El doble rasero de la recontextualización informativa

Many trials provided data on only some of the variables which are used in the UKPDS Outcomes Model. For example, SBP changes were often not reported. This applied more to older trials of comparators than to the more recent trials of the SGLT2 inhibitors.

Some trials provided no data with which to calculate TC/HDL ratios. However, a more important problem is that when TC levels were reported, they were often high, giving quite high TC/HDL–C ratios. It is likely that greater use of statins renders such data obsolete. For our modelling, we will assume that all general practitioners (GPs) and diabetologists follow NICE guidance and are using atorvastatin 20 mg for primary prevention in all people with type 2 diabetes. This will produce a TC/HDL ratio of about 3.0.

Another problem is with effect sizes after intensifications. For example, there are reviews of the effects on HbA1cand weight of sulfonylureas when added to monotherapy, but the bulk of evidence is addition to

metformin monotherapy. The weight gain after adding gliclazide to a SGLT2 inhibitor may be different–it may only restore weight to the baseline before weight loss on the flozin. And the weight gain after adding gliclazide to pioglitazone may be less because pioglitazone itself causes weight gain.

In passing, it is worth noting that the weight gains in trials may be greater than in routine primary care. De Fine Olivariuset al.168_{reported that 330 patients did not gain weight after starting on sulfonylureas.}

They make the point that most patients with type 2 diabetes are treated in primary care and are seldom recruited to trials, and that trials may therefore not be generalisable to all patients.

As regards reductions in adding sulfonylurea to monotherapy, some reviews report that adding a sulfonylurea to metformin results in a reduction in HbA1cof around 1%. However, the size of the

reduction will depend on the HbA1clevel on metformin alone. Genuth169quotes a reduction of 1% from a

baseline of 8.3%. This may be a bigger reduction than would be seen in people who have just crept over the NICE switching threshold of 7.5%.

In the same review, Genuth169_{reports that pioglitazone added to metformin reduces HbA}

1cby 1.0%, and a

DPP-4 inhibitor does so by 0.7%.

Hirstet al.170_{produced a good-quality systematic review and meta-analysis in which they examined}

reductions in HbA1cafter starting sulfonylureas in dual therapy. Sulfonylureas (glibenclamide, glipizide and

glimepiride) reduced HbA1cby 0.95% on average but with considerable heterogeneity–reductions ranged

from 0.47% to 1.3%. They found little variation in HbA1creductions by baseline HbA1cbut most of those

baselines were well above 8%, ranging from 7.5% to 9.5%. The only trial with baseline HbA1cunder

8.4%, had starting HbA1cof 7.5%, and that was the trial by Feingloset al.,171which showed a reduction

guideline,8_{and with baseline HbA}

1cof 7.5%, the reduction in HbA1cof 0.47% would be sufficient to

improve HbA1cto around 7.0% and would be seen as a reasonable result.

One problem with the review by Hirstet al.170_{was that most trials were short term. A very useful}

observational study by Cooket al.172_{used data on 2220 patients from the UK General Practice Research}

Database (GPRD) to study glycaemic control over time after a sulfonylurea was added to metformin, because of poor glycaemic control, with median HbA1cof 8.8%. There was a prompt reduction to median

of 7.3% after 6 months of sulfonylurea, but thereafter, HbA1cstarted rising again, by 0.32% between

months 6 and 12. Half of the patients had HbA1cof 8.0% or over by 1 year of starting sulfonylureas.

Cooket al.172_{also noted that intensification of treatment was often delayed until HbA}

1cis over 9%.

However, their data were from 1998 to 2004 and may no longer apply. Nevertheless, the large drops often reported after sulfonylureas are started may be because of very poor control, and we should not expect such large reductions in HbA1cin carefully monitored patients who have only recently gone above

the NICE switching threshold of 7.5%.

In a trial comparing dapagliflozin with glipizide as add-ons to metformin, and with baseline HbA1cof about

7.7%, the reductions in HbA1cby week 52 were 0.50% on dapagliflozin and 0.48% on glipizide.173

The durability issue with sulfonylureas has been reported by several studies, of which the best known may be the ADOPT (A Diabetes Outcome Progression Trial) trial174_{in which time to monotherapy failure was}

longer with rosiglitazone and metformin than with glibenclamide, with 34% of the glibenclamide patients needing additional treatment by 5 years compared with only 15% of those on rosiglitazone.

Del Pratoet al.173_{looked at duration of effect of dapagliflozin and glipizide in dual therapy when added}

to metformin. HbA1cfell more rapidly, and further on glipizide, but then rose again more quickly. So at

about 12 weeks, the falls were (from graph) about 0.8% on glipizide and 0.5% on dapagliflozin, but by 52 weeks the curves had met at reductions of about 0.5%, though about 20% of patients were absent by that time point. After 52 weeks, HbA1crose on both drugs, but more on glipizide, with a gap of 0.30%

by 208 months. However, the numbers by that time point were low–20% of the dapagliflozin group and 18% of the glipizide group. The reductions were due to patients starting rescue therapy after HbA1crose.

Rescue was mandatory once HbA1creached 8.0% or more, and was at the investigator’s discretion

between 7.0% and 8.0%. So similar proportions in each group had to move to rescue therapy, implying no difference in durability.

There is a 2015 abstract by Baconet al.175_{from Janssen, comparing time until insulin is started between}

canagliflozin and dapagliflozin, when used in dual or triple therapy. It also used the ECHO-T2DM

(Economic and Health Outcomes Model for Type 2 Diabetes Mellitus) model. In triple therapy, the authors report insulin being started on average at 5.1 years with canagliflozin (starting with 100 mg daily and increasing as required to 300 mg) compared with 3.3 years with dapagliflozin. Insulin was started when HbA1cexceeded 7.5%.

For the effects of adding sitagliptin we have two useful trials with HbA1cbaseline 7.7% and 7.8%,

which reported reductions in HbA1cof 0.67% and 0.79% (Scott 2007,176Nauck 2007177) giving a mean

of 0.73%.

A recent report from the Canadian Agency for Drugs and Technologies in Health (CADTH) (see appendix of CADTH report)178_{concludes that pioglitazone added to monotherapy reduces HbA}

1cby 0.78%. It also

gives the reduction with DPP-4 inhibitors as a mean of 0.7%.

At intensification to triple therapy, one option would be to introduce a long-acting (LA) GLP-1 analogue. NICE has so far approved only exenatide LA for this purpose, but there are now other drugs in this group, including dulaglutide and albiglutide.179

In the DURATION-1 (Diabetes Therapy Utilisation: Researching Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once Weekly) trial, Druckeret al.180_{compared exenatide LA with the}

short-acting, twice-daily form. Patients were on a mixture of baseline treatments with only 38% on dual therapy. However, reductions in HbA1cwere reported to be similar across baseline treatment groups. On

exenatide LA, HbA1cfell by 1.9% from a baseline of 8.3%, with 60% of patients getting HbA1cunder

6.5%. The advantages of using a GLP-1 analogue, compared with insulin, are the once-weekly injection, weight loss (in DURATION 1 weight fell by 3.7 kg on exenatide LA), a low risk of hypoglycaemia (there were no severe hypoglycaemia in DURATION 1 and minor hypoglycaemia was seen only in patients on sulfonylurea) and some reduction in SBP (4.7 mmHg). Another advantage of adding a GLP-1 analogue to treatment with a SGLT2 inhibitor is that the latter increases plasma glucagon levels, which would be suppressed by the former, though if triple therapy includes a sulfonylurea such as gliclazide, glucagon secretion may already be suppressed.181

Chapter 4

Clinical effectiveness aspects of the

submissions from the manufacturers

T

hree submissions were received, from: 1. Janssen for canagliflozin

2. AstraZeneca for dapagliflozin

3. Boehringer Ingelheim for empagliflozin. The submissions had three main sections:

1. a review of the evidence on clinical effectiveness and safety 2. a NMA comparing SGLT2 inhibitors with comparators 3. cost-effectiveness analysis.

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