Behandling minskar risk för sjukhusvård för patienter med diabetes typ 2 

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Patienter med diabetes typ 2 som behandlas med läkemedlet Jardiance löpte 51 procent mindre risk att läggas in på sjukhus på grund av hjärtsvikt jämfört med dem som behandlas med DPP-4-hämmare, visar en ny studie med 35 000 patienter. Även antalet akuta vårdbesök på sjukhus var signifikant färre. (1)

Resultaten har nyligen presenterats vid två vetenskapliga konferenser i San Diego (AMCP) respektive New Orleans (ACC) i USA. (2, 3)

Den aktuella studien (EMPRISE) som startade 2016 är en pågående studie med syfte att jämföra behandling i klinisk vardag med Jardiance (empagliflozin) respektive DPP-4-hämmare hos patienter med diabetes typ 2. Resultaten som baseras på de två första åren visar:

  • Behandling med Jardiance visade 39 procents mindre relativ risk för det sammansatta effektmåttet hospitalisering på grund av hjärtsvikt eller totalmortalitet jämfört med behandling med DPP-4-hämmare. (1)
  • Behandling med Jardiance var associerad med signifikant färre akuta vårdbesök på sjukhus jämfört med patienter som fick DPP-4-hämmare. (2)
  • Det fanns ingen ökad risk för frakturer eller amputation av underben vid behandling med Jardiance jämfört med DPP-4-hämmare. (3)

-Det är mycket glädjande att i den amerikanska studien EMPRISE kunna se en minskning av sjukhusinläggningar på grund av hjärtsvikt, en komplikation som dels är allvarlig för patienterna dels resurskrävande för vården. Det pågår ett arbete med en liknande studie som innefattar data från norden. Nordiska registerdata är en fantastisk källa till kunskap som ger oss möjlighet att undersöka hur ett läkemedel fungerar i klinisk vardag. De första resultaten förväntas redan nästa år, säger Rikard Amberntsson, medicinsk rådgivare vid Boehringer Ingelheim.

Den kliniska studien Empa-Reg-Outcome har tidigare visat att patienter med diabetes typ 2 och etablerad hjärt-kärlsjukdom och som behandlats med Jardiance har en 35 procent lägre risk för att drabbas av sjukhusinläggning på grund av hjärtsvikt samt en minskad risk för kardiovaskulär död. EMPRISE studien skall ses som ett komplement till denna studie. 

SGLT2-hämmare

Jardiance har efter studien Empa-Reg-Outcome kommit att rekommenderas i alla regioner utom Gotland. Jardiance är godkänt för behandling av diabetes typ 2 hos vuxna vars sjukdom inte kan kontrolleras med enbart kost och motion. Läkemedlet verkar genom att blockera effekten av proteinet SGLT2 i njurarna. Därmed försvinner blodsocker ur kroppen med urinen och nivåerna i blodet sjunker. Jardiance kan också bidra till att förebygga hjärt - kärlsjukdom.

DPP-4-hämmare

DPP-4-hämmare är en typ av diabetesläkemedel som stärker kroppens egen förmåga att reglera blodsockret genom att öka nivån av tarmhormoner som kallas inkretiner. De frisätts i samband med måltid och har betydelse för kroppens reglering av blodsocker. Vid diabetes typ 2 är denna funktion i obalans på grund av ett enzym, DPP-4, som bryter ner inkretiner. DPP-4-hämmare blockerar denna mekanism.

(1) EMPRISE ACC 2019 poster_FINAL.pdf

(2)Academy of Managed Care Pharmacy (AMCP) Annual Meeting 2019; March 25-28, 2019, San Diego, US

(3)American College of Cardiology´s (ACC) 68th Annual Scientific Session & Expo; 16-18 March 2019, New Orleans, Louisiana, US.

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Is CREDENCE a Game Changer for Diabetic Nephropathy?

For nearly 20 years, diabetic nephropathy has been an albatross around nephrologists' collective necks. It's the most common ailment bringing patients across our thresholds, the one for which we have the fewest tools.

Where novel biomarker discoveries breathed new life into glomerular disease and advances in transplantation continue to extend graft function, the principal strategies for the management of diabetic nephropathy have remained unchanged for two decades: control blood pressure, control glucose, and block the angiotensin system.

But nephrologists are optimists. Secondary analyses in studies[1,2] of novel SGLT2 inhibitors, which act to increase urinary excretion of glucose, suggested that they slow progression of kidney disease.

But we've been burned by secondary analyses before. Large clinical trials rarely have significant numbers of patients with chronic kidney disease (CKD), and the CANVAS[1] and EMPA-REG[2] studies (which demonstrated efficacy of canagliflozin and empagliflozin, respectively) were no exception. The nephrology community waited for a definitive trial the way I waited on my prom night: hopeful, but prepared for disappointment.

Enter CREDENCE.[3] In the past 24 hours, the study has been described as "landmark," "breathtaking," and "game changing."

But has the game changed? In my lectures on medical studies, I remind learners that one study should never change practice. In the case of CREDENCE, I may have to eat my words.

The CREDENCE Trial

CREDENCE was a randomized trial of 4401 patients with diabetic nephropathy, as defined by an eGFR of 30 to < 90 mL/min/1.73 m2 and modest proteinuria of > 300 mg per gram of creatinine. Let me stop here to mention what a feat it is to enroll this many patients with CKD in a clinical trial. An adequately powered study in the CKD population is a landmark already.

Critically, the CREDENCE protocol specified that all patients be on a stable dose of renin-angiotensin system (RAS) blockade. A less savvy or more unscrupulous study team may have tried to avoid the coadministration of angiotensin-converting enzyme (ACE) inhibitors (which have a known benefit in diabetic nephropathy) so as not to "drown out" any signal of benefit from the novel agent. They made the right choice to include a background of standard therapy here.

The primary outcome was the so-called "3 Ds": doubling of creatinine, dialysis, and death. While some may take issue with the composite nature of the outcome (is a doubling of creatinine really as bad as dying?), I don't. Powering for an all-cause mortality outcome alone is daunting, even for an industry-sponsored study like this one, but looking at doubling of creatinine alone risks undercounting those who die or initiate dialysis before the creatinine has a chance to double. In short, the primary outcome is good enough. Let's move on.

That outcome occurred in 11% of those treated with canagliflozin, compared with 15.5% in the placebo group—a relative reduction of 30%, which carried with it an impressive level of statistical significance (P < .0001). Rates of end-stage kidney disease were similarly significantly reduced. And although the difference in overall mortality (17% lower in the canagliflozin group) did not meet our traditional definition of statistical significance, this should hardly discourage use of the medication, given the effect on other outcomes that matter so much to patients.

Prior studies had suggested an increased risk for amputation among individuals treated with canagliflozin, leading the trialists here to mandate examination of patients' feet at each trial visit. Seventy participants in the canagliflozin group and 63 in the control group required amputations of some kind during the study—a nonsignificant difference that should provide some reassurance to both patients and physicians. Rates of acute kidney injury and urinary tract infection were also no higher in the canagliflozin group.

But there were significantly more genital mycotic (ie, yeast) infections in the canagliflozin group, though the rates were quite low (around 2% compared with 0.5% in the placebo group). Diabetic ketoacidosis was also seen more often in the canagliflozin group, with 11 episodes compared with just one in the placebo group. Clearly, canagliflozin has side effects, but they seem to be rare.

More Questions Than Answers

The drug seems to work, but the main unanswered question is why does it work?

By inhibiting the sodium-glucose cotransporter, SGLT2 inhibitors have multiple physiologic effects. They promote glucosuria, which leads to osmotic diuresis, lowering blood pressure. By increasing glucose excretion, they may improve glucose control. They may induce weight loss, reducing glomerular hyperfiltration. Or they may work through as-yet undefined mechanisms.

 

Trolling through the supplemental data leaves more questions than answers. A1c levels were barely different in the two groups when the study ended, arguing against improved diabetic control as the mechanism of benefit. Systolic blood pressure was lower (by around 2.5 mm Hg) in the canagliflozin group, but if such modest reductions in blood pressure were this protective in terms of renal and cardiovascular outcomes, we'd be awash in useful therapies for diabetic nephropathy.

Those treated with canagliflozin did lose more weight, though—about 1 kg. It's not much, but weight loss is a tough thing to achieve. Finally, canagliflozin significantly reduced proteinuria compared with placebo. It is worth noting that the only other class of medications with proven efficacy at reducing rates of progression in diabetic nephropathy (RAS inhibitors) also significantly reduce protein excretion.

Eating My Words

CREDENCE should change practice. There—I wrote it.

Yes, it is one study. But it is a study that fits firmly into an emerging understanding of the role of SGLT2 inhibitors in diabetes and is bolstered by secondary analyses of previous trials. The sheer magnitude of effect, coupled with the relatively small adverse event rate, suggests that we should reach for SGLT2 inhibitors quickly and fearlessly in diabetic nephropathy.

But not first. All patients in this study had adequate RAS blockade. And cheap, reliable ACE inhibitors and their cousins should still be the first line of defense against progression of this disease. 
 
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