Dyslipidemia AACE 2020 guidelines: Drug treatment.

 

 Drugs to lower LDL cholesterol (LDL-C)

• General principles:
• HMGCoAreductase inhibitors
  
• Sponsored trials, mostly with statins, but also with ezetimibe and PCSK9i proved continuos reduction of ASCVD along LDL reductions.
• According to risk category, LDL goal goes from 130 to 55 mg/dL
  
• Nonfatal MI or CV death ↓29-37% every 38 mg/dL LDL reduction, depending on LDL level.
• Revascularization and stroke also ↓ but less
• Other metaanalysis show the lowest CV death for LDL <50. 
• Initiate moderate-high intensity statin unless contraindicated. 
• For residual risk reduction, adding ezetimibe (improve-it) or pcsk9i (fourier, oddisey) further ↓ composites about 15-20%. Colesevelam and bempedoic trials are ongoing. 
• Cholesterol absorption inhibitors: ezetimibe: ↓C 10-25%, in improve-it ↓CVD with simvastatin
• Monoclonal Ab PCSK9 inhibitors: alirocumab and evolocumab. Very potent, SC every 2-4 weeks. 
• Bile acid sequestrant: ↓LDL 15-25%, contraindicated if Tg>500, colesevelam also indicated for DM
• Bempedoic acid ↓LDL 15-25%, no proved CV reduction, ↑uric acid and gout, tendon rupture. 
• Niacin ↓LDL 20% ↑HDL. No demonstrated CV benefit. ↑glycemia, flushing, hepatotoxicity. 
• Other: lopitamide: microsomal triglyceride transfer protein (MTP) inhibitor, for HoFH, hepatotoxic.
• When to start statin
• Low risk patients unable to maintain LDL-C <130 mg/dL
• Moderate, high, very high or extreme risk patient regardless LDL level. 
• Dose titration
• Measure LDL every 3 months , if >goal stepwise:
• Check adherence
  
• Increase statin dose-intensity
• Add 2nd drug: ezetimibe, PCSK9i, colesevelam, bempedioc acid depending needed↓
• Add 3rd drug
• Statin adverse effects:
• Myopathy: 5-20% in clinical practice
• Always warn
  
• Muscle pain, weakness, crumps
  
• ♀ >65, lean, frail
• CK not necessary, confirms if >x4, rhabdomyolisis >x10
• If not severe, try another or same statin lower dose
• Hyperglycemia, 10% ↑DM risk
• Contraindicated in active hepatic disease, the do not harm liver themselves.  

Drugs to lower triglycerides.

• General principles:
• 150 mg/dL cut-off is somehow arbitrary. 
• Trial of lowering Tg on ASCVD have failed until REDUCE-IT (IPE, icosapent ethyl) ↓CVD probably by TG-independent mechanism (only 18% TG↓). Beware adverse effects.
  
• Below mentioned measures are aimed to ↓TG and its consequences rather than CVD
• Non drug therapy:
• Weight loss:
• diet: ↓CH, fat, alcohol
• Exercise
• Investigate and treat secondary causes (see post 1)
• Drugs:
• Fibrates, the most potent, PPAR alpha agosnists, ↑beta oxidation, ↓TG 45-55%, may ↓CVD in TG>200+HDL<40
• Omega 3, EPA +-DHE, ↓TG 20-45%
• Niacin ↓TG 20-30% by ↓lipolysis
• Statins and PCSK9-a (moderate) and ezetimibe (mild).
• Algorithm:
• TG>=500 = pancreatitis risk, treat with fibrates, niacin or omega-3. Consider combination
• Tg <500:
  
• No ASCVD or DN +>=2 RF: if Tg >150 on statin, consider add fib, o-3 or niacin
• ASCVD: if Tg 135-500 on statin: add IPE (reduce-it ↓25% CV events). If TG>=150 on statin + IPE, consider add fibrates etc. 

Drugs to lower Lp(a). No drug is aproved by FDA. 

• AACE recommends measuring it in:
• ASCVD
• Family history (FH) of premature CVD or elevated Lp(a)
  
• Blacks and asians
• FH or antecedents of aortic stenosis 
• LDL irresponsiveness to drugs
• 10y risk score >10%
• PCSK9i, estrogens, aspirin and niacin ↓Lp(a), antisense oligonucleotide trial are under way, and apheresis in extreme cases is possible.
  

Dyslipidemia AACE 2020 guidelines: Definition, Epidemiology, Etiology, Diagnosis, General Measures.

 

DEFINITION

• The term dyslipidemia is a hotchpotch. Certain features of serum lipids and lipoprotein profile are associated to aterosclerosis (AS), which is a disease, and to triglyceride-related outcomes. Serum cholesterol in LDL, VLDL, VLDL remnants, and Lp(a) lipoproteins are risk factors for AS. triglycerides in VLDL and chylomicrons are risk factors for TG related events (see below).
  

EPIDEMIOLOGY

• About 30, 25 and 20% of US citicens have LDL, TG and Lp(a) values above which experts consider risk threshold. Important to know that thresholds are arbitrary. 
• Prevalence of specific syndromes of dyslipidemia are listed in etiology.
  

ETIOLOGY

• Primary hyperlipidemias:
• Hypercholesterolemia (HC).
• As said, 30% of US adults have cholesterol levels above threshold. Be careful, it's not a disease, it's just defined according to CVD risk. 
• Familial hypercholesterolemia. Mutations affecting LDL receptor function. Codominant:
  
• Heterozygous: 1/250-500. LDL >190 mg/dL in adults (160 in children) and CVD.
  
• Homozygous: 1/1-4 million. Extreme CVD risk, LDL >500 mg/dL.
  
• Hypertriglyceridemia (HT). The same, defined if fasting Tg >=150 mg/dL (25% of US adults) and severe if >=500.
• Both HC+HT: three main possibilities:
•  HC and HT with no known specific cause. By far the most common, generally mild, treat both according to guideline. 
• Familial combined hyperlipidemia (FCH). 1-3% of US adults. Defined as ↑C or Tg in >=2 family members and premature ASCVD. 
• Dysbetalipoproteinemia. ↑VLDL and chilomicron remnants, ↑Tg and C and premature ASCVD. Recessive, usually no family members seen.
  
• Elevated Lp(a). ↑CV disease. 20% of US adults. 
• Other, less common:
  
• Familial Chylomicronemia syndrome. 
• Hypoalphalipoproteinemia.
• Beta-sitosterolemia.
• Lisosomal acid lipase deficiency. 
• Secondary hyperlipidemias: quite a lot. The document says the most frequent in developed countries are sedentary lifestyle and carbs in diet, but without references. That means that either they get their knowledge directly from God or they make it up.
  
• Lifestyle: sedentary LS, alcohol, saturated fat, carbohydrates and sugar. In the document there's also "malnutrition" but I think that's a different context.
  
• Diseases: 
• Obesity - metabolic syndrome
• Uncontrolled hyperglycemia
• Pregnancy
• Hypothyroidism
• CKD stage >=3
• Nephrotic syndrome
• Cholestasis
  
• Paraproteinemia
• Lipodystrophy
  
• Rheumatologic diseases like SLE or RA 
• Drugs:
• Sex hormones: estrogens, gestagens, androgens, SARM
• Antihypertensive: thiazides, beta-blockers
• Immune drugs: IFN, cyclosporine, mTOR-K inhibitors
• Chemotherapy: taxols, cyclophosphamide, L-asparaginase
• Glucocorticoids
• Retinoids
• Bile acid sequestrants
  

DIAGNOSIS

• Percent undiagnosed and time from onset to diagnosis: already stated in epidemiology. Most people at risk are not taking drugs, which could have terrible consequences for big pharma CEOs.
  
• Diagnostic workup:
• Perform serum lipids in:
• people included in secondary causes
• personal or family history of premature ASCVD, corneal arcus, tendon xantomas or xanthelasmas (cholesterol)
  
• pancreatitis, lipemia retinalis or eruptive xanthomas (Tg)
• Physical exam: include BMI, BP, pulses, ABI, waist circumference, xanthelasmas, eruptive and tendon xanthomas, corneal arcus, lipemia retinalis. 
• Laboratory:
• Basic: cholesterol, LDL, HDL, TG, biochemistry with A1c, uric acid and TSH. 
• Optional: ApoB, LDL particles, Lp(a), hs-PCR. 
• ECG: resting or treadmill, chemical or nuclear stress
• Image:
• Coronary Artery Calcium (CAC): recommended
• Carotid intima-media thickness, used for years, not predictive of CVD. 
• Risk Calculators:
• Framingham
• MESA (Multiethnic Study of Atherosclerosis) incorporating CAC.
• Reynolds
• UKPDS
• ACC/AHA
  
• ASCVD risk categories and goals: Now we're leaving science and enter a world of fantasy. The panel has established 5 categories of risk, from low to extreme, with corresponding LDL goals. We're sure that, if you changed panel members, or even same members joined another day, categories and goals would be different, but that's what we've got. 
• Goals (specific goals are different for each category, see below):
• LDL colesterol. It is the main goal because many RCT proved that the lower level the lower CVD events, mostly with statins, but also with statin+ezetimibe and PCSK9i.
  
• Non HDL colesterol. Usually the goal is 25-30 mg/dL higher than LDL. It includes not only LDL but also all other atherogenic particles: VLDL, IDL, Qm and Lp(a).
  
• ApoB. Important in metabolic syndrome, where LDL levels may be OK but small dense particles are disclosed by measuring ↑ApoB. It is the sum of B100, that is included in all atherogenic particles (VLDL, IDL, LDL) and B48.
  
• TG. Values >150 are high and >500 mg/dL extremely high. Its reduction lowers CVD in reduce-it with EPA and in subgroup analysis with fibrates if low HDL. 
• HDL. Low levels are associated to CVD but pharmacologic raising does not ↓CVD. Recommendation is non-drug-raising and then use statins to lower LDL.
• Categories:
  
• Extreme risk: LDL-C <55, non-HDL-C <80, ApoB <70, TG <150:
• Proggressive ASCVD including unstable angina
• Established clinical ASCVD + DM or CKD >=3 or HeFH
• Premature (<55a♂ <65♀) ASCVD
• Very high risk: LDL-C <70, non-HDL-C <100, ApoB <80, TG <150
• Established clinical ASCVD
• 10-y risk >=20% 
• DM + other RF
• CKD >=3 + albuminuria
• HeFH
  
• High risk: LDL-C <100, non-HDL-C <130, ApoB <90, TG <150
• 10-y risk 10-20% and >= 2 RF
  
• DM with no other RF
• CKD >=3 with no other RF
• Intermediate risk: LDL-C <100, non-HDL-C <130, ApoB <90, TG <150. Yes, they're the same as in high risk. Maybe that day they were in a hurry for some reason to finish the meeting.
  
• <2 RF + 10-y risk <10%
• Low riks: LDL-C <130, non-HDL-C <160, TG <150
• No RF

MANAGEMENT

• General measures:
• Diet: no consensus no single strategy:
• DASH and mediterranean diet satisfy the general recommendations: fruits and vegetables, whole grains, legumes and soluble fibre, avoid processed food and reduce total calories.
• With no evidence whatsoever, the panel favor diets with total fat 25-35% of calories  (i.e. DASH > mediterranean), Diets with <25% fat ↑TG and ↓HDL, although those with 10% fat (ineadible!) ↓CV events. 
• Soluble fiber ↓LDL, insoluble fiber ↓CVD.
• Exercise:
• ↓obesity, waist, glycemia, HT, dyslipidemia
  
• ↓Tg and hsPCR, ↑HDL, no clear effect on LDL. 
• >150 min moderate aerobic + weights and resistance 
• Sleep hygiene:
• 6-8 h sleep ↓CVRF: HT, glycemia, lipidemia, inflammation. 
• OSA ↑ CVD
  
• Mental issues: depression, schizophrenia, bipolar disorder, anxiety andpost-traumatic syndrome ↑CV risk, but no evidence that any intervention prevents it. 
• Alcohol: 
• some meta-analyses associate OH and lower CV events, but its consumption is obviously not recommended
• Excess OH ↑TG and HDL, but not the protective subfraction, ↑HT, cardiomyopathy and atrial fibrillation.
  
• Stop smoking 
• Smoking ↑CV risk x3, stopping ↓risk very early, 1st year, and at year 5 risk is similar to non-smokers. 

That's enough for today, about 1000 words = 10 min. Next post, drug therapy,

Management of differenciated thyroid cancer (ESCO 2019)

Concept, epidemiology, etiology, clinical picture, diagnosis and prognosis of Differenciated Thyroid Cancer are taken for granted. There are quite a lot of book chapters and reviews about that. 

The article we comment is this and appeared in Annals of Oncology in September 2019. 

In the next post we review management of advanced disease. 

 

 

First of all, staging. It will give us the prognosis i.e. death risk:

• TNM (TNM 8 staging system):
• T1: a: <= 1 cm: b: 1-2 cm.
  
• T2: 2-4 cm
• T3: 
• a: > 4 cm limited to thyroid
• b: gross extrathyroidal extension invading strap muscles
  
• T4: 
• a: macroscopic extrathyroidal extension: soft tissues, larynx, trachea, oesophagus, recurrent nerve.
  
• b: prevertebral fascia, carotid artery or mediastinal vessel
• N0: no nodes
  
• N1a: nodes in level VI (pre- or paratrachear, delphian or prelaringeal) or VII (superior mediastinum)
  
• N1b: nodes in levels I-V.
  
• M0: no metastasis
  
• M1: metastasis
• Stage 
• <55:
• I: M0
• II: M1 
• >=55:
• I: T1-T2 (N0M0)
  
• II: T3 or N1
  
• III: T4a
  
• IVa: T4b
  
• IVb: M1

Secondly, Surgical Management: 

•  Unifocal papillary microcarcinonas (T1aN0M0): 
• Surveillance has been proposed with US every 6-12 m and surgery if nodes or >3mm growth is seen. Younger age is risk factor for operation. 
• Surgery is the alternative for rest of cases (for type of operation, read below). If history of neck radiation, TC family history, or aggressive cytology, surgery (TT) is proposed.
  
• Rest of T1 through T4a: 
• Total thyroidectomy (Standard therapy).
• In low risk T1-T2N0 low-quality evidence (bias-prone large database studies) shows that lobectomy gets similar survival but slightly higher local recurrence. In any case, TT is always proposed:
• As initial surgery if posterior or adyacent to trachea
• After lobectomy if postoperatively we find aggressive histotype, vascular invasion, T3, N1 or residual tumor (R1)
•  Prophylactic central neck dissection (CND):
• In low risk tumors T1-T2 no high quality evidence (HQE) exists for or against it in terms of survival. Advantages are better staging and possible lower local recurrence. 
• T3-T4a CND improves regional control. 
• T4b: no surgery, consider external beam radiotherapy (EBRT)
• N1a: TT+- therapeutic CND
• N1b: TT+- therapeutic CND +- therapeutic compartment oriented lateral neck dissection (LND)

Third: Risk Stratification for prediction of persistent or recurrent disease:

• Low (<5%):
• NIFTP (<1%)
• PTC (1-6%): all of them:
• T: no remnants, no local invasion, no aggressive histotype, Braf V600E if <1cm, no vascular invasion
• N: Clinical N0 or pathological N1 with <5 nodes< 2 mm each 
• M: no metastasis, no RAI foci outside thyroid bed
• FTC (2-3%): intrathyroidal, well diferenciated, no or <4 foci of vascular invasion, capsular invasion.
  
• Intermediate (5-20%):
• PTC: 
• Microscopic ETE (8%)
• Symptoms (10%)
• Braf V600E if <4 cm (10%)
• Aggressive hystology (15%):
• tall
• columnar
• hobnail
• diffuse sclerosant
• squamous
• solid/trabecular
  
• Vascular invasion (15-30%)
• Extrathyroid neck foci in 1st WBS
• Clinical N1 or pathological >5 nodes < 30 mm (20%)
  
• Multifocal + ETE + Braf V600E (20%)
• FTC:
• Clinical N1 or pathological >5 nodes < 30 mm (20%)
• Extrathyroid neck foci in 1st WBS
• High (>20%):
• PTC:
• Gross ETE (30%)
• Nodes >3 cm (30%)
• Extranodal extension (40%)
• Braf V600E + TERT (40%)
• Tg suggesting metastasis (100%)
  
• Incomplete resection (100%)
• Metastasis (100%)
• FTC:
• Vascular invasion >4 foci (30-55%)
• Tg suggesting metastasis (100%)
  
• Incomplete resection (100%)
• Metastasis (100%)

Fourth: consider RAI therapy:

• No residual disease (remnant ablation, adjuvant):
• Low risk:
• T1aN0: no RAI
• Other low risk: no consensus, no HQE for or against. If given, 30 mCi with rTSH is proposed. 
• Intermediate risk: also no consensus, if given, RAI 30-100 mCi with rTSH or withdrawal. 
• High risk: consensus RAI >100 mCi with rTSH (better QoL) or withdrawal (recommended if distant metastasis). 
• Residual disease (therapeutic, incomplete surgery or methastasis): 100-200 mCi, with withdrawal:
• Refractory: no more treatment:
• no uptake in WBS
• no uptake after RAI therapy
• some MTS uptake, other not
• RECIST progression after RAI
• *other (controversial): aggressive histology, positive PET, persistance after several treatment courses
  
• No refractory: repeat every 6-12 months until 600 mCi reached.

Fifth: evaluate response to treatment. It'll depend on serum thyroglobulin (Tg) and image:

• Serum Tg
• Undetectable levels have high negative predictive value, but detectable have low positive PV, they can be false positive.
• Always measure antiTg Ab. If positive, false negative or, more rarely, false positive value is possible and Tg level is unreliable.
• Almost 60% of TT with no RAI have Tg<0,2 ng/mL, which indicates absence of disease. If detectable, serial measurement is mandatory. 
• Neck US: useful in PCT, in FTC only to explore thyroid bed. 
• Whole Body Scan (WBS). Low sensibility 27-55%, high specificity, better with spect. Indicated when suspected residual disease. 
• 18F-PET: More sensitive less specific than WBS, indicated in agressive WBS- tumors. Prognostic marker, but no indicator of tumor growth. 
• CT: for neck and chest. Contrast for neck and mediastinum, not for lungs. Delay RAI 6 weeks if contrast. 
• MRI: for liver, bones and brain. 

This way response to treatment can be classified in 4 groups:

•  Excellent: 
• TT+RRA: no image + Tg<0,2 ng/mL or stTg<1 + negative TgAb
• TT alone: no image + Tg<0,2 ng/mL or stTg<1 + negative TgAb
• Lobectomy: no image + stable Tg + negative TgAb
  
• Indeterminate:
• TT+RRA: nsp image, or nsp thyroid bed uptake on thyroid bed, or Tg0,2-1 ng/mL, stTg 1-10 or stable or declining TgAb with no image
• TT alone: nsp image, or Tg 0,2-5 ng/mL, or stable or declining TgAb with no image
  
• Lobectomy: nsp image
• BQ incomplete:
• TT+RRA: no image + Tg >1 or stTg>10 ng/mL or rising TgAb
  
• TT alone: no image + Tg >5 or rising Tg on stable TSH or rising TgAb
  
• Lobectomy: Rising Tg on stable TSH or rising TgAb
  
• Structural incomplete:
• Positive image regardless of Tg or TgAb

Sixth: follow-up strategy, it'll depend on 4 variables: 1.-Histotype, 2.- Initial treatment (surgery, RAI); 3.- Recurrence risk; and 4.- Response to treatment.

After initial therapy (surgery +- RAI), measure Tg(+Ab) + neck US at 6-18 months:

• In low risk PTC + negative image, intermediate risk PTC + excellent response, or (although based in LQE) low risk FTC + excellent response:
• 12-24 month serum Tg
• TSH range 0,5-2 mcU/mL
• Neck US based on serum TG
• In low and intermediate risk PTC + indeterminate or BQ incomplete response (i.e. negative image):
• serum Tg + neck US every 6-12 months, if rising Tg perform conventional image
• TSH level 0,1-0,5 in intermediate risk. 
• In high risk PTC, poorly-differenciated TC and invasive FTC with negative image (excellent, indeterminate or incomplete response): Tg every 6-12 m, perform image if detectable Tg or of high risk even with negative Tg (for risk of dedifferentiation)
  
• Structural incomplete response (positive image): local or systemic therapy.
  

Diabetes mellitus. Generalities

 

DEFINITION

•  Chronic hyperglycemia as a result of inability of the pancreatic beta cells to secrete the amount of insulin the organism needs. 
  

EPIDEMIOLOGY

• Prevalence 8.5% in >18years = 422 M (WHO) in 2014.
  
• 90% type 2 diabetes, 5-10% type 1 diabetes, <5% other types. 
  

ETIOLOGY

• Type 1 diabetes: (post) destruction of pancreatic islet beta cells:
• 1A: autoimmune, circulating GAD, IA2, Zn8T Ab. There might be a subtype -LADA-: clinically type 2 diabetes with +Ab. Genetically heterogeneous with type 1 traits (HLAQB1) and type 2 traits (TRF7L2).
  
• 1b: non-autoinmmune
• Type 2 diabetes: (post) heterogeneous etiology where insulin-resistance is mixed to partial beta cell failure. 
• Insulin secretion genetic defects:
• MODY. The most common genetic diabetes, 2-5%. Diabetes diagnosed <25y secondary to mutations in genes related to insulin secretion:
• HNF4a (MODY1): 10%. Unclear mechanism. Progressive. Prone to complications.
  
• GK (MODY2): 25-30%. Stable, mild, diet alone.
  
• HNF1a (MODY3): 50-65%. ↓ glucose renal threshold → glucosuria precedes diabetes. Unclear mechanism. Progressive. Sensitive to SU. Prone to complications.
• IPF (MODY4).
• HNF4b (MODY5): kidney dysplasia and cysts, genital malformations. 
• Neuro D1 (MODY6). 
• Other, less frequent. 
• Non-mody beta cell defects (rare):
• SUR1 defects: hypos in childhood, diabetes when adult. 
• Proinsulin-insulin conversion defects. 
• Mutant insulin. 
• Mitochondrial DNA defects: MIDD: diabetes and deafness with onset 30-40y. 
• Wolfram (DIDMOAD): WFS1 gen defect (wolframin): DI, DM, optic atrophy and deafness. Very rare. 
• Defects in insulin action: 
• Genetic:
• Leprechaunism
• Rabson Mendenhall
• Type A IR (receptor defects)
  
• Lipodystrophies 
• Secondary:
• Obesity
• Type B IR (Ab against IR)
• Other: stress, drugs, pregnancy, inactivity.
• Pancreatic diseases. 
• Cystic fibrosis
• Hemochromatosis
• Chronic pancreatitis
• Fibrocalculous diabetes
• Genetic defects of pancreas development: Carboxyl Ester Lipase (CEL) defect. 
• Endocrinopathies:
• Cushing
• Pheochromocytoma
• Acromegaly
• Glucagonoma
• Somatostatinoma
• Drug induced diabetes
• Viral induced diabetes
• Gestational diabetes
• Uncommon immune mediated diabetes:
• Stiff man syndrome (GAD Ab)
• Ab against insulin receptor.
  

CLINICAL PRESENTATION

• Asymptomatic if glycemia <kidney threshold
• Classical symptoms: polyuria, polydipsia, weight loss, blurred vision when glycemia > threshold, about 180 mg/dL. 
• Ketosis and DKA (post) when not enough insulin to control lipolysis: nausea, vomiting, abdominal pain. 
• Hiperosmolar hyperglycemic state (HHS) (post) when polyuria not compensated by drinking in fragile patient. 
• Diabetic mycro- or macrovascular complication in longstanding undiagnosed diabetes.
  

DIAGNOSIS

• Percent undiagnosed and time from onset to diagnosis: 
• Negligible if important insulin deficiency like type 1 (particularly in children), or pancreatectomy
• Variable in partial ID (asymptomatic) like type 2. Depends on screening, up to 50%. Unknown time to diagnosis, might be years.
  

• Diagnostic workup:
• Biochemistry, some of these:
  
•  two of these in same or different samples: fasting glycemia >=126 mg/dL, HbA1c >6,5%, any glycemia >200 mg/dL, 2h 75g-OGTT >200 mg/dL
  
• Classic symptoms or DKA or HHS + glycemia >200 mg/dL
  
• DD: before biochemistry: syndromes of polyuria-polydipsia: diabetes insipidus, other.
  

 HEALTH IMPACT

• Mortality:↑ depending on hyperglycemia degree and time
  
• Morbidity:
• Microangiopathy, small vessel specific diabetic complications, depend on degree and time of hyperglycemia:
• Retinopathy (post), may lead to blindness
• Nephropathy (post), may progress to ESRD and ↑mortality. 
• Neuropathy (post).
• Macroangiopathy (atherosclerosis), unspecific large vessel disease, depend on hyperglycemia and other CVRF (post)
  
• Estimated morbidity in undiagnosed cases:
• ↑mortality mostly by macroangiopathy and CKD
• ↑morbidity by macro- and microangiopathy
  

MANAGEMENT

• Post
  

Diabetes care October 2020

Diabetes drug costs. Simeon Taylor discusses the issue of rising costs in dabetes treatment. From 2005-2007 to 2015-2017 it increased by 240% (more patients and more expensive drugs). Costs are mainly due to new molecules and new insulins, remaining stable metformin and other older drug costs. Apart from that, this commentary does not consider the impact of recent mandatory GLP-RA or SGLT2-i prescription in case of ACVD, HF or CKD. I keep the last sentence: "If the U.S. wishes to promote health care equity and social justice, major changes need to be implemented". Original here

Pisa Covid Study. Copelli and many others present us data from 271 hospitalized covid patients in Italy. Hyperglycemia at admission was strong mortality predictor although, paradoxically, patients from 5th quintile of hyperglycemia survived more thant those from 4th quintile. This results do not mean, needless to say, that hyperglycemia treatment reduce mortality. Let's be serious. Original here.

Albiglutide replace bolus in half of type 2 diabetes on basal-bolus patients. Julio Rosenstock (has this man time to see patients?) presents us a 1:1 randomized, 26-week, open-label trial of almost 800 type 2 patients on basal-bolus, leaving basal insulin and trying to replace bolus with the poor sister of GLP-RAs, albigutide. Only 54% could do it, the remaining had to continue with them. Not surprisingly, albi group reduced weight a bit, but had more gut discomfort. Nothing new. Here the original.

Primary hyperparathyroidism

 

DEFINITION

•  Hypersecretion of PTH relative to calcemia due to abnormal regulation, excluding FHH. 
  

EPIDEMIOLOGY

• Prevalence about 1/430 ♀ - 1/1250 ♂, Peak age 50-65
  
• 85% single parathyroid adenoma, 5% multiple adenomas, <10% hyperplasia, <1% carcinoma. 

ETIOLOGY

• Mostly unknown. 
• Radiation, dose-dependent, only significant in Chernobyl or similar. 
• Genes: proto-oncogene gain-of-function: RET, cyclin D1/PRAD1 or tumor-supression gene lose-of-function: MEN1, CDC73. 
• Familial conditions (rare): MEN1 (menin), familial isolated hyperparathyroidism FIHP (unknown genetics, maybe hotchpotch), HPT-JT (CDC73), MEN2A (RET), familial hypocalciuric hypercalcemia FHH (CaSR).

CLINICAL PRESENTATION

• 80% asymptomatic hypercalcemia <1 mg/dL above upper limit.
• Remaining 20%:
• Normocalcemic PHPT. Elevated PTH + normal total and ionized calcium, excluded secondary HPT (see DD, mostly vit D deficiency and CKD). Considered initial form of PTPT, some develop hypercalcemia or bone/kidney damage. 
• Parathyroid crisis: severe and symptomatic hypercalcemia. Rare, 1-2%.
• Classical form (rare): Kidney stones or rarely nephrocalcinosis + osteitis fibrosa cystica + neuromuscular symptoms.
  

DIAGNOSIS

• Percent undiagnosed and time from onset to diagnosis: unknown, but high % and long prediagnosis time suspected based on hypercalcemia without further investigation in medical records.
  

• Disgnostic workup is biochemistry based:
• Serum calcium: elevated, except in normocalcemic HPT. Ionized Ca little value except in normocalcemic HPT to exclude hypercalcemia.
  
• Serum PTH: 80-90% modestly elevated, 10-20% normal range, usually upper half.
• 24h-urinary calcium: Not always required for diagnosis. 40% of PHPT >200 mg. <200 mg if low vitD or Ca intake, but poses DD with FHH (75% <100 mg).
• Ca/Cr clearance ratio = 24hCa x serumCr / 24hCr x serum Ca (spot urine not validated): <0.01 suggests (not confirm) FHH, especially in vitD depleted, 0.01-0.02 may be FHH or PHPT (genetic testing for CaSR in selected individuals), >0.02 is PHPT. 
• 25OH-D useful in two cases:
• ↑serum PTH and Ca + not elevated 24h Ca: DD PHPT+vitD deficiency vs. FHH
• normal serum Ca + ↑PTH: DD normocalcemic HPT vs. secondary HPT. 
• Not needed for diagnosis but for management plan (surgical criteria):
• eGFR (<60 mL/min→surgery)
  
• Renal imaging if surgical criteria not met (usually US, also CT or plain RX) finds stones in 7-21%, rarer calcinosis. 
• BMD in spine, hip and distal forearm. 
• Vertebral imaging by RX or Vertebral Fracture Assessment (VFA) for unnoticed fracture.
  
• DD:
• Malignancy: PTH is low.
  
• FHH: mild↑serumCa + normal/mildly ↑PTH + low 24hCa + family history + no symptoms.
  
• Drugs: thiazides (renal action) and lithium (↓CaSR activity mimicking FHH)
  
• Secondary HPT: low or normal serum Ca:
• CKD
• ↓Calcemia: low intake, malabsorption (including vitD deficiency), renal loss (hypercalciuria, loop diuretics)
• Low bone resorption: biphosphonates, denosumab, hungry bone.
  

 HEALTH IMPACT

• Mortality: ↑ in severe, unclear in mild cases. 
• Morbidity:
• Kidney
• Stones in 15-20%, calcium oxalate. Nephrocalcinosis is rare.
• GFR decline: Up to 17%, only in long-term important hypercalcemia.
  
• Bone 
• Fractures ↑ risk 2-3 fold. Despite preserved cancellous and affected cortical bones, vertebral fracture is more frequent, but all fracture sites are ↑, particularly in aged ♀.
• Chondrocalcinosis in severe cases: wrist and knees. 
  
• Neuromuscular-psychiatric symptoms. Present in severe cases. In remaining, just mildly in any case and no clear response to therapy.
  
• CV risk. Hypertension, arrhytmia, ventricular hypertrophy, vascular stiffening, vascular-valvular calcification. No proved ↑ CV death. Hypertension present even in mild cases, no proved causal relationship.
  
• Overweight and hyperglycemia mildly ↑, no proved causal relationship
• Estimated morbidity in undiagnosed cases: unknow, probably low because they are probably the mildest cases. 
  

MANAGEMENT

• Symptomatic patients (fractures, kidney stones, symptomatic hypercalcemia): surgery is indicated. It has proved:
• Nephrolithiasis improvement (not operated worsen)
• BMD improvement
• So far not proved but possible fracture reduction
• Some QoL improvement. 

Note: mild symptoms like fatigue, weakness, depression or memory impairment are vague and not indication for surgery. 

• Asymptomatic patients. Most do not progress (hypercalcemia or -calciuria, stones, fracture) but up to 1/3 do, and long-term data (>8y) show BMD worsening in most asymptomatic patients. Forth International Workshop for Asymptomatic Primary Hyperparathyroidism guidelines advise surgery for patients with high progression risk:
• Serum Ca >=1 mg/dL above upper normal range. 
• BMD TScore <2.5 at any site or vertabral fracture.
• eGFR <60, nephrolitiasis or -calcinosis, or 24h calcium > 400 mg (arbitrary cut-point not supported by evidence). 
• Age <50. 
• Any patient that prefers operation. 
  
• Effects of surgery:
• Neuropsychiatric symptoms: very low quality evidence of improvement. 
• Subclinical kidney disease (stones, hypercalciuria, eGFR<60):
• eGFR neither decline in untreated nor improve in treated. 
• Observational studies show that parathyroidectomy may reduce stone formation but do not prevent them completely.
  
• CV events: not all studies show mortality reduction. In rest of parameters no or weak evidence of improvement. Hypertension usually persists. 
• Bone: BMD mildly modestly at all sites 1-2 y after parathyroidism compared to observation, where it remains stable the first 5y, then there may be a decline. Fractures may modestly improve with surgery.
• Calcemia: little effect of surgery in follow-up except in younger patients that progress more if no treated. 
• Types of surgery: classical (bilateral neck exploration BNE) or minimally invasive parathyroidectomy (MIP) based in preoperative localization. Both similar success (95-100%) and risks when expert surgeon. 
• Preoperative localization studies are needed to MIP. The most frequently used is 99Tc-sestaMIBI (plain, spect or spect-CT) because of its high sensitivity, followed by US, 4d-CT, MRI, and invasive techniques (arteriography, venous sampling)
• If negative, BNE is performed because 20-40% are hyperplasia or multiple adenoma. 
• In reoperation, studies are mandatory, usually two (sestamibi+other depending of local experience). 
• BNE is recommended in young males (hereditary form suspected), or if studies show 0 or >1 affected gland.
  
• Conservative follow-up in patient not candidate to surgery:
• General measures:
• avoid thiazide and lithium
• encourage exercise, avoid >1g dietary calcium
• moderate dietary vit D 400-800 UI (maintain 20-30 ng/mL)
• encourage hydration. 
• Annual eGFR and calcium. 
• 2-3 yearly BMD
• Renal imaging not indicated unless clinical suspicion. 
• Surgical candidates not operated due to refusal / contraindications:
• Cinacalcet if hypercalcemia as surgical indication:
• Typical dose 30 mg/12h
  
• ↓Ca in most patients, mean 7%, normalize in 75%, irrespective of severity
• No efect in PTH, BMD or 24hCa, unknown effect in stone and neurocognitive symptoms (not indicated in asymptomatic PHPT)
  
• Frequent adverse effects: nausea and arthralgia (1/3), diarrhea, myalgia and paresthesia (1/5).
  
• Biphosphonates if osteoporosis as surgical indication (alendronate most experience), they improve BMD but not proved ↓fracture. 
• Cina + biph if ↑Ca+osteoporosis, but no RCT evidence of efficacy and safety.
  
• In other cases no treatment. Umproved therapies are:
• Estrogen-progestin, denosumab or raloxifen for OP, no proven fracture effect. 
• Vitamin D. Expert opinion, not evidence, recommend treat to >20, but careful if high hypercalciuria because it can worsen. Otherwise it seems safe but no proven benefit. Presurgical replacement advised to avoid postoperatory hypocalcemia.
  
• Normocalcemic HPT. Same criteria than hypercalcemic:
• Symptomatic patients: operation
• Asymtomatic, parathyroidectomy if 4th IWAPH criteria met. 
• Preoperative localization (US, sestamibi, CT, MRI), if + MIP, if - clasical surgery. Some prefer BP if negative localization and OP as indication. 
• Pregnancy
• Rare, but case reports included hyperemesis, nephrolitiasis, pancreatitis, miscarriage, and neonatal hypocalcemia due to fetal PTH suppression. 
• Surgery in 2nd trimester is recommended except mild cases, where observation is preferable. 
• Rely on ionized calcium, total is lower than normal due to ↓albumin.
  

10 Minute Osteoporosis

 

This is the first chapter of a new series "10 Minute Endocrine Update". The idea is to make micro-reviews of endocronology topics to be read in 10 minutes in a post. Every post will have just 2 parts: the first is Introduction, that includes definition, epidemiology, pathophysiology, clinical presentation and diagnosis, and the other, the most important, Treatment. I want them to be very very concise, don't use 3 words if it can be said in 2. I don't want anyone but me to read it. Therefore, based in my previous experience, I thought the best strategy to keep it hidden is to write it in my blog.

OSTEOPOROSIS

 

INTRODUCTION

• Definition. Decreased bone mass and architectural disruption resulting in bone fragility and risk of fracture. It can be primary or secondary. Glucocorticoid-induced OP is not included here.
  
• Epidemiology. Estimated 200 M (2.5% of world population) and 9M OP fractures. Risk factors are:
• Unmodifiable: female sex, age, caucasian ethnicity
• Habits: smoke, alcohol, sedentary lifestyle.
  
• Medications: glucocorticoid, hormons (aromatase inhibitors, gonadotropin analogues) chemotherapy, antieconvulsivants, anticoagulants.
  
• Physiological and pathological conditions: low BMI, low calcium intake, immobilization, AR
  
• Etiology/pathophysiology
• Uncoupled bone remodelling.
  
• Postmenopausal women resorption > formation, both in cortical and cancellous bone
  
• Clinical presentation. None until fracture:
• Vertebral, the most frequent, 2/3 asymptomatic
• Hip, 15% of women and 5% of men by 80 have it. Risk raises with age, most occur >8
• Colles, shortly after menopause.
  
• Diagnosis. 
• Criteria: One of them:
• Fragility fracture: spontaneous or by minor trauma (stress fractures, due to repetitive minor trauma, is different). Most common in hip, wrist and spine. Also in ribs, humerus and pelvis. Not in skull, hands, feet, ankle or cervical spine.
  
• BMD 
• Postmenopausal women and men >50: <=2.5 SD below peak, at any site by DXA (preferred method), excluding other causes of low BMD like osteomalacia. Sites: hip and spine (this one has less variability in follow-up excluding osteophytes and vascular calcifications). Some say BMD at one site predicts FR there, other that BMD at any site predicts FR at any.
  
• Premenopausal women and men <50: not applicable, BMD not correlated to fracture risk.
• <20: not applicable, peak BMD not reached. 
• DD: osteomalacia, malignancy (myeloma), Paget, hyperparathyroidism, renal osteodystrophy.
• In CKD, diagnose OP only after excluding kidney bone disease, where secondary HPT, adynamic bone disease, osteomalacia and acidosis are frequent.
  
• Diagnostic workup: BMD, biochemistry, complete blood count, 25OHD, FRAX, other if suggested.
• Bone-turnover markers, not necessary:
• Bone formation: Alkaline Phosphatase (AP) (unspecific), Osteocalcin (OC), procolagen-1 N- and carboxiterminal propeptides (P1NP, P1CP). Best: OC and P1NP.
  
• Bone resorption: Hydroxyprolin (unspecific), pyridinolin and deoxypyridinolin, tartrate-resistant acid phosphatasa 5b (TRAP), Carboxy- and N-terminal cross-link  type 1 procollagen telopeptides (CTX-1 and NTX-1). Best CTX-1. 
• There are quite a lot of effort to estimate fracture risk (frax and stuff like that) in people with osteopenia (TSc from -2.5 to -1) cause most fractures occur in people with BMD in this range, but it smells like "big pharma seeking patients to sell drugs", because these people (people, not patients) do not have OP and are therefore beyond this review. Societies recommend drugs in osteopenia in FRAX 10y hip fracture risk >3% or overall fracture risk >20%, but treatment in this situation is not evidence-based (see later)
  

TREATMENT 

Never forget that the only aim is fracture prevention, therefore one cannot know efficiency of treatment at individual level (BMD recovery is not good predictor). 

Drugs are indicated if patient meets diagnostic criteria for osteoporosis (fragility fracture or TScore >=2.5). That includes 50% of women >65 in US. Societies also recommend it in high 10y FRAX risk, but that's not supported by clinical trials. That would increase candidates to >70% in >65y and >90% in >75y. 

No high-quality comparison between drugs is available, therefore choice of drug is not evidence-supported. Common practice is start biphosphonate except in very high risk, CKD or intolerance/contraindication, commonly an oral BP (alen- risedronate). Second choice drugs are denosumab and anabolic drugs (teri > abaloparatide > romosozumab), according to patient characteristics.

• General measures: exercise, avoid smoking and alcohol, no proven effect. Exercise reduce overall fractures in a 10-trial metaanalysis but with risk of publication bias.
  
• Calcium and vitamin D: no proven effect. Adequate intake of 1200 mg Ca and 800 IU of D is recommended and supplement is advised if low dietary intake, particularly on drug therapy.
  
• Biphosphonates. Antiresorptive agents, reduce osteoclast activity. 
• Alen- rise- (both oral) and zoledronic (IV) reduce spine, non-vertebral and hip fractures. Ibandronate (oral, IV) reduce spine fractures when oral, no RCT data for IV iban-. 
• Usual initial therapy oral (preferred) 5y, zole 3h, then no evidence-based guides (see below).
  
• Adverse effects: GI frequent when oral, flu-like in 1/3 of IV zoledronic, hypocalcemia, osteoarthralgias, jaw osteonecrosis, atypical fractures >2-3 y. 
• Avoid oral in CKD with GFR<30 mL/min, esophageal diseases, inability to stay upright and roux-en-y gastric bypass. 
  
• RANK-L inhibitors. Denosumab 60 mg SC/6m
• Effective in vertebral, non-vertebral and hip fractures.
• Rapid protection lose after discontinuation, consider need for life-long therapy or switch to other drug.
• Adverse effect: flu-like syndrome, atypical fractures, jaw osteonecrosis. 
• No first-line therapy except:
• Contraindications or intolerance to BP
• Extremely high fracture risk
• CKD
  
• Estrogen. Effective in postmenopause spine and non-vertebral fractures. Raise CV risk if initiated >10y after menopause and not indicated. Accepted soon after menopause if indicated for other reasons. 
• SERM. Raloxifene (similar bazedoxifene with less experience) reduce only spine fractures and also breast cancer. Adverse effect: worsens flushes, venous thrombosis, stroke. 
• Anabolic therapy. Not initial choice, except in high risk or intolerance for other drugs:
• Teriparatide. daily SC for 18-24 months, reduce spine and non-spine fractures better than risedronate, but not hip. Adverse effects: hypercalcemia, don't use in bone malignancies or previous RT for that reason. 
• Abaloparatide. PTH-rP analogue, daily SC. Reduces vertebral and (less) non-vertebral fractures, not hip. Less hypercalcemia than teri, but produces tachycardia. Not approved in Europe. 
• Romosozumab, sclerostin-inhibiting monoclonal Ab.
• Monthly.
• Reduces vertebral and non-vertebral fractures. 
  
• Increase CV events.
• Only one-year therapy because of lack of experience. 
• Non-recommended drugs: calcitonin, calcitriol, strontium ranelate, vitamin K, tibolone, androgens, tibolone, isoflavones, fluoride. Read technical reviews elsewhere to see explanation.
  

Monitoring:

• Common practice is repeat BMD regularly but no evidence that BMD response correlates with fracture risk. If BMD lowers on drug therapy, make sure drug and adequate Ca+vitD is being taken, if so investigate other conditions. Not evidence in this case to support decision to change or discontinue drug.
  
• Bone markers like CTX or NTX are generally not neccesary.

All RCTs are performed in postmenopausal women. Translating recommendations to men or premenopausal women means leaping from science to adventure. I prefer science. 

Combination therapy is not supported by clinical studies. 

Duration of therapy: all but biphosphonates lose protective effect after discontinuation, BP retain effect 1-2y for oral or 2-3 for IV. RCT of BP show efficacy only for trial duration (2-3y) and its extensions, but beyond 5y there is no evidence. Recommendation (expert opinion = rubbish) is to treat for 5y (oral alen-rise) or 3y (IV zole) and continue if fracture, high dose of GC or >75y. Rest of cases, individualize.

REFERENCES:

• UpToDate (my institutional subscription)
  
• Osteoporosis Current Concepts. Joints 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6059859/
• Osteoporosis Lancet Jan-19. https://pdf.sciencedirectassets.com/271074/1-s2.0-S0140673619X00045/1-s2.0-S0140673618321123/main.pdf