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

Diabetes Sept 2020: RAS and severity of SARS-COV-2. Precision medicine in diabetes.

 Here the link

Renin-Angiotensin System and severity of SARS-COV-2. 

Aleksandr Obukhov et al have written a review about the possible pathophysiological mechanism of dysregulared Renin-Angiotensin System (RAS). Quite a lot have been commented about the role of the Angiotensin-2 converting enzyme 2 (ACE-2) as linking site to SARS-COV-2 spike glycoprotein and therefore a path for the virus to entry into the organism. In this article they draw the hypotesis that viral infection hijacks ACE-2 receptor dysregulating thereby the whole RAS system, unchaining cytokine storm and other deletereous consequences. In summary, RAS system works like this:

In this way, ACE2 sequestration by the evil coronavirus leads to increase of ATII effects, not only globally but also locally in gut, bone marrow and lung. This could have unwanted consequences:

• Bone Marrow: Local RAS regulates hematopoiesis, and its dysregulation could lead to proinflammatory cells and cytokines, as well as prothrombotic state. The topic is complicated, there are quite a lot of implicated cells and humoral factors, I suspect there are no more that 10 people in the world that really master this topic. As usual, when something is complex, intricated and unexplainable someone made up a term to name it: myeloidosis.
  
• Gut: It's the quantitatively most important ACE-2 expession site in the organism. As it of weren't enough tangled, there is the role of gut microbiota, that critically affects bone marrow activity throug bacterial antigen presentation.

Well, all this is pure speculation because so far there is not a single effective therepy or intervention on RAS system in SARS-COV-2 infection. 

PRECISION MEDICINE IN TYPE 2 DIABETES

Diabetes is a heterogeneous disease and precision medicine (PM) is more difficult than in other pathologies like cancer or monogenic diabetes, where genetic data leads to clear-cut subgroups as to response to therapies or side effects. 

Nevertheless, one field of PM is the Heterogeneity of Treatment Effect (HTE). In this regard T2DM is a very good example for HTE because 1.- It's a heterogeneous disease; 2.- There are multiple drugs for it; 3.- glycemic response is very heterogeneous; 4.- no drug class is clearly superior to other. This review focuses only on glycemic (A1c) responses of type 2 diabetes drugs and is only based on available clinical data, not in genetic or other research markers. 

No single available factor cam predict which drug may be more beneficial for a single patient. PD tries to identify combinations of factors that could be associated to it. In this sense, data from real-life clinical practice like UK Datalink as well as from RCT (both types have strengths and weaknesses) have been used to draw initial associations, all of them congruent with mechanism of action of drugs:

• Lean males have a better initial response to SU than to TZD. the oposite for obese (BMI >30) females. 
• DPP4-i get better response in patients with lower BMI and lower insulin resistance (IR). 
• IR does not affect effect of GLP-RAs, but in insulin-treated patients low insulin secretion is associated to worse response. 
• Response to SGLT2-i is, compared to SU or DPP4-i, directly proportional to basal glycemia (A1c) and eFGR, not only for those <60 mL/min but all through the GFR range (0-90)

Two strategies are proposed to benefit from this knowledge:

• To create subgroups according to age, gender, BMI and other characterystics, as proposed by Ahlquist using Scandinavian registry data. 
  
• To develop an individualized prediction approach i.e. consider available unique characterystics (diagnosis age, gender, BMI, and A1c as continuous variables) of every patient to predict his or her unique differential responses to every treatment. This approach can also be used to predict CV or microvascular risk. 

 

 The authors compared both strategies using external validation data from RCT and found better the second one. 

Future directions in this field are:

• Incorporation of other individual data, like genomics, could refine the procedure.
• Taking into account not only glycemic response but also individual propensity to side effects, microvascular complications, cardiovascular risk and eventually mortality. 
• RCT to evaluate effectiveness of this approach.
  

ADA Standards: Type 1 diabetes drugs.

 

No astounding news compared to 2019. The main novelty is the efficacy of closed-loop CSII systems. Here the original. 

Main recommendations are:

• Most individuals with T1DM must be treated with multiple daily insulin injections (prandial and basal) or continual subcutaneous insulin infusion (CSII)
• Most individuals with T1DM must use rapid-acting analogs to reduce hypoglycemia
• People with T1DM should be trained (C) to adjust prandial insulin dose to carbo counting, glycemic levels, and physical activity

Historically, three landmarks may be distinguished in type 1 diabetes treatment:

• Conventional insulin treatment with 1 or 2 daily insulin inyections preserve life and prevent acute metabolic complications in type 1 diabetes. 
• DCCT trial showed that intensive insulin treatment, including: 1.- CSII or MDII with short-acting regular and intermediate-acting NPH insulin; 2.- SMBG (self-monitoring of blood glucose) and 3.-DSMES (diabetes self-management education and support) reduce microvascular disease.
• New rapid-acting and long-acting analogs have proved reducing A1c, hypoglycemia or body weight. 

CSII may be modestly superior to MDI in terms of A1c or hypoglycemia. Benefits of recent clinical implementation of CGM are still not established. CSII with closed-loop systems have proven superiority to sensor-enhanced pumps in terms of A1c and hypos in some recent trials.

Basal and prandial insulin are typically 50% of total daily dose (0.4-1 IU/Kg, more in prgnant, teenagers or acute ilness). Starting dose is about 0.5 IU/Kg. Basal insulin, usually once-a-day bedtime, is adjusted using pre-breakfast glycemia. Prandial insulin is given before every meal and must be individualized and adjusted to carbo count, physical activity and glycemia, but in some individuals fat and protein counting may be appropriate. 

Insulin must be applied in SC fat. Proper sites are abdomen, buttocks, tighs and upper arm. IM deposit must be avoided because of hypoglycemia risk. Factors for IM deposit are leaner and younger patients, limb injection and long needles. Short needles of 4 mm are suitable even for obese people. 

Lipohypertrophy increase glucose variability. Rotation of inyection sites avoids it, and regular education and advice about this topic is part of good clinical practice. 

OTHER DRUGS APART FROM INSULIN

• Pramlintide, an amylin analogue, modestly reduces A1c 0-0.3% and weight 1-2 Kg. 
• Metformin modestly reduce weight and lipids, but not A1c. 
• GLP-1RAs very modestly reduce A1c <0.2% and weight 3 Kg
• SGLT2-i improve A1c and weight but raise DKA 2-4 fold. 

SURGICAL TREATMENT 

• Pancreas transplantation needs life-long immunosuppression and is only indicated associated to simultaneous or previous renal transplant.
• Other indications, like recurrent DKA and hypoglucemia, must be careful avaluated in view of new closed-loop systems.
  

ADA Standards 2020: Obesity management in type 2 diabetes.

With no scientific evidence whatsoever, the expert panel recommends frequent measurement of weight and BMI , particularly when rapid weight changes or heart failure. 

LIFESTYLE INTERVENTIONS. 

Evedence-based recommendations are:

• Patients with T2DM and overweight or obesity who want to lose weight benefit in A1c and triglycerides from a diet and exercise program with the aim of losing at least 5%. Larger loses achieve even more benefits (HDL, LDL, reduction in medication for diabetes and CV risk factors). 
• Such interventions should be high intensity (>16 sessions in 6 months) and include diet, exercise and behavioural changes to achieve a negative caloric balance of at least 500 Kcal. That was evidenced in the Look Ahead trial.
  
• Motivation and life circumstances, like culture or food availability, must be taken into account in these interventions. 
• Dietary plan must be individualized. 
• For those achieving short-term weight lose, a long-term management program that includes monthly contact, weekly weight monitoring and >200 weekly exercise minutes is advisable. 
• More intense short-term programs with <800 Kcal or food replacement may be employed inicially by trained professionals in selected patients, always followed by a long-term strategy. 

All this looks like science fiction for me. Offering 16 sessions in 6 months to every overweight T2DM patient in my clinical setting is absolutely unachievable, not to mention a monthly long-term program, but it's worth it to know the way things are right done. 

PHARMACOTHERAPY.

• When choosing antidiabetic drugs, consider effects on weight. ADA says GLP1-RAs, SGLT2-i and metformin (?) reduce weight, DPP4i are neutral and insulin, secretagogues and TZD increase weight.
  
• Consider weight effect in drugs used in comorbidities. Antipsychotics, antidepressants, gabapentin or glycocorticoids raise weight.
  
• If weight lose medications are used, always balance benefit and risk. FDA has approved quite a lot of weight-lose drugs: phentermin (inly <12 weeks), orlistat, lorcaserin, phentermin/topiramate, naltrexone/bupropion and liraglutide. In Spain there are only three: liraglutide, naltrexone/bupropion and orlistat.
  
• If weight lose drugs are used, discontinue in weight lose <5% or adverse effects. 

MEDICAL DEVICES.

There are no clinical data, so they are currently not part of the standard of care in diabetes. 

BARIATRIC/METABOLIC SURGERY.

• Patients with BMI >40 and those with BMI 35-40 in whom nonsurgical methods have failed must be considered candidates for bariatric surgery.
• Patients with BMI 30-35 may be considered if other methods have failed.
  
• Experienced centers and surgeons are preferable, although this is just an expert opinion, i,e, nothing. 
• Postoperative surveillance of nutritional deficits is advisable. Dumping syndrome or hypoglycemia are also long-term complications.
  
• Psychiatric preoperative evaluation is mandatory. Substance abuse, depression, and suicidal ideation must be carefully taken into account before surgery is chosen.
  
• Psychiatric postoperative surveillance is recommendable, particularly for patients suffering from thea aforementioned conditions. 
  

RCT have shown that MS is superior to medical approach in diabetic and risk factor control. Nonrandomized trials have shown reduction in micro-, macrovascular complications and cancer. Observational studies suggest that MS reduce death rate. 

Young age, short duration of diabetes, absence of insulin, weight lose manteinance, and visceral fat are predictors of metabolic success. 

Some type 1 morbid obese diabetic patients may benefit from MS, but further data are necessary. 

MS is costly, long-term cost-effectiveness is not well established. 

Adverse effects have reduced over time. Mortality is 0,1-0,5%, similar to a cholecystectomy. Major complications like pulmonary embolism or reoperation are 2-6%, and minor complications are 15%.