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There are several issues to consider in choosing sequences, including:

l The assumption that in most patients, the condition will progress, requiring intensification of therapy by adding a second glucose-lowering agent–dual therapy–and, later, one or more others.

l Whether or not the second drug should vary according to what the first was. For example, after a flozin as first drug, the choice of second drug includes sulfonylureas, gliptins and pioglitazone. l Whether or not these drugs could also come in at later stages. For example, if dual therapy with

canagliflozin and gliclazide is failing, one option might be to add sitagliptin. Others include pioglitazone, insulin and a GLP-1 analogue.

l We assume that if intensification to dual therapy is required, the doses of empagliflozin and canagliflozin will already have been raised to 25 mg and 300 mg, respectively.

These options could create a need for a very large number of pathways which is beyond the scope of this report. We also need to keep regimens after monotherapy as similar as possible in order to focus on the differences arising from the initial monotherapy.

Dual therapy

The NICE guideline on type 2 diabetes envisages, for patients who cannot take metformin, dual therapy with one of the following combinations:

l pioglitazone and a sulfonylurea l pioglitazone and a gliptin l sulfonylurea and a gliptin.

In the interest of simplicity, we have chosen the sulfonylurea as the second drug, except after gliclazide monotherapy, when we use pioglitazone. The sulfonylurea was preferred to pioglitazone because of the latter’s safety record. Pioglitazone is preferred to a DPP-4 inhibitor only on cost grounds.

We have assumed that patients are at the maximum tolerated dose of each monotherapy drug before moving to dual therapy.

Triple therapy

Moving to triple therapy is more complicated, as after some of the dual regimens, pioglitazone and a gliptin are still available, and the GLP-1 analogues and insulin enter the frame. It is not possible to review all options. At this stage, the NICE guideline recommends that insulin-based treatment should be considered.16

In the interests of simplicity, our base case is therefore to bring in NPH insulin for triple therapy. We therefore have sequences as follow:

l empagliflozin 25 mg→empagliflozin+gliclazide→empagliflozin+gliclazide+NPH insulin l canagliflozin 300 mg→canagliflozin+gliclazide→canagliflozin+gliclazide+NPH

l dapagliflozin 10 mg→dapagliflozin+gliclazide→dapagliflozin+gliclazide+NPH l sitagliptin 100 mg→sitagliptin+gliclazide→sitagliptin+gliclazide+NPH

l pioglitazone 45 mg→pioglitazone+gliclazide→pioglitazone+gliclazide+NPH l gliclazide→gliclazide+pioglitazone→gliclazide+pioglitazone+NPH.

Some patients will progress to needing short-acting insulin to control blood glucose after meals. We assume that once patients move to a basal-bolus insulin regimen, the sulfonylurea will be stopped. Note that we have not introduced any of the flozins beyond monotherapy, as those situations were dealt with in the three single technology appraisals (STAs).

An alternative to bringing in insulin as third drug, is to consider the GLP-1 analogues. These are simpler for patients to manage, involving a once-a-week injection, and a low risk of hypoglycaemia.

The National Institute for Health and Care Excellence has adopted a very restrictive position on the GLP-1 analogues, based on a minimum BMI, and stopping rules requiring both a 1% reduction in HbA1cand

3% weight loss, but that was not based on any cost-effectiveness analysis and is due for review.

Only one long-acting GLP-1 analogue has been appraised by NICE–long-acting exenatide. If we bring that in as a third drug, basal insulin would be the fourth drug, with sequences as follow:

l empagliflozin 25 mg→empagliflozin+gliclazide→empagliflozin+gliclazide+exenatide LA→ empagliflozin+gliclazide+exenatide+NPH insulin

l canagliflozin 300 mg→canagliflozin+gliclazide→canagliflozin+gliclazide+exenatide LA→ canagliflozin+gliclazide+exenatide+NPH

l dapagliflozin→dapagliflozin+gliclazide→dapagliflozin+gliclazide+exenatide LA→ dapagliflozin+gliclazide+exenatide+NPH

l sitagliptin 100 mg→sitagliptin+gliclazide→sitagliptin+gliclazide+exenatide LA→ sitagliptin+gliclazide+exenatide+NPH

l pioglitazone 45 mg→pioglitazone+gliclazide→pioglitazone+gliclazide+exenatide LA→ pioglitazone+gliclazide+exenatide+NPH.

One problem with deriving effect sizes for modelling is that most trials recruit patients with rather poorer control than would be expected amongst patients who are being followed up according to NICE type 2 guidelines that recommend measuring HbA1cat 3–6 monthly intervals until HbA1cis stable (and presumably satisfactory).

So if the above guideline is being followed, patients whose HbA1crises above the 7.5% intensification

threshold, should have that detected within a few months, before it has gone much higher. Their HbA1c

levels might be in the 7.5–8.0% range. Whereas most trials of intensification to dual or triple therapy recruit patients with much higher HbA1c, often in the 8.7–9.05% range but sometimes well over 9%.

The importance of this is that reductions in HbA1ctend to be larger when baseline HbA1cis higher. So the

effect sizes in HbA1cseen in most trials will be larger than expected in management of type 2 diabetes

according to the NICE guideline, with close monitoring and prompt intensification.

So we need to be selective in the trials from which we extract data, rather than using effect sizes from broad-spectrum meta-analysis.

The generalisability of trials to routine care has been examined by Thomsenet al.7_{in Denmark. They}

looked at the effects of adding a second drug to metformin in a large population-based cohort, and concluded that the results were similar to those seen in the trials. The mean HbA1cat intensification was

8.0%. They observed reductions in median HbA1cof 1.2% with sulfonylureas, 0.8% with DPP-4 inhibitors,

1.3% with GLP-1 receptor agonists and 2.4% with insulin. However, these differences reflect different baseline HbA1clevels, notably 9.5–10% amongst those who started insulin. Despite intensification, 41%

had not achieved HbA1c<7.5% 6 months later.

Thomsenet al.7_{also noted that the threshold for intensification had fallen over the years, from about}

8.8% in 2000–3 to about 8.1% in 2010–12 (estimated from graph in supplementary material; figure 3). If this has also occurred in the UK, it reinforces the need to be selective in extracting effect sizes for modelling. In past studies, patients with type 2 diabetes were often left poorly controlled for several years

before intensification,189,190_{but this may be happening less nowadays, with improved control promoted by}

the Quality Outcomes Framework of payments to general practices for demonstrating performance against HbA1ccontrol indicators,191including DM007 for the HbA1cindicator. The three bands are now 59, 64 and

75 mmol/mol. All of them (not just the tightest) probably encourage initiation of insulin in practice.