortality (higher in men), 40% of people never walk independently after hip fx, 25% wind up needing care in long-term care facility

Bone density scan (i.e. DEXA) is a screening tool. But it only captures 60-80% of bone strength. You should be using  the FRAX score (10 year risk of fracture) in addition to the T score to direct treatment

• FRAX: >3% risk of hip fracture, >20% risk of any fracture are indications for treatment
• Usng a T score of <-2.5, about 30% of menopausal women will qualify as having osteoporosis
• 1/2 of women with fragility fracture do not qualify as having osteoporosis on DEXA (i.e. T score will be >-2.5)
• Indications for DEXA:
• women and trans-people >65
• men >70
• any adult over 50 with a fragility fracture
• monitoring treatment
• lots of other people:
• primary hyperparathyroidism
• chronic steroids
• hypogonadism
• premature menopause
• longstanding hyperthyroidism
• celiac disease
• pregnancy w/fragility fracture
• people on GnRH agonists

Risk factors for Osteoporotic Fractures:

Age

History of previous fracture

FALL risk

Family history

Cigarette smoking (1/8 people with hip fx are smokers see below)

ETOH >3 drinks/day

Immobilization

Inadequate Ca and Vitamin D (during childhood, leading to low peak in 30s)

Smoking!!!

Treatment:

Don't forget fall prevention!

Calcium and Vitamin D were given to every patient in every treatment arm of every trial for osteoporosis. They are still the mainstay of osteoporosis treatment and prevention. There is old data demonstrating they definitely decrease risk of fracture. Dosing is all over the place, but Dr. Hamann generally recommends 1000mg of Calcium and 800u of Vitamin D/day. It's fine to get your calcium through dietary means (particularly if you have a history of kidney stones and cannot tolerate supplements), just make sure you're getting 1000mg/day. 

Who should receive treatment?

-anyone with T score <-2.5

-anyone with hx of vertebral/hip fracture from standing

-anyone with 10 year fracture risk (FRAX) > 20%

-anyone with 10 year hip fracture risk (FRAX) >3%

-clinical judgement

Bisphosphonates are the mainstay of osteoporosis treatment. They inhibit osteoclast. Data for fracture risk reduction is robust-- decreased fracture risk 30-50% reduction after about 6 months on bisphosphonates. Cost is low. We have 25+ years of experience now with these meds. 

PO alendronate, ibandronate, risendronate

IV zoledronic acid, ibandronate

Risk of osteonecrosis of the jaw (ONJ) is low but real 1/10,000, risk of atypical femur fracture 1/50,000-1/100,000-- much lower than the number of fractures prevented by the medication.

Side effects: GI 10% (heartburn, upset stomach, nausea), aches (1%), hypocalcemia (check vitamin D and replete  before starting), 1 in 5 people will get a flu-like infusion reaction to zoledronic acid. These should NOT be used in childbearing women. 

Newer agents=Anabolic agents: Romozosumab (sclerostin inhibitor, sq monthly x 1 year, only approved in women), teriparatide & abaloparatide (parathyroid hormone agonists, sq daily x 2 years)

Costly, only approved for 1-2 years

Romozosumab: treat to target T>-2.5, should be used FIRST line for "severe osteoporosis" (T score <-3.0)

Order matters (see image below)-- these anabolic agentsshould be followed by bisphosphonates (not the reverse)

IN particular with denosumab (prolia), fragility fractures of the spine and rebound fractures are real. MUST always be followed by a bisphosphonate. 

order matters!!

Dr. Hamann's General Approach:

Drug holidays and repeat DEXA?

Consider drug holiday after 5 years on bisphosphonate (if not fracturing)

Check DEXA 2-5 years into treatment, at start of drug holiday, then 2-5 years later

When to consult endocrinology?

-intolerance of oral bisphosphonate

-severe osteoporosis (T<-3.0)

-multiple fractures despite treatment

-anyone needing to stop denosumab (prolia)

Thyroid Hormonal Disease (Magnotti, 4/17/2024)

 A recording of this presentation is available HERE.

***

Thanks to Dr. Mike Magnotti, SMGR Endocrinologist, for an excellent presentation on Hypo and Hyperthyroid. This was a jam-packed presentation. Check out the link above or my notes below.

Hypothyroidism

Hypothyroidism is characterized by non-specific and relatively common constellation of symptoms, including fatigue, weight gain, mental cloudiness, cold intolerance, etc. Plenty of people with these symptoms believe they have thyroid disease (and will even feel better on thyroid replacement), but this doesn't mean they actually have thyroid disease. 

Of note, weight gain is a known symptom of hypothyroidism, but obesity is not generally caused by hypothyroidism. Treating a patient's hypothyroidism can help mood, mental acuity, and focus but likely little (if any) weight loss.

Also of note, alopecia 2/2 hypothyroid takes a very LONG time to get better -- 6 months to 1 year, even with normalization thyroid hormone. Patients need to either be patient or use another med (e.g. Rogaine) in the meantime.

The only test you need to diagnose hypothyroidism is TSH. A normal TSH range is 0.5 to about 5 and excludes thyroid disease (except in very rare cases). Always want to check twice (there are lots of transient highs that can self-resolve), on repeat TSH, also check FT4, consider thyroid antibodies (not recommended in guidelines). Ft4 distinguishes between subclinical and clinical hypothyroidism. Antibody results do NOT change treatment, but can be helpful to patients to know WHY they have hypothyroid. No need to monitor antibodies -- levels change due to immune system activity and do not indicate illness state. 

High TSH, low FT4--> overt hypothyroidism, treat with levothyroxine

High TSH, normal FT4--> subclinical hypothyroidism, consider treatment**

If thyroid antibodies are elevated, dx is most likely Hashimoto's thyroiditis

TSH increases with age. A TSH of 6-8 may be normal in patients >70 years old; TSH can also be low in younger people (0.3-0.5 can be normal in young).

**Treat patients with subclinical hypothyroidism if they have symptoms, if TSH>10 (even no symptoms because of reduced risk CAD), TSH 7-10 if under 65. Only treat elderly patient <7 if you really believe they are symptomatic. 

Note: Biotin supplements alter the ability of the assay to detect thyroid hormones (it doesn't change actual thyroid hormone). Must be high dose biotin-- e.g. those in hair and nail formulations. Should avoid products with biotin 3 days before the assay. Biotin generally makes people look hyperthyroid (Low TSH, high FT4)

Treatment of hypothyroidism

Treatment of hypothyroidism is Levothyroxine (T4)

1.6 mcg/kg/day is the FULL replacement dose of thyroid hormone (patients with NO thyroid will need this full dose)

• If older patient, start slow to avoid cardiac issues, arrhythmia
• Younger person with a very HIGH TSH probably needs most of the high replacement dose right up front. If they have a lower TSH, can start with 1/2 the dose
• take 30 minutes before food, 4 hours before calcium/iron/vitamin (absorption). 
• brand does NOT matter unless someone has intolerance to fillers/dyes in a certain brand
• Tirosint brand is a gel cap formulation with no filler, also liquid version, theoretically has least likelihood of having adverse reaction, but very expensive
• For rare patients who are super sensitive to batch variations, use the same brand to maintain consistent
• Only use TSH to monitor (goal is anywhere in the normal range), titrate to patient's feeling about how they feel
• no need to monitor T3 levels, which vary more with stress and illness (helpful in hyperthyroidism)
• Never use T3 alone! Our system has no way to regulate T3 levels in our body. T3 is the more active form. There is internal regulation of conversion T4>T3 (e.g. hospitalized patients have inhibition of conversion, normal stress response), but T3 is unregulated.
  

T3/T4 combination not generally recommended as first line treatment because most people feel fine on T4 alone. T3 is converted to T4 via deiiodinase. There are some (rare) patients with reduced ability to convert T4 to T3 (no ability is not compatible with life). Most people feel better on T3 because it gives them more energy. T3 makes people feel better like caffeine makes people feel better. 

• Most trials adding T3 to T4 show no benefit, though a few studies show some benefit. Hard to quantify symptoms energy, focus, sleep. Some people feel a rush when they take T3. 
• Consider adding T3 if patients are not better on T4 (but not an excessive amount)
• T3 has a very short half-life (needs to be taken am/pm, e.g. 7am, 3pm)
• Armour thyroid formulation (pig and cow thyroid) contains more T3 than normal human (4:1 ratio T4:T3 in Armour, humans generally have T4: T3, 13-16:1)
• if you check T3 levels, you will see relatively high T3, low T4 and normal TSH
• more variability from batch to batch (higher risk over-replacement)
• Dr. Magnotti generally does not recommend Armour, unless a patient is stable on it and you are just continuing it
• If you want to give T3, should dose separately
• T4 is 4x potent as T3
• Goal is maintain ratio T4/T3 13-16:1, e.g. 5mcg T3, 75mcg T4
• T3 only comes as 5mcg and 25 mcg. Generally don't use 25mcg pills
• Do NOT use T3 in pregnancy (doesn't cross placenta, so mom can be euthyroid and baby can be hypothyroid)
• Only monitor via TSH, symptoms

Secondary hypothyroidism is VERY rare. Unlikely to be de novo or surprising diagnosis. Patients with known pituitary tumor, history of pituitary or sella radiation, other pituitary hormone deficits (prolactin, LH, FSH). In these rare patients, TSH is useless. You treat using FT4 to monitor, goal mid normal.

Hypothyroid in pregnancy

• As soon as woman is pregnant, increase the dose up front 20-30% (right away) because risk of hypothyroidism on the fetus is WAY higher than hyperthyroidism 
• Check TSH q4 weeks (up through the second trimester)
• No T3 alone in pregnancy 
• Current goal in pregnancy is TSH<2.5
• Immediately after delivery, back to usual delivery
• Recheck TSH 8-12 weeks post partum (not too soon) because lots of women have post partum thyroiditis, which can confuse things and make you worried they have levothyroxine too high
• Let patient symptom guide 

If patient diagnosed with hypothyroidism during pregnancy. Guidelines vary about screening. 

BUT . . .

If TSH>4, treat

If TSH <2.5, no treatment

If between 2.5-4, check TPO, especially if recurrent miscarriage.

Starting dose based on level of TSH. If above 15-20, be more aggressive

Recheck 4 weeks even though not fully equilibrated.

***

Hyperthyroidism can definitely be more complex than hypothyroidism; there are more causes to consider, and the treatment is more nuanced.

Best first test for hyperthyroidism is TSH.

• If TSH is LOW, check BOTH FT4 and FT3 (elevations in either can cause overt disease),
• Also check TSI and/or TRAB (same test, different assay). 
• If Ab positive, your patient almost certainly has Grave's disease.
• If TSH is LOW, but BOTH FT4 and FT3 are normal>> this is by definition, subclinical hyperthyroid. 
• Treat subclinical hyperthyroidism if TSH<0.1 (or <0.3 if older, atrial fibrillation).
• CV risks of hyperthyroidism are definitely increased when TSH<0.1.
• If TSH is NORMAL with elevations in FT4 or FT3, this either secondary hyperthyroidism (VERY very very rare) OR T4 resistance (genetic)
• Refer to endocrine.

Additional lab findings: isolated elevation in alk phos is common with significant hyperthyroidism, will go down when treated. Transaminitis can be caused by methimazole but sometimes is also seen in hyperthyroidism.

Causes of hyperthyroidism

Grave's disease is by far the main cause of hyperthyroidism (75-80%, especially in younger patients), toxic multinodular goiter relatively more common in older population, also single functional nodule. Knowing the cause of hyperthyroidism doesn't impact who needs to be treated but can influence treatment decisions. 

• +TSI and no palpable nodules on exam (usually sizeable on exam, 2-4 cm) >> patient almost certainly has Grave's disease (no scan needed)
• -TSI and/or no nodules on exam >> need uptake scan (to r/o functional nodule)
• If palpable nodule>> need both ultrasound and uptake scan
• Toxic multinodular goiter usually is HUGE, nodular on exam

NOTE: If TSH is NOT close zero, the radioactive uptake scan is not reliable (even at 0.2 or 0.3, scan will generally be normal). If you cannot get uptake scan, ultrasound can be helpful (even without nodules). they evaluate blood flow. If blood flow is low, likely thyroiditis. High blood flow, likely Grave's. 

If no uptake>> likely dx thyroiditis (unless people taking iodine supplements, kelp, seaweed, or recent contrast in last 3 months. Amiodarone can also cause no uptake, even 3 months after taking it.

If normal or increased uptake>> dx Grave's

If uptake in single nodule>> dx toxic solitary nodule

Patchy uptake all around >> toxic multinodular goiter

Treatment of hyperthyroidism

3 options: methimazole, iodine (I-131), thyroidectomy. Beta blocker for symptom management

Methimazole is first line for most causes. 

Methimazole 10 mg/day, 20 mg/day, 40 mg/day for mild (<2x ULN), mod (2x ULN), severe (>2x ULN) disease, respectively. Taper down to 5-15mg (usual maintenance dose). Leave people on methimazole for 1-2 years before stopping. Want to be sure to have negative TSI (antibody) if they have positive to begin with. Don't stop methimazole in anyone who still has antibody at the receptor (+TSI is causing the hyperthyroidism).

There are some exceptions.

• Iodine should be considered for young women who desire pregnancy and people without eye disease
• Younger women who desire pregnancy may benefit from treatment with iodine treatment because methimazole can take years to get into remission. 
• Can get pregnant 6-9 months, need normal TSH (with levothyroxine). 
• Even after 3-4 years, with methimazole may not be in remission. Delays childbearing.
• Iodine is also great for single toxic nodule because people will come out euthyroid. Likely curative. Normal gland not affected. 
• Very severe hyperthyroidism in a younger person, especially with a large gland, they are very unlikely to have long-term remission at all with methimazole. Consider iodine vs. surgery.
• Surgery may be best option if need to get thyroid hormone levels down quickly. It will still take weeks (body has to metabolize FT4 already floating around)
• Consider surgery in case of: 1) very large goiter,  2) need for rapid correction, 3) concern for malignancy, 4) combo hyperthyroid+ hyperparathyroidism

Hyperthyroid eye disease: Send to neuro-ophtho if thyroid eye disease. Iodine can worsen thyroid eye disease. (if mild, can do Iodine with 3-4 months of prednisone to protect against progression). 

Hyperthyroid in pregnancy: 

Do NOT treat subclinical disease. 

Use PTU in first trimester, change to methimazole in 2nd and 3rd trimesters.

Target Total T4 and Total T3 in the high normal range, which is 1.5x ULN for pregnancy range due to higher estrogen, binding globulin. 

Diabetes Medications for Cardiovascular, Heart Failure, and Renal Risk Reduction (Magnotti - 7/20/22)

 A recording of the presentation can be found HERE.

Type 2 Diabetes Management: What is new in 2021? (Magnotti, 8/18/2021)

SMGR Endocrinologist, Dr. Michael Magnotti, gave an information-packed review of the latest and greatest in DM2 management at Grand Rounds this week. It was fast and furious and full of really great info on updated management of DM2. A video recording of Dr. Magnotti's presentation is available HERE .

Here are my take home points up front:

1) Goals for DM management should include: achieving a specific a1c goal (based on age, risk factors, etc), avoiding hypoglycemia, avoiding weight gain (promoting weight loss if possible), minimizing side effects, and decreasing CV events. Insulin, unfortunately, doesn't accomplish many of these goals.

2) SO. . .first line, old school for DM management, is still metformin AND comprehensive lifestyle changes (including weight loss and physical activity)

3) Second line meds should be GLP-1 receptor agonist OR an SGLT-2 inhibitor for ALL diabetics. This is because these meds reduce a1c, do not cause hypoglycemia (unlike sulfonylureas), promote weight loss, and decrease CV events. This is even true if a1c is at goal (see ADA guidelines below)

4) SGLT-2 and GLP-1 have additional indications for which we might consider them regardless of DM; with established ASCVD, and heart failure (HFrEF and HFpEF), and chronic kidney disease with GFR>30 and/or proteinuria. There is rapidly evolving evidence that even in the absence of DM2 (or DM with good control), these medications can improve outcomes. More and more, the are be covered by insurance for these indications alone

5) GLP-1 agonists have the most potent a1c lowering and weight loss effects. They also clearly reduce CVD risk.

6) In addition to CVD risk reduction, SGLT-2 have evidence for improved outcomes in heart failure and CKD. This is a class effect. Don't get caught up on individual indications for which med. All SGLT-2 except ertugliflozin, the oldest and cheapest) impact all three conditions.

***

Dr. Magnotti showed us this image of the Ominous Octet-- the eight pathways through which hyperglycemia occurs with DM2. You can see which mechanisms are in effect with the GLP-1 and SGLT2 medications. 

This, too, for your reference is the most updated graphic version of the 2020 ADA guidelines. Note the two LEFT columns, we are to consider the addition of meds for ASCVD, HF and CKD independently of a1c. The RIGHT two thirds of the page direct us to consider medications based on a1c not being at goal.

https://care.diabetesjournals.org/content/diacare/43/Supplement_1/S98/F1.large.jpg

For the life of me, I cannot EVER remember their names of these newish classes of meds and which is which. I think I am getting old. So for your reference and mine:

GLP-1 Analogs: semaglutide (Ozempic injectable, *newer oral form Rybelsus), liraglutide (Victoza), dulaglutide (Trulicity), and exenatide (Byetta)

SGLT-2 Inhibitors: canagliflozin (Invokana), dapagliflozin (Farxiga), empagliflozin (Jardiance), ertugliflozin (Steglaro)

Okay, so let's recap the key points on both these categories of meds. 

First GLP-1:

• GLP-1 agonists begin working as soon as food hits the mouth--> hormonal disruption leading to decreased glucagon production and increased insulin, early satiety, and slowed gastric emptying (which is why they help with weight loss)
• if patients complain of nausea with GLP-1 it's probably because they are eating too much, need to cut back on food intake and nausea may improve
• GLP-1 agonists have been shown:
• 1-1.8% reduction in a1c
• 4-13 pounds weight loss
• NO hypoglycemia
• CV risk reduction
• Side effects: nausea/vomiting/constipation/Headache/injection site reaction/hypoglycemia (only if combined with insulin or sulfonylurea), and unclear link with pancreatitis
• Absolute contraindication: black box for animal studies showing association with medullary thyroid cancer and MEN2
• Relative contraindications: CrCl<30 (except exenatide, which has no SCr cutoff and okay in HD). There is a warning of AKI, which is a result of volume depletion
• GLP-1 Agonists that are HUMAN GLP-1 based: semaglutide, liraglutide, and dulaglutide (all of them EXCEPT exenatide) have CV risk reduction
• Oral semaglutide has no CVD reduction data (trials ongoing)

What's new about GLP-1 medications in 2021?

• Higher doses of dulaglutide (Trulicity (3.0 and 4.5mg)) have new data showing even more improvements in Hba1c, increased weight loss, but also more nausea (makes sense). 
• Titration can happen weekly, starting with 0.75mg--> 1.5mg--> 3--> 4.5 as tolerated
• Newish oral semaglutide MUST be taken on a completely empty stomach (with no other meds and <4 oz of water) to be effective. Otherwise it doesn't work
• Injectable dulaglutide now how has primary prevention data for CVD 
• consider rx'ing for patients with high CV risk
• Injectable semaglutide at high doses (2.4 mg vs. normal 1.0mg dose) has shown promise for even more weight loss 10-16% of body weight, with over 50% of patients losing 15% of their body weight

Okay, onto SLGT-2: 

• SGLT-2 meds block reabsorption of some (not all) of glucose from the tubules, causing glucosuria and urination, essentially a diuretic effect. They also have a Na effect on urine
• You can consider their positive impacts as a class effect, except ertugliflozin. You can use most of these interchangeably for CV risk reduction
• SGLT-2 studies show:
• A1c reduction 0.8-1.2% (little less than GLP-1)
• BP reduction of about 5mm Hg
• Weight loss 2-4% of body weight
• Renal protection (DM or CKD without DM)
• CV mortality risk reduction
• HF reduction (diagnosis and exacerbation, HFrEF and HFpEF)
• 3 point MACE reduction
• Contraindications to SGLT2: renal insufficiency (GFR<30, though data evolving), caution in advanced age (risk of orthostasis, volume depletion)
• Side effects: yeast infection (women>>> men, okay to treat through the first yeast infection, but if recurs, should stop), polyuria, volume depletion and transient decrease in GFR, orthostasis, small bump in LDL, hypoglycemia when combined with insulin/sulfonylureas, DKA with minimally elevated blood sugar, fournier's gangrene

What is new in SGLT-2 in 2021?

• Renal protection data (in BOTH diabetic and non-diabetic CKD)
• Canagliflozin RCT in pts with DM2 w/CKD with proteinuria--> decreased doubling of SCr, ESRD, renal death
• Empagliflozin in pts with DM2 with or without CKD--> reduced rates of doubling creatinine, progression to proteinuria, initiation of RRT, and renal death
• Dapagliflozin in pts with CKD GFR 25-75 and proteinuria (+/- DM)--> decreased doubling SCr, end stage renal disease, renal death (almost 50% risk reduction)
• HF risk reduction data (also presence/absence of DM)
• studies found decreased exacerbation of HF as well as diagnosis of HF in patients on SGLT-2 medications
• 30% reduction in hospitalization 
• Full data on HFpEF coming out this month. Stay tuned
• CV risk reduction data
• empagliflozin study found 38% reduction in CV mortality after 3 years of treatment (this is the most dramatic result)
• canagliflozin showed 0.86 reduction in 3 point MACE, liraglutide 0.87 reduction, semaglutide 0.74 reduction

Cardiovascular Benefit of New Diabetes Medications (Magnotti, 4/22/2020)

One of the reasons I love Grand Rounds is that each week I know-- whatever the topic, whomever the speaker-- I will walk away wiser. My curiosity will have been piqued. I will have learned something. I will have been challenged.  I will be a better family physician. And I will have often have new (more educated) questions.

And as expected, this week, Dr. Mike Magnotti (SMGR Endocrinology) did not disappoint. He gave an excellent presentation on the cardiovascular benefits of two classes of "new" diabetic medications: GLP-1 analogs and SGLT-2 inhibitors. Definite practice changer for me.

Here are a few questions to start you off:

• Do you manage your diabetic patients with cardiovascular disease  (CVD) differently than those without CVD?
• Are you aware of the evidence that both the GLP-1 and SGLT2-inhibitors reduce stroke, MI and possibly even CV death in diabetics with CVD?
• Are you using GLP-1 agonists for cardiovascular benefit?  What about SGLT-2 inhibitors?
• How do you (and your patients) assess whether or not they should be on one of these new meds?

I don't know about you, but I have a hard time keeping these medications in my head-- the names are complicated, the abbreviations don't make it simpler, the mechanisms of action are new, and nothing sticks. Plus, until recently they have been unavailable to most of my patients due to cost and/or insurance restrictions.

In case you are in the same boat as me, here's a brief summary of the two classes of meds Dr. Magnotti presented evidence for in CV risk reduction:

GLP-1 agonists: glucagon-like peptide 1 agonists (aka incretin mimetics) are almost all INJECTABLE medications (except for one new oral version of semaglutide). They act on the gut: improve glucose-dependent insulin release, suppress glucagon, suppress hepatic glucose output, decrease the rate of gastric emptying, and suppress appetite.  

• Benefits of GLP-1 agonists include HbA1c reduction of 1.2-1.7%, weight loss, no risk of hypoglycemia (unless combined with insulin or sulfonylurea), and CV risk reduction  (non fatal heart attack and stroke-- see below for details)
• Side effects: mostly GI (nausea, vomiting, constipation, diarrhea), headache, injection site reaction, possibly pancreatitis, and a black box warning MEN2 or medullary thyroid cancer
• Currently available forms: short and long acting exenatide, liraglutide, dulaglutide, semaglutide (oral and sq)

SGLT-2 inhibitors: sodium-glucose co-transporter-2 inhibitors (aka gliflozins) are ORAL medications that inhibit resorption of glucose into the kidneys, thereby lowering blood sugar

• Benefits of SGLT-2 inhibitors include: Hba1c reduction 0.8-1.2%, systolic BP reduction (~5mm Hg), weight loss (2-4% of body weight), heart failure risk reduction, slowed progression of CKD, CV risk reduction (non fatal heart attack and stroke-- see below for details), and even CVD death reduction (empagliflozin only)
• Side effects:  yeast infections (women>>men), UTI/pyelo, polyuria, transient decrease in GFR, orthostasis (esp in elderly), small increase in LDL, hypoglycemia (if combined with sulfonylurea, insulin), DKA with minimal glucose elevation, increase in fractures, possible increase in amputation, fournier's gangrene
• Currently available forms: canagliflozin, empagliflozin, dapagliflozin, ertugliflozin

Is HbA1c lowering the only outcome that matters?
Standard diabetes management has focused on reduction of HbA1c, which we know prevents progression of microvascular disease but has little effect on macrovascular outcomes. HbA1c goals are the metric by which we have considered a patient "controlled" or "uncontrolled". You all know, our  goal is HbA1c<7 in most adults, <8 in elderly and those with significant comorbidity.  Secondary goals have been to prevent/avoid hypoglycemia and prevent weight gain/promote weight loss.

It may be time to rework our paradigm; start thinking diabetes meds in CV Risk Reduction
Yes, we know lowering HbA1c is important to prevent retinopathy, diabetic nephropathy, peripheral neuropathy. However, we also know that cardiovascular disease (CVD) is an important cause of morbidity and mortality in diabetic patients. What if there were medications that reduce HbA1c and also reduce the risk of MI, stroke, and CV death?

Guess what? There are! Both the GLP-1 agonists and the SGLT-2 inhibitors seem to have a positive effect on CV outcomes (ie they reduce heart attack, stroke, and maybe even CV death). To be right up front, no one is exactly sure why.

Since 2008-- due to concern about thiazolidinidiones (TZD) actually showing increased CV risk in diabetic patients-- the FDA has required that any new blood sugar lowering med be evaluated for cardiovascular safety ("a cardiovascular outcome trial" or CVOT). Most of these studies use a composite endpoint called a 3 point MACE (time to a Major Adverse Cardiac Event, including non-fatal MI, CVA or cardiovascular death). Initial studies found most novel diabetes meds to be neutral, but  more recently, they started to show some benefit.

Here are the studies Dr. Magnotti reviewed during Grand Rounds:

• EMPA-REG: (empagliflozin), NEJM 2015
• DM2, a1c range 7-10%, BMI<45, established CVD--> primary outcome 3P MACE 
• Relative risk reduction of 38%, 2.2% Absolute risk reduction
• NNT 46 patients for 3.1 years to prevent on CV death (for comparison sake, NNT is 31 patients for simvastatin x5.4 years, 49 patients with ramipril x 5 years)
• There were also significant reductions in all-cause mortality and heart failure hospitalizations
• FDA indication for empagliflozin: to reduce risk of CV death in diabetic patients with known CVD
• CANVAS/CANVAS R (canagliflozin), Circulation 2018
• Primary outcome: 3P MACE
• Relative risk reduction 14%, NNT=224
• LEADER: (liraglutide), NEJM 2016
• Primary outcome: 3P MACE
• Relative risk reduction, 13%, 3P MACE
• Reduction in all cause mortality 15%, CV death 22%
• SUSTAIN 6 (semaglutide injection), NEJM 2016
• 26% relative risk reduction 3P MACE

Dr. Magnotti's summary of the literature: 

• To date, 5 new diabetes agents have been shown to lead to a significant reduction in 3 point MACE. 
• This effect is INDEPENDENT of A1c and other risk factors. 
• These were all measured in addition to other standard of care therapies (such as ASA and statin)

In light of these studies, both the American Diabetes Association (in 2018, again in 2020) and the American COllege of Cardiologists (ACC, 2020) have updated their guidelines with regards to using SGLT-2 and GLP1 medications in diabetes. 

For patients with known ASCVD, these medications should now considered first line after metformin (see diagrams below from ADA and ACC).

ADA guidelines HERE in FULL text (snippet of image).

ACC guidelines HERE in FULL text (snippet of image). 

In Type 2 patients with Diabetes AND CVD (ie. known CAD, hx MI, hx CVA, PVD), regardless of A1c or current diabetes therapy, patient should be started on EITHER GLP-1 (liraglutide daily injection, dulaglutide weekly injection, semaglutide weekly injection) OR SGTL-2 (empagiflozin oral, canagliflozin oral)

Dr. Magnotti's Considerations when choosing an SGLT2 vs. GLP-1

• SGTlL-2 in patients with Heart Failure, CKD (GFR>30), those who might need improved BP control (or who you aren't worried to be on a diuretic), someone with history of pancreatitis, gastroparesis, significant nausea, or MEN2/MTC
• GLP-1 in patients who need MORE Hba1c reduction, CKD with GFR<30, recurrent yeast infections or UTI, concern for risk of DKA or other potential side effects from SGLT-2

Some practicalities:

You don't need to adjust a patient's other diabetes meds UNLESS they are on insulin or sulfonylurea (for risk of hypoglycemia)

• IF they are on a sulfonylurea:
• A1C<7 to 7.5, stop the sulfonylurea
• A1C 7.5-8.5, cut sulfonylurea dose in half
• A1c >8, no change
• IF on basal insulin
• a1c<7, cut insulin dose in half
• a1c7-8, reduce insulin dose by 20%
• IF on prandial insulin, consider getting endocrinology input OR cut prandial insulin at least in HALF. 
• IF patient on antihypertensive, for SGLT2, consider reducing dose, if diuretic cut dose or stop

What about insurance coverage?

Coverage has substantially improved for these medications with CV indications. (Even with Partnership Health Plan). There are NO other medications that can be used for "step therapy" for CV risk reduction, so be sure to prescribe these under CVD (rather than DM). 

What about patients who don't want to take an injection?

If the patient meets criteria for a GLP-1 but doesn't want an injection, remind them: 1) this isn't insulin 2) they will likely LOSE weight and improve their blood sugar control and 3) they will reduce their risk of heart attack and stroke. Then get them nursing and diabetic educator assistance with getting over the injection!

If you work in the hospital, you might at least consider discharging every diabetic patient with established CVD (MI, CVA, TIA, PVD) on a GLP-1 or SGLT-2 agent. 

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Another reason I love Grand Rounds is that I love sitting in the same room with engaged, big-brained, big hearted colleagues. (This is the part I miss during our shelter in place-- Zoom works-- but it sure isn't the same). Join us next week on Zoom. We will be back in that conference room eventually.