In insulin-treated type1 diabetes,canagliflozin increased diabeticketoacidosis.

Reference: Peters AL, Henry RR, Thakkar P, Tong C, Alba M. Diabeticketoacidosis with canagliflozin, a sodium-glucose cotransporter 2inhibitor, in patients with type 1 diabetes. Diabetes Care. 2016;39:532-8.

Date of presentation: 1395/12/1Presented By: dr.m.shabani

Dr Shabani95.12.1

Question

In adults with type 1 diabetes mellitus treated with insulin, doescanaglifozin add-on treatment increase the risk for diabeticketoacidosis (DKA)?

Methods

Patient: 351 patients 25 to 65 years of age {mean age42 y,56% men} who had type 1 diabetes for ≥ 1 year,hemoglobin(Hb) A1c level 7.0% to 9.0% (53 to 75 mmol/mol),body mass index 21 to 35 kg/m2, and were receiving a stableinsulin regimen(multiple daily injections or continuoussubcutaneous infusion) for ≥ 8 weeks.

Exclusive criteria

included history of type 2diabetes mellitus; DKA or severehypoglycemic event in the past6 months; myocardialinfarction, unstable angina, coronary revascularization, orcerebrovascular accident in the past 12weekshistory of New York Heart Association class III to IV cardiacdisease; uncontrolled hypertension;estimated glomerular filtration rate < 70 mL/min/1.73 m2; ortreatment with an anti-hyperglycemic other than insulin in thepast 12 weeks.

Intervention: Canagliflozin, 100 mg (n = 117), canagliflozin,

300 mg (n = 117), or placebo (n = 117) once/d before the first meal

Outcomes : Safety outcomes included ketone-related adverseevents (i.e., acidosis, blood ketone body increased, blood ketonebody present, DKA, diabetic ketoacidotic hyperglycemic coma,ketoacidosis, ketonemia, ketonuria, ketosis, metabolic acidosis, orurine ketone body present) and serious DKA.

Main results

Risks for any ketone-related adverseevents and for serious DKA eventsrequiring hospitalization were increasedwith canagliflozin compared withplacebo

Table & figure

Conclusion

In patients with insulin-treatedtype 1 diabetes, canagliflozinincreased diabetic ketoacidosis

• To date, pramlintide and insulin are the only medications approved totreat patients with type 1 diabetes. Since their introduction, sodium–glucose cotransporter 2 (SGLT2) inhibitors have drawn substantialinterest as an add-on to insulin in type 1 diabetes.

• There have, however, been unexpected reports of increasedincidence of ketoacidosis in patients with type 2 diabetes using theseagents (1).

• Peters and colleagues used data from the pivotal trial of canagliflozinin type 1 diabetes (1) to evaluate the association between SGLT2inhibitors and DKA. The results are limited by lack of precision andinadequate information about insulin dosing around each event.

Commentary

Aside from the reduction in daily insulin dose for patientsreceiving canagliflozin, 2 factors may contribute to the observedincreased risk for ketoacidosis.First, despite a reduction in fasting glucose, SGLT2 inhibitorsincrease endogenous glucose production and glucagon levels inpatients with type 2 diabetes (2). The amplitude of thisparadoxical physiologic response has yet to be determined intype 1 diabetes. However, it does have a direct effect on hepaticketone production, thus contributing to the development ofketoacidosis (3).

Commentary

Second, patients and clinicians may not recognize DKA withoutsevere hyperglycemia, and this could lead to delays in diagnosisand treatment.This is especially true if patients do not have good guidanceabout when to look for ketonuria or when to seek medical care inthe absence of hyperglycemia. In all, for most patients with type1 diabetes, the modest reduction in HbA1c level conferred bySGLT2 inhibitors (1) may not outweigh the cost and potential riskfor DKA requiring hospitalization.

Commentary

In type 2 diabetes sodiumglucose cotransporter 2inhibitors do not increasemajor CV events or mortality

Reference: Tang H, Fang Z, Wang T, et al. Meta-analysis of effects of sodiumglucosecotransporter 2 inhibitors on cardiovascular outcomes and all-cause mortality among patientswith type 2 diabetes mellitus. Am J Cardiol. 2016;118:1774-80.

Question

In type 2 diabetes mellitus, what are theeffects of sodium–glucose cotransporter2 (SGLT2) inhibitors for major adversecardiovascular events (MACE) and allcause mortality?

Review scope

Included studies compared SGLT2 inhibitors(canagliflozin, dapagliflozin,empagliflozin), aloneor combined with other antidiabetes drugs, withplacebo, each other, or other active antidiabetesdrugs in adults ≥ 18 years of age with type 2diabetes; had duration ≥ 24 weeks; and reported≥ 1 outcome of interest.

Methods

37 RCTs (n = 28 859, mean age 52 to 69y,44% to 72% men, follow-up 24 to 260 wk)

Outcomes:

Primary outcomes were all-cause mortality and MACE

(cardiovascular [CV] death, nonfatal myocardial infarction, or nonfatalstroke).

Secondary outcomes included heart failure (HF)or hospitalization for HF, unstable angina or hospitalization forunstable angina, atrial fibrillation, and transient ischemic attack

Main results

Meta-analysis of RCTs comparing SGLT2 inhibitors with control(placebo or other active antidiabetic drugs) showed thatempagliflozinreduced MACE outcomes, all-cause mortality, and HF; canagliflozinand dapagliflozin did not differ from control for theseoutcomes (Table). No SGLT2 inhibitor differed from control forunstableangina, atrial fibrillation, or transient ischemic attack. Networkmeta-analysis, which included direct and indirect comparisons,showed no differences among SGLT2 inhibitors for any outcome.

Conclusion

In type 2 diabetes, sodium–glucosecotransporter 2 inhibitors do notincrease major adversecardiovascular events or all-causemortality.

Commentary

CV disease is the leading cause ofdeath and complications in type 2diabetes mellitus.Because of previous controversies,regulatory authorities now require CVsafety of new therapies for type 2diabetes to be established

Commentary

Tang and colleagues performed a systematicrandom-effects network meta-analysis assessingthe benefits and risks of SGLT2 inhibitors for CVoutcomes.They conclude that the 3 common SGLT2inhibitors are not associated with increased all-cause mortality or CV outcomes and thatempagliflozin, largely driven by a single trial, mayhave a protective effect.

CommentaryAn intriguing question is whether evidence is betterinterpreted by assessing each study independently or byalso examining indirect comparisons.The development of rigorous standards for networkmeta-analyses (4) allows integration of more evidenceand arguably leads to improved evidence synthesis anddecision making.Tang and colleagues followed recommended guidelinesand performed analyses to ensure transitivity(comparable groups) and consistency between directand indirect comparisons, and assessed individual studybias, thereby enhancing the validity of their analysis..

However, their conclusion, “Neither dapagliflozin norcanagliflozin was significantly associated with any harm”,is not supported by the data. The upper 95% CI formortality is > 2 for both drugs, meaning that the studiesare underpowered to rule out a potentially importantdoubling of mortality.In addition, the mortality benefit with empagliflozin wasalmost entirely driven by 1 trial in patients withestablished coronary artery disease, and it would beinappropriate to extrapolate these results to primaryprevention.As Tang and colleagues point out, more definitiveconclusions will require the completion of ongoingconfirmatory studies

In adults with diabetes,aspirin does not preventCV events compared withplacebo

Reference: Kunutsor SK, Seidu S, Khunti K. Aspirin for primary prevention of cardiovascularand all-cause mortality events in diabetes: updated meta-analysis of randomizedcontrolled trials. Diabet Med. 2016. [Epub ahead of print].

Question

In patients with diabetes, what are the efficacy andsafety of aspirin for primary prevention ofcardiovascular (CV) events and mortality?

Review scope

Included studies compared aspirin with placebo orno treatment for ≥ 12 months in adults ≥ 18 years ofage who had diabetes mellitus and no history orclinical evidence of CV diseases(CVD)

MethodsPatients: (n = 16 690, age range 18 to 90 y,treatment duration 3.6 to 10y, aspirin dose75 mg to 650 mg daily)

Exclusion criteria: included comparisons ofaspirin with other antiplatelet agents orstudies involving patients with known CVD

Design:randomized controlled trials (RCTOutcomes:included major adverse CV events (MACE)(composite of nonfatal myocardial infarction [MI],nonfatal stroke, or CV mortality), MI, stroke,coronary heart disease, CV mortality, all-causemortality, and bleeding.

Main results

Main results are in the Table. Whenanalyses were restricted to trials ofpatients without prevalent CVD, aspirindid not reduce MACE or any individualoutcomes compared with placebo or notreatment

Table & figure

Conclusion

In patients with diabetes and nocardiovascular disease, aspirin did notprevent cardiovascular events orincrease bleeding compared withplacebo or no treatment

Commentary

Aspirin has been recommended for primary prevention of CVDbased on RCTs that showed reduced risk for nonfatal MI .Theeffect of aspirin on CVD is modest, and the decision to initiateaspirin therapy should be individualized to optimize overallbenefit Diabetes is a risk factor for CVD, so aspirin might beeffective in preventing CVD in patients with diabetes. However,the updated meta-analysis by Kunutsor and colleagues confirmsearlier reviews indicating that the effects of aspirin are, at best,limited in reducing the risk for overall CVD in diabetes patientswithout known CVD.

Aspirin for primary prevention of CVD in patients withoutdiabetes has the most favorable benefit-to-risk ratio inpatients with increased risk for CVD and lower risk forgastrointestinal complications.Subgroup analyses by Kunutsor and colleagues suggestedthat patients with lower risk for CVD might derive greaterbenefit from aspirin than patients with higher risk for CVD,but the difference was not statistically significant. Thisconclusion is counter to most recommendations and, as asecondary analysis, should be cautiously interpreted.Currently, the largest clinical trial with targeted enrollment ofpatients with diabetes (n > 15 000) is ongoing and mightclarify the benefits and risks of aspirin therapy for primaryCVD prevention and which subgroups benefit most

Commentary

Given the current lack of conclusive evidencesupporting the use of aspirin for primary prevention ofCVD in patients with diabetes, how can clinicians bestminimize CVD risks?With the notable exception of lipid-lowering therapy,most clinical trials have not shown a benefit of lifestyleinterventions, weight loss, or blood pressure control onprimary CVD prevention in patients with diabetes (4).Nevertheless, these interventions can be justified due totheir beneficial effects on glycemic control andmicrovascular disease along with an exceptional safetyprofile.

Commentary

The Ipswich Touch Test athome had 78% sensitivity and94% specificity for detectingloss of foot sensation

Reference:

Sharma S, Kerry C, Atkins H, Rayman G. The Ipswich Touch Test: a simple and novelmethod to screen patients with diabetes at home for increased risk of foot ulceration.Diabet Med. 2014;31:

Question

Does the Ipswich Touch Test doneby a nonprofessional in the homedetect loss of foot sensation inpatients with diabetes?

MethodsPatients:331 patients (mean age 60 y, 53% men) with

diabetes.Exclusion criteria:

Patients with amputations

Design:Blinded comparison of Ipswich Touch Test done bya nonprofessional in the home with a standard 10-gmonofilament assessment done by a clinician.Setting:Diabetes clinics at Ipswich Hospital, England, UK.Outcomes:Sensitivity, specificity, and likelihood ratios.

Main results

The Ipswich Touch Test had 78% sensitivity and 94%specificity for detecting loss of foot sensationcompared with monofilament testing

Table & figure

Conclusion

In patients with diabetes, the Ipswich Touchdone by a nonprofessional in the home

detected loss of foot sensation.

Commentary

A patient with diabetes has about a 25%lifetime risk for a foot ulcer, and diabeticneuropathy is associated with an increasedrisk for ulceration. Early detection of loss ofsensation in the feet allows clinicians tostart a management plan,which includes improved metabolic control,education, and accommodative footwear.

Detection of neuropathy at home could increase awarenessof diabetic foot complications, engage patients in self-management of the diabetic foot syndrome, and potentiallyreduce ulceration.To date, however, insufficient evidence exists on the benefitof patient education in preventing diabetic foot ulcers

Commentary

It is not unusual for patients to attend a clinic visit with a foot ulcerwhile being unaware of any trauma. The trial by Sharma andcolleagues provides a realistic method to potentially interruptthis pattern. The study showed that home testing had good sensitivityand specificity compared with monofilament testing inthe clinic. The nonblinding of clinicians to other patient characteristicsis unlikely to have introduced bias in the results. TheIpswich Touch Test is simple to conduct and seems reliable. It isgeneralizable to a larger number of patients and caregivers andcould reduce development of diabetic foot ulcers if coupledwith preventive foot care

Commentary

NEJM case imagegas in the left atrium and ventricle

A 60 years old-man with CAD and ischemic cardiomyopathy with biventricularICD,and AF persented with chest pain and numbness in both arms.During his initial presention,he suddenly collapsed and became unresponsive.In the CT-angiography of chest,abdomen and pelvic was perfomed to evaluatethe possibility of aortic dissection.The image showed gas in the left ventricle(panell A)Further review revealed gas in the left atrium with a cnnection to theesophagus(panell B).His family later reported that he had undergone radiofrequency ablation 6weeks earlier.

The gas in the heart was thought to be from an atrial-esophageal fistula thatmay have developed after this procedure.Imaging also showed renal infarct,probably from ari emboli.The patient died a few hours after his initial presentation.An atrial-esophageal fitula can be a complicatin of radiofrequency ablation andis associated with a substantial risk of death.Chest CT is the preferred dignostic test for this condition.Transesophaegal echo should be avoided becouse intubating the esophagus cancouse further gas embolization.